| quarta-feira, 11 de novembro de 2009
ON NEUROBIOLOGIC RESEARCH . . . . . . . . . . . . . . 1
Eric R. Kandel, M.D.
With commentary by Judith L. Rapoport, M.D.
PSYCHIATRY . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Eric R. Kandel, M.D.
With commentary by Thomas R. Insel, M.D.
FOR PSYCHIATRY REVISITED. . . . . . . . . . . . . . . . 59
Eric R. Kandel, M.D.
With commentary by Arnold M. Cooper, M.D.
INTO THE NATURE OF ANXIETY . . . . . . . . . . . . . 107
Eric R. Kandel, M.D.
With commentaries by Donald F. Klein, M.D.,
and Joseph LeDoux, Ph.D.

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Washington, DC
London, England
Eric R. Kandel, M.D.
With commentaries by
Arnold M. Cooper, M.D.
Steven E. Hyman, M.D.
Thomas R. Insel, M.D.
Donald F. Klein, M.D.
Joseph LeDoux, Ph.D.
Eric J. Nestler, M.D., Ph.D.
John M. Oldham, M.D.
Judith L. Rapoport, M.D.
Charles F. Zorumski, M.D.
Note: The authors have worked to ensure that all information in this book is accurate
at the time of publication and consistent with general psychiatric and medical
standards, and that information concerning drug dosages, schedules, and routes of
administration is accurate at the time of publication and consistent with standards
set by the U.S. Food and Drug Administration and the general medical community.
As medical research and practice continue to advance, however, therapeutic standards
may change. Moreover, specific situations may require a specific therapeutic response
not included in this book. For these reasons and because human and
mechanical errors sometimes occur, we recommend that readers follow the advice of
physicians directly involved in their care or the care of a member of their family.
Books published by American Psychiatric Publishing, Inc., represent the views and
opinions of the individual authors and do not necessarily represent the policies and
opinions of APPI or the American Psychiatric Association.
Copyright © 2005 American Psychiatric Publishing, Inc.
Manufactured in the United States of America on acid-free paper
09 08 07 06 05 5 4 3 2 1
First Edition
Typeset in Adobe’s Berkeley and Eurostile
American Psychiatric Publishing, Inc.
1000 Wilson Boulevard
Arlington, VA 22209-3901
Library of Congress Cataloging-in-Publication Data
Kandel, Eric R.
Psychiatry, psychoanalysis, and the new biology of mind / by Eric R. Kandel ; with
commentaries by Arnold M. Cooper ... [et al.].—1st ed.
p. ; cm.
Includes bibliographical references and index.
ISBN 1-58562-199-4 (alk. paper)
1. Psychiatry. 2. Psychoanalysis. 3. Neurobiology. 4. Molecular biology.
[DNLM: 1. Psychoanalysis—Collected works. 2. Mental Processes—physiology—
Collected Works. 3. Molecular Biology—methods—Collected Works. 4. Psychiatry—
methods—Collected Works. WM 460 K16p 2005] I. Title.
RC435.2.K36 2005
616.89—dc22 2004029916
British Library Cataloguing in Publication Data
A CIP record is available from the British Library.
Paul and Minouche,
who have taught me much
about the
biology of mind
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CONTRIBUTORS . . . . . . . . . . . . . . . . . . . . . . . . . XI
FOREWORD . . . . . . . . . . . . . . . . . . . . . . . . . . . XIII
Herbert Pardes, M.D.
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . XVII
ON NEUROBIOLOGIC RESEARCH . . . . . . . . . . . . . . 1
Eric R. Kandel, M.D.
With commentary by Judith L. Rapoport, M.D.
PSYCHIATRY . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Eric R. Kandel, M.D.
With commentary by Thomas R. Insel, M.D.
FOR PSYCHIATRY REVISITED. . . . . . . . . . . . . . . . 59
Eric R. Kandel, M.D.
With commentary by Arnold M. Cooper, M.D.
INTO THE NATURE OF ANXIETY . . . . . . . . . . . . . 107
Eric R. Kandel, M.D.
With commentaries by Donald F. Klein, M.D.,
and Joseph LeDoux, Ph.D.
THE SECOND ENCOUNTER . . . . . . . . . . . . . . . . 157
Eric R. Kandel, M.D.
With commentary by Eric J. Nestler, M.D., Ph.D.
AND THE MYSTERIES THAT REMAIN . . . . . . . . . .199
Thomas D. Albright, Ph.D.
Thomas M. Jessell, Ph.D.
Eric R. Kandel, M.D.
Michael I. Posner, Ph.D.
With commentary by Steven E. Hyman, M.D.
AND SYNAPSES . . . . . . . . . . . . . . . . . . . . . . . .337
Eric R. Kandel, M.D.
With commentary by Charles F. Zorumski, M.D.
HUMANISM . . . . . . . . . . . . . . . . . . . . . . . . . . .373
Eric R. Kandel, M.D.
With commentary by John M. Oldham, M.D.
AFTERWORD . . . . . . . . . . . . . . . . . . . . . . . . . .385
INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .389
Thomas D. Albright, Ph.D.
Professor, The Salk Institute for Biological Studies, San Diego, California; Investigator,
Howard Hughes Medical Institute, Chevy Chase, Maryland
Arnold M. Cooper, M.D.
Stephen P. Tobin and Dr. Arnold M. Cooper Professor Emeritus in Consultation-
Liaison Psychiatry, Weill Cornell Medical College; Training and Supervising
Analyst, Columbia University Center for Psychoanalytic Training and
Research, New York, New York
Steven E. Hyman, M.D.
Provost, Harvard University; Professor of Neurobiology, Harvard Medical
School, Cambridge, Massachusetts
Thomas R. Insel, M.D.
Director, National Institute of Mental Health, Bethesda, Maryland
Thomas M. Jessell, Ph.D.
Investigator, Howard Hughes Medical Institute, Chevy Chase, Maryland;
Professor of Biochemistry and Molecular Biophysics, Columbia University
Medical Center, New York, New York
Donald F. Klein, M.D.
Professor of Psychiatry, Columbia University College of Physicians and Surgeons,
New York, New York
Joseph LeDoux, Ph.D.
Henry and Lucy Moses Professor of Science, Center for Neural Science, New
York University, New York, New York
x Psychiatry, Psychoanalysis, and the New Biology of Mind
Eric J. Nestler, M.D., Ph.D.
Lou and Ellen McGinley Distinguished Professor and Chairman, Department
of Psychiatry; Professor, Center for Basic Neuroscience, The University
of Texas Southwestern Medical Center, Dallas, Texas
John M. Oldham, M.D.
Chairman, Department of Psychiatry and Behavioral Sciences, Medical University
of South Carolina, Charleston, South Carolina
Herbert Pardes, M.D.
President and Chief Executive Officer, New York-Presbyterian Hospital,
New York, New York
Michael I. Posner, Ph.D.
Professor Emeritus, University of Oregon, Eugene, Oregon; Adjunct Professor,
Department of Psychiatry, Weill Medical College of Cornell University,
New York, New York
Judith L. Rapoport, M.D.
Chief, Child Psychiatry Branch, National Institutes of Health, Bethesda,
Charles F. Zorumski, M.D.
Samuel B. Guze Professor and Head of Psychiatry, Professor of Neurology,
Washington University School of Medicine, St. Louis, Missouri
Eric Kandel is the first American psychiatrist ever to have won the Nobel
Prize in physiology or medicine and only the second psychiatrist to have
done so in the prize’s 102-year history. Much of Kandel’s work was done at
Columbia University College of Physicians and Surgeons, where for the past
20 years he has been University Professor, the institution’s highest academic
rank. He is one of only 11 scholars at Columbia who have been awarded that
distinction. In addition, he is a professor in the departments of psychiatry,
physiology, and biochemistry.
I first met Eric in the late 1960s, when my family and I were vacationing
in Wellfleet, Massachusetts, a small village on Cape Cod where Eric and his
wife, Denise, have their summer home. Over the ensuing years, I came to
know him well, both as a colleague and as a friend. While I was head of the
National Institute of Mental Health, I repeatedly sought his counsel. By the
time I arrived at Columbia as chairman of the Department of Psychiatry, I was
not surprised to find that Eric was one of the mainstays of the academic community
and that his advice was valued at all levels of the university.
Eric Kandel received his undergraduate degree at Harvard College and
his medical training at New York University School of Medicine. He took
postdoctoral training at the National Institutes of Health from 1957 to 1960
and then a residency in psychiatry at the Massachusetts Mental Health Center,
which is affiliated with Harvard Medical School. In 1962, he took a fellowship
year abroad at the Institut Marey in Paris with Ladislav Tauc, where
he began work on the marine snail Aplysia.
Eric arrived at Columbia in 1974 as the founding director of the Center
for Neurobiology and Behavior. In 1984, he, Richard Axel, and James
Schwartz were asked by the Howard Hughes Medical Institute to form a
Howard Hughes Medical Institute in Neural Science at Columbia. They, in
turn, recruited Tom Jessell and Steven Siegelbaum. These steps helped the
xii Psychiatry, Psychoanalysis, and the New Biology of Mind
Center for Neurobiology and Behavior at Columbia become what is arguably
the leading research group in the world in brain science. As director of the
center, Eric organized the neural science course for medical students at Columbia,
a course that combines the basic biology of brain and behavior with
an introduction to clinical neurology and psychiatry. With James Schwartz
and later with Tom Jessell, Eric edited Principles of Neural Science, now generally
recognized as the standard textbook in the field.
Eric’s research has focused on the molecular basis of synaptic plasticity
in the central nervous system and on the relationship of this plasticity to
cognitive functions. By approaching simple forms of learning in Aplysia on
the cellular and molecular levels, and then combining this approach with
molecular genetics and extending it to forms of learning in the mouse, Eric
opened up the study of long-term synaptic plasticity and its relationship to
learning and memory storage.
His discoveries are many. He provided the first direct evidence that learning
leads to changes in synaptic strength at specific synapses and that memory
is associated with the persistence of those changes. Moreover, Eric’s
success at linking molecular biology and behavior has been extraordinarily
influential. He has shown that long-term memory differs from short-term
memory in requiring the activation of a cascade of genes and that this genetic
program leads to the growth of new synaptic connections.
Eric’s work—and Eric himself—has been a source of pride for psychiatry.
He has fostered the careers of a number of important young investigators
and has thereby stimulated greatly the flow of people and ideas into the molecular
study of behavior.
For those achievements, Eric was elected a member of the National
Academy of Sciences in 1974 and went on to receive honorary degrees from
12 academic institutions. He has been honored with the Albert Lasker Basic
Medical Research Prize, the National Medal of Science awarded to him by
President Reagan, the Gairdner International Award for Outstanding
Achievement in Medical Science, the Harvey Prize in Medicine awarded by
the Technion in Israel, the Wolf Prize of Israel, the Bristol-Myers Squibb
Award for Distinguished Achievement in Neuroscience Research, and the
Heineken Prize in Medicine from Holland, in addition to the Nobel Prize in
physiology or medicine.
The eight previously published articles assembled here cover a range of
issues in neurobiology, psychiatry, and psychoanalysis and have influenced
the progress of psychiatry over the last 3 decades. Eric’s early interest in psychoanalysis
and his clinical training have given him a deep appreciation of
the implications of his work for psychology. In turn, his continued interest
in psychiatry has had a great impact on the overall direction of his work.
Central to Eric’s thinking has been the idea that a fuller understanding of the
Foreword xiii
biological processes of learning and memory would illuminate our understanding
of behavior and of its disorders, an aspiration shared by many leaders
of psychiatry, including Sigmund Freud.
The outstanding essays collected in this volume will prove invaluable
reading for everyone interested in these areas of research, and they will be
treasured as a resource for our thinking about the future.
Herbert Pardes, M.D.
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Consistent with my long-standing aspiration to become a psychoanalyst,
I trained in psychiatry at the Massachusetts Mental Health Center of Harvard
Medical School in the early 1960s and completed a residency there.
Then I changed direction. I decided not to obtain psychoanalytic training or
even to have a clinical practice. Rather, I spent the next 40 years doing biological
research—developing a reductionist approach to learning and memory,
first in snails and then in mice.
As a result of the radical change in my career path, I am often asked,
“What did you gain from your psychiatric training? Was it profitable for
your career as a neural scientist?” I am always surprised by such questions
because it is clear to me that my training in psychiatry and my interest in
psychoanalysis are central to my thinking; they have provided me with a perspective
on behavior that has influenced almost every aspect of my work.
Had I skipped residency training and gone to France earlier to spend time in
a molecular biology laboratory—say, with Jacques Monod and François
Jacob in Paris—I might have worked on the molecular biology of the brain
at a slightly earlier point in my career. But the overarching ideas that have
influenced my work and fueled my interest in conscious and unconscious
memory derive from a perspective on the mind that psychiatry and psychoanalysis
opened up for me.
The essays in this volume reflect that influence. They also reveal neurobiology’s
influence on my view of psychiatry and psychoanalysis; namely, my
hope that molecular biology will provide a fresh perspective on the study of
behavior and that the ensuing insights will lead to a new science of the mind,
one that is grounded in the rigorous empirical framework of molecular biology
yet incorporates the humanistic concepts of psychoanalysis.
When I look back on these essays, some written more than 30 years ago,
I appreciate even more that one of the great privileges of an academic career
xvi Psychiatry, Psychoanalysis, and the New Biology of Mind
is being allowed to pursue different interests at different times in one’s life.
At various points in my career, I have grappled with psychoanalysis and psychiatry,
with cellular neurobiology, and, since 1980, with molecular biology.
I have benefited greatly from the freedom afforded me by academic life and
have learned both from the nuanced analytic thinking of psychoanalysis and
psychiatry and from the rigorous methods of modern biology. The transitions
in my career were not accidental; they reflected the evolution of my
thinking about how memory storage might be studied most effectively.
My interest in memory dates back to early childhood. I was born in
Vienna in November 1929, 8 years before Austria embraced Hitler. In April
1939, my brother and I emigrated to the United States, followed by our parents
a few months later. As an undergraduate at Harvard College, I tried to
understand my European past. I took honors in an area called History and
Literature and wrote my dissertation on the attitudes toward National Socialism
of three German writers. Each of the writers I examined—Carl Zuckmayer,
Hans Carossa, and Ernst Junger—represented a different position
along the spectrum of intellectual responses to National Socialism. Zuckmayer,
a courageous liberal and lifelong critic of National Socialism, left
Germany early and went first to Austria and then to the United States. Hans
Carossa, a physician-poet, took a neutral position and remained in Germany.
He and other more passive intellectual opponents of Hitler undertook a socalled
inner emigration: physically, they remained in Germany, but their
spirits lay elsewhere. Ernst Junger, a dashing German military officer in
World War I, extolled the virtues of the warrior and was an intellectual precursor
of the Nazis.
Although I was fascinated with the subject of my thesis—it was my first
large-scale, independent intellectual accomplishment—I did not continue
the study of modern European intellectual history. While at Harvard,
I befriended several students who had been born in Vienna and whose parents
were psychoanalysts from the Freud circle. Through Anna Kris (later
Anna Kris Wolf), I became interested in psychoanalysis. She introduced me
to her parents, Ernst and Marianne Kris, two gifted and remarkable people
who were extremely enthusiastic about the future of psychoanalysis and encouraged
me to think about a career in their field.
In the 1950s, psychoanalysis seemed to have a future filled with promise.
It had developed a family of new insights into the mind and unconscious
mental processes, as well as into the complex factors that motivate human
behavior. I found the possibility of becoming a psychoanalyst exciting. To
pursue this career in the early 1950s, one needed to go to medical school, so
I enrolled at New York University School of Medicine in 1956.
Throughout my 4 years of medical school, I stayed with the plan of becoming
a psychoanalysis-oriented psychiatrist. In my senior year, believing
Introduction xvii
that a psychoanalyst should have some insight into the biology of brain
function, I took an elective period in a neurophysiology laboratory at Columbia
University. This belief was a minority view within the psychoanalytic
community, but it certainly was not unique. Two psychoanalysts whom I had
met, Lawrence Kubie and Mortimer Ostow, had been trained in neurology.
Both of them appreciated the importance of Wilder Penfield’s finding that
stimulating the surfaces of the temporal lobe elicits memory-like experience.
Both Kubie and Ostow wrote articles for the Psychoanalytic Quarterly indicating
that some of the ideas of psychoanalysis might be validated by direct
exploration of the human brain. To me, the idea that one could delineate key
psychoanalytic ideas about mental structure in biological terms was simply
My elective period at Columbia gave me the chance to work with two
outstanding neurophysiologists, Dominick Purpura and Harry Grundfest.
The experience influenced me profoundly. It also led to a very desirable postdoctoral
position at the National Institutes of Health (NIH), a position I was
given in large part, I suspect, because of Grundfest’s nomination. Upon finishing
my medical internship, I went to the National Institute of Mental
Health at the NIH as a research associate and member of the Public Health
Service. I entered the NIH an enthusiastic but inexperienced research scientist
and came out 3 years later a competent neurophysiologist.
I was extremely lucky. During my second year at the NIH, Alden Spencer
(a fellow research associate) and I obtained the first intracellular recording
from the hippocampus, a part of the mammalian brain studied by Wilder
Penfield and Brenda Milner concerned with memory. Alden and I were euphoric.
Two young, relatively inexperienced scientists had succeeded in
opening up a new area of research. We obtained our initial results in the fall
of 1958. I had already made a commitment to start my residency in psychiatry
in July 1959, so I wrote to Dr. Jack Ewalt, director of the Massachusetts
Mental Health Center and professor of psychiatry at Harvard Medical
School, telling him of my situation and asking if it were possible to have a 1-
year extension. He replied immediately that I should stay as long as necessary.
That third year proved crucial not only for my collaborative work with
Alden on the hippocampus, but also for my maturation as a scientist.
Encouraged by this cordial beginning, I visited Dr. Ewalt upon my arrival
at the Massachusetts Mental Health Center on July 1, 1960. I asked him
if it might be possible to have some space and modest resources to set up a
laboratory. He looked at me in astonishment then pointed to the pile of résumés
from the 22 other residents who were about to begin their training.
“Who do you think you are?” he bellowed. “What makes you think that you
are better than any one of these?”
I was completely taken aback, both by the content of his remarks and by
xviii Psychiatry, Psychoanalysis, and the New Biology of Mind
the tone. In all my years as an undergraduate at Harvard and a medical student
at NYU, none of my professors had ever talked to me like that. I assured
him that I had no illusions about how my clinical skills compared to those
of my peers, but that I did have 3 years of research experience that I did not
want to lie dormant.
Dr. Ewalt told me to go to the wards and take care of patients. I left his
office depressed and confused, and I briefly entertained the idea of switching
to the residency program at the Boston Veterans Administration. Jerry
Lettvin, a neurobiologist and friend to whom I described the conversation,
urged me to take the position at the Veterans Administration, stating,
“Working at the Massachusetts Mental Health Center is like swimming in a
Nevertheless, because of the excellent reputation of the psychiatry residency
program, I decided to swallow my pride and stay at the center. It
proved a wise decision: a few days later, I went across the street to the physiology
department of Harvard Medical School and discussed my situation
with Elwood Henneman, a senior neurophysiologist on the faculty, who immediately
offered me space in his laboratory. Several weeks later, Dr. Ewalt
approached me and said, “I gather from my colleagues at the medical school,
Steven Kuffler and Elwood Henneman, that you are a good person to invest
in. What do you need? How can I help you?” He then made available all the
resources necessary to continue research in Henneman’s laboratory throughout
my 2 years of residency training.
In those days, residents worked from 8:30 A.M. to 5:00 P.M. with only a
rare duty on evenings and weekends. As a result, I was able to carry out a
fairly interesting and somewhat original series of experiments on hypothalamic
neuroendocrine cells in my spare time. In those experiments, I found
that neuroendocrine cells have all the electrophysiologic characteristics of
conventional nerve cells. It was the first direct evidence that cells in the
brain that look glandular and secrete hormones also act like nerve cells in
their signaling capability.
From that time onward, Dr. Ewalt became a strong supporter of my research,
and he went out of his way to help me develop as a scientist. While
I was still a second-year resident, he appointed me to a permanent civil service
position in the state of Massachusetts, thereby giving me the opportunity
to stay indefinitely. Three years later, in 1965, when I was beginning to
think about moving to New York, the highly influential and charismatic psychoanalyst
Grete Bibring stepped down as head of the Department of Psychiatry
at Beth Israel Hospital. Dr. Ewalt and Howard Hiatt, the head of the
search committee and chairman of the Department of Medicine at Beth Israel,
offered me the position.
Even though I decided to pass up that opportunity in favor of a research
Introduction xix
career, I have remained deeply indebted to Dr. Ewalt for the support he gave
me and other research-oriented people. He believed that basic science would
be important to the future of psychiatry, an attitude that was at odds with the
predominant view at the Massachusetts Mental Health Center. Elvin Semrad,
the head of clinical services, and most of our supervisors were heavily
oriented toward psychoanalytic theory and practice. Few of them thought in
biological terms, few were familiar with psychopharmacology, and most discouraged
us from reading the psychiatric or even the psychoanalytic literature
because they thought we should learn from our patients and not from
our books.
I hasten to add that despite the narrowness and lack of inquisitiveness of
many of the clinical teaching faculty, we nevertheless learned a great deal as
residents. We had excellent supervision for individual psychotherapy. Moreover,
we learned a great deal from one another. I was fortunate to have in my
residency class several people with extraordinary intellectual gifts: Judith L.
Rapoport, Joseph Schildkraut, Paul Wender, Alan Hobson, Paul Sapier, Tony
Kris, Ernest Hartmann, George Vaillant, and Dan Buie all emerged in later
years as leaders of American psychiatry. We influenced each other, and to
some degree we influenced our faculty.
The residents organized a discussion group on descriptive psychiatry
that met monthly. Tony Kris invited Mark Altschule, an outstanding Harvard
internist who was interested in schizophrenia, to lead the discussion. We
took turns presenting an original essay that we had prepared for the occasion.
I remember, in particular, Vaillant presenting an outstanding paper on
good prognosis and bad prognosis in schizophrenia. Prior to our arrival, the
Massachusetts Mental Health Center had almost never invited outside
speakers to address the residents or the faculty. This was a reflection of the
vaunted self-confidence of Harvard and Boston at large, which is best represented
by the canard of the Boston matron who, when asked about her travels,
responded, “Why should I travel? I’m already there.”
Kris, Schildkraut, and I therefore also initiated academic grand-rounds,
which brought important people with new views to the hospital to address
the staff. While at NIH, I had been spellbound by a lecture by Seymour Kety
in which he reviewed the contributions of genetics to schizophrenia.
I therefore thought we might kick off our lecture series with that topic. In
1961, I could not find a single psychiatrist in all of Boston who knew anything
about the subject. Somehow, I found out that Ernst Mayr, the great
evolutionary biologist at Harvard, was a friend of the late Franz Kallmann, a
pioneer in the genetics of schizophrenia. Mayr generously agreed to come
and give us two (splendid) lectures on the genetics of mental illness.
I had entered medical school with a strong conviction about the promising
future of psychoanalysis. Now, I found myself questioning psychoanalyxx
Psychiatry, Psychoanalysis, and the New Biology of Mind
sis. I was not alone: my view was shared by Paul Wender, Alan Hobson,
Judith Livant Rapoport, Tony Kris, and Ernest Hartmann. Of this group,
Tony, Ernest, and I were probably the most sympathetic to psychoanalysis.
At NIH, I had gotten off to a good start in my studies of the hippocampus,
which has a role in the process of storing memories of facts and events.
However, the function and neural circuitry of the hippocampus are very
complex, and I gradually realized that if the power of modern biology were
to be applied to the study of memory, the effort would have to begin with the
simplest examples of learning and memory—that is, with a radical reductionist
approach. I therefore decided to study the marine snail Aplysia. I had
decided that after 2 years at the Massachusetts Mental Health Center,
I would spend a year in Paris working on Aplysia. Fortunately, this proved
to be a productive and immensely enjoyable career choice.
I returned to Harvard in 1963 as an instructor in the Department of Psychiatry.
I carried out full-time research on Aplysia and spent a few hours a
week supervising residents in their psychotherapeutic work. As I look back,
I am amazed to see how far psychiatry has progressed in the last 40 years.
Even as recently as 1980, several psychoanalysts held the extreme view that
biology is irrelevant to psychoanalysis. Two anecdotes illustrate this view:
one relating to my career decision, the other to the relationship between psychiatry
and biology.
In 1965, I made what was probably the most difficult career decision of
my life. Despite the fact that I was a good therapist and enjoyed working
with patients, I decided I would not apply for training at the Boston Psychoanalytic
Institute as I had planned (and as many of the other residents at the
center in fact did). Rather, I would devote myself to full-time research. In an
upbeat frame of mind, having put this decision behind us, my wife and
I took a brief holiday. We accepted Henry Nunberg’s invitation to spend a
few days at his parents’ summer home in Yorktown Heights, New York.
Henry was a very good friend, and Denise and I knew his parents moderately
well. His father, Herman Nunberg, was an outstanding psychoanalyst and an
influential teacher whose textbook I much admired for its clarity. He also
had a broad, albeit dogmatic, interest in many aspects of psychiatry. At our
first dinner together, after I had enthusiastically outlined my new career
plans, Herman Nunberg looked at me in amazement and muttered, “It
sounds to me as if your analysis was not fully successful; you seem never really
to have quite resolved your transference.”
I found that comment both humorous and irrelevant—and reminiscent
of Elvin Semrad’s failure to understand that a psychiatrist’s interest in brain
research need not imply a rejection of psychoanalysis. On reading an earlier
version of this introduction, my longtime friend and colleague Donald
Klein, a hard-nosed academic psychiatrist, commented, “Another issue that
Introduction xxi
you may, or may not, want to deal with is whether you have undergone a
fruitful personal analysis. Those who have been through an analysis, and feel
it was useful, often maintain a positive attitude toward analytic ideas in general.
Of course, bad outcomes breed negative evaluation.” I certainly think
that my analytic experience has been useful to me, and there is no question
that this positive attitude contributes to my insistence (Klein would call it
my delusional optimism) that biology can transform psychoanalysis into a
scientifically grounded discipline. But the point I would emphasize here is
that if Herman Nunberg were alive today, it is almost inconceivable that he
would pass the same judgment on a psychiatrist who moved into brain
In 1986, I attended a symposium in New Haven in honor of Morton
Reiser’s retirement as chairman of the Department of Psychiatry at Yale University.
Mort invited me and several other colleagues to give talks. One of the
invitees was Mort’s close associate Marshall Edelson, a philosopher of the
mind and professor of psychiatry at Yale. In his lecture, Edelson recapitulated
some of the arguments he had developed in his book Hypothesis and
Evidence in Psychoanalysis. He argued that the effort to connect psychoanalytic
theory to a neurobiologic foundation, or to try to develop ideas about
how different mental processes are mediated by different systems in the
brain, should be resisted as an expression of logical confusion. Mind and
body must be dealt with separately. He went on to say that scientists might
eventually conclude that the distinction between mind and body is not
merely a temporary methodologic stumbling block stemming from the inadequacy
of our current ways of thought; rather, it is a logical and conceptual
necessity that no future developments will ever mitigate.
When my turn came, I gave a paper on learning and memory in the snail.
I pointed out that all mental processes, from the most routine to the most
sublime, emanate from the brain and that all mental illness, irrespective of
symptomatology, must be associated with distinctive alterations in the brain.
Edelson rose during the discussion and said that while he agreed that psychotic
illnesses were disorders of brain function, the disorders that Freud described
and that are seen in practice by psychoanalysts, such as obsessivecompulsive
neurosis and anxiety states, could not be explained on the basis
of brain functioning.
Edelson’s views and Herman Nunberg’s more personal judgment represent
idiosyncratic extremes, but they were representative of the thinking of
a surprisingly large number of psychoanalysts not so many years ago. The
insularity of these views hindered psychoanalysis from growing during the
recent golden age of biology, a hindrance that I hope will soon disappear.
Marianne Goldberger has made an interesting point regarding these issues:
it was not that Nunberg, or perhaps even Edelson, thought that mind
xxii Psychiatry, Psychoanalysis, and the New Biology of Mind
and brain were separate; it was rather that they did not know how to join
them. Since the 1980s, the way in which mind and brain should be joined
has become clearer, and consequently psychiatry has emerged in a new role.
It has become not only a beneficiary of modern biological thought but also
a stimulus to that thought. In the last few years, I have seen significant interest
in the biology of the mind, even within the psychoanalytic community.
The next step is to incorporate components of a psychoanalytic perspective
into the modern biology of the mind and to create a unified view, from mind
to molecules that will be intellectually inspiring to psychiatrists and therapeutically
satisfying to patients. Who would predict that this new biology of
mind could prove to be not only central to psychiatry and psychoanalysis
but also of interest to the whole academic enterprise? For there is every reason
to believe that the biology of the mind will be the central pursuit of modern
scholarship in the twenty-first century much as the biology of the gene
was the central pursuit during the last half of the twentieth century.
This volume includes eight published essays, arranged thematically
rather than chronologically, and an afterword. In each case they are preceded
by an introductory commentary written respectively by Judith L. Rapoport,
Tom Insel, Arnold Cooper, Donald Klein, Joseph LeDoux, Eric Nestler, Steve
Hyman, Charles Zorumski, and John Oldham. I am grateful to each of them
for their scholarly essays and to Herbert Pardes, my longtime colleague and
friend, for his introductory comments.
The first essay, “Psychotherapy and the Single Synapse: The Impact of
Psychiatric Thought on Neurobiologic Research,” addresses the issues raised
by Edelson. It is based on the first annual Elvin Semrad Memorial Lecture,
which I gave at the Harvard Club in Boston on June 9, 1978. Semrad was the
clinical role model at the Massachusetts Mental Health Center. An extraordinarily
charismatic person and a brilliant interviewer of patients, he made
an indelible impression both on our patients and on us. Patients could remember
several years later a single encounter with Semrad, even though
they might have completely forgotten anything that happened to them in
therapy with us. Semrad had a magical influence on many residents because
of his poetic insights into patients and their diseases. He strongly encouraged
us to sit with psychotic patients, listen to them carefully, and care about
them. He discouraged reading and research because he believed that reading
interfered with our ability to listen to and learn about patients directly from
them. One of his famous epigrammatic remarks was “There are those who
care about people and those who care about research.” Semrad was less concerned
about a stronger intellectual fabric for psychiatry or advancing
knowledge toward that goal than about developing therapists who could
empathize more deeply with patients.
I respected Semrad and learned from him, but we disagreed profoundly
Introduction xxiii
about the role of research and the function of a training program in psychiatry.
In particular, I was disappointed at his failure to see that better patient
care in psychiatry cried out for new knowledge through more focused research
and that it was the job of Harvard Medical School to provide an environment
in which such knowledge could grow. The essay is an attempt to
explain what neurobiologic research could mean for psychotherapy and how
a unified psychoanalytic and biological perspective could influence one’s
work in the laboratory. The theme of this essay is that insofar as psychotherapy
works, it works at the same level—that of neural circuits and synapses—
as drugs do, a point of view that the field is only now beginning to explore.
“A New Intellectual Framework for Psychiatry” is an extended version
of a talk I gave in 1997 on the occasion of the hundredth anniversary of the
New York State Psychiatric Institute. The thrust of my argument is that the
future of psychiatry is deeply rooted in its past and in its connection with
biology and that the training of residents in psychiatry and neurology should
begin on common ground. Much as internal medicine is the basic training
for residents who become cardiologists or nephrologists, so too the biology
of the brain should be the common focus of first-year neurology and psychiatry
residents. “A New Intellectual Framework for Psychiatry” was published
in the American Journal of Psychiatry, and it stimulated the largest
number of letters the journal had received in recent years in response to a
single article—not all of them positive.
“Biology and the Future of Psychoanalysis: A New Intellectual Framework
for Psychiatry Revisited” was written in response to those letters, many
of which focused on the relevance of biology to the future of psychoanalysis.
I outlined two alternative futures for psychoanalysis: In one, psychoanalysis
evolves as a hermeneutic discipline focused on elaborating Freud’s powerful
set of intuitive insights into the mind, without attempting to document its
key conclusions. In the other, psychoanalysis becomes a source of rich ideas
that can be tested experimentally—that is, an experimentally based science
of the mind. The latter course requires psychoanalysis to collaborate with
other experimental sciences. I find it encouraging that the ability to detect
functional changes in the brain after psychotherapy has opened up a new,
objective way of evaluating the effects of psychotherapy on individual patients.
“From Metapsychology to Molecular Biology: Explorations Into the Nature
of Anxiety” is an expanded version of the John Flynn Memorial Lecture
presented to the Department of Psychiatry at Yale University School of Medicine,
which I gave in a modified form in response to an invitation from
Donald Klein at the American College for Neuropsychopharmacology. Published
in 1983, the essay argues that psychiatry is badly in need of animal
models of psychiatric disorders. Learned fear is a prime example: one can
xxiv Psychiatry, Psychoanalysis, and the New Biology of Mind
use animals ranging in evolutionary complexity from snails to monkeys to
study learned fear because fear is a universal behavior and is conserved in
evolution. I also developed the idea that molecules and cellular mechanisms
for learning and memory might represent a molecular alphabet that could be
combined in various ways to produce a range of adaptive and maladaptive
behaviors. This idea turned out to be useful in some of my later work.
“Neurobiology and Molecular Biology: The Second Encounter” is based
on a summary I gave at the Cold Spring Harbor Symposium of 1983 at the
invitation of James Watson, then director of the Cold Spring Harbor Laboratory.
I first met Watson in the early 1970s, while I was on the faculty at NYU.
He had become interested in neural science and thought that the Cold
Spring Harbor Laboratory should give a summer course in this area. He
asked me to help organize one based on Aplysia. I was fortunate to recruit
JacSue Kehoe and Philippe Ascher, two outstanding young French neurobiologists
working on Aplysia, to lead the experimental portion of the course.
Two parallel lecture series were also organized for the course, one by Jack
Byrne, Larry Squire, Kier Pearson, and me and the other by John Nicholls.
The courses were very successful, sparking a long-term interest in neurobiology
at Cold Spring Harbor. Watson punctuated this interest with a symposium
in 1975 on “The Synapse” and again with the 1983 symposium, which
was historic. Neuroscientists had been aware of the growth of molecular biology
for some time, and many outstanding molecular biologists—including
Francis Crick, Seymour Benzer, Sidney Brenner, and James Watson—had already
moved into neurobiology. But it was only with the emergence of recombinant
DNA that molecular biology began to have an explosive impact
on the field of neurobiology. The 1983 symposium signaled the beginning of
extraordinary activity in neuroscience.
“Neural Science: A Century of Progress and the Mysteries That Remain,”
published in Cell in 2000, is a collaborative effort with Tom Albright, Tom
Jessell, and Michael Posner. It was written at the request of the editors of Cell
to review the achievements of brain biology in the twentieth century. In
some ways, this essay is an update of the report given at Cold Spring Harbor
in 1983. By 2000, the range and ambition of neuroscience was broader, extending
from genes to mental processes. The four of us outlined the emergence
of the new science of the mind: a great unification into one intellectual
framework of behavioral psychology, cognitive psychology, neuroscience,
and molecular biology.
“The Molecular Biology of Memory Storage: A Dialogue Between Genes
and Synapses” is the lecture I gave at the Karolinska Institute when I was
awarded the Nobel Prize in physiology or medicine in 2000. I shared the
prize with Arvid Carlsson and Paul Greengard. Carlsson, who had discovered
that dopamine is a key modulatory transmitter in the brain, suggested
Introduction xxv
that reduced dopaminergic transmission is critical to Parkinson’s disease,
whereas enhanced transmission contributes to schizophrenia. Greengard
had discovered that dopamine acts on a receptor that increases the amount
of the second messenger cAMP and that cAMP activates a specific kinase, the
cAMP-dependent protein kinase. This kinase phosphorylates a variety of
substrate proteins in the cell to initiate synaptic actions. Greengard went on
to describe that a variety of transmitters act through second messengers.
I was recognized for finding that learning depends on changes in synaptic
strength. A transient alteration in the strength of synaptic connections gives
rise to short-term memory, while the growth of new synaptic connections
extends the memory. Learning recruits modulatory neurotransmitters that
act on receptors to increase cAMP, which activates the cAMP-dependent protein
kinase and leads to the increased synaptic strength needed for shortterm
memory. In long-term memory, the cAMP-dependent protein kinase
moves into the nucleus of the cell and prompts the activation of genes that
lead to the growth of new synaptic connections.
“Genes, Brains, and Self-Understanding: Biology’s Aspirations for a New
Humanism” is an abbreviated version of the commencement address I gave
to the graduating class of 2001 at Columbia University College of Physicians
and Surgeons. In it I explore the implications of the mapping of the human
genome for medicine in general and for psychiatry and mental health in particular.
I also indicate that the new science of the mind and the human genome
studies have social implications that will be important for the future
of medicine.
I conclude with a brief essay, “Afterword: Psychotherapy and the Single
Synapse Revisited,” in which I suggest that the time is ripe for psychiatry to
take a major step forward. Psychiatry has been revitalized by effective new
drugs, and it is being revolutionized by molecular biology, genetics, and neuroimaging.
Now we need to use the power of biology and cognitive psychology
to take up the task of healing the many mentally ill persons who do not
benefit from drug therapy. We need to put psychotherapy on a scientific basis
and to explore its biological consequences, using imaging and other empirical
means of evaluation. In this way, we may be able to explore which
form of psychotherapy is most effective for different categories of patients.
All of these essays were written during the 30 years in which I have been
a member of Columbia University College of Physicians and Surgeons and
the Department of Psychiatry. I was recruited to Columbia in 1974 as the
founding director of the Center for Neurobiology and Behavior, which ultimately
included Alden Spencer, James H. Schwartz, Irving Kupfermann,
Richard Axel (who went on to win the Nobel Prize in physiology or medicine
in 2004), Tom Jessell, John Koester, Steven Siegelbaum, Rene Hen,
Lorne Role, Michael Shelanski, Samuel Schacher, Jack Martin, Claude Ghez,
xxvi Psychiatry, Psychoanalysis, and the New Biology of Mind
Mickey Goldberg, and Daniel Saltzman, among many others. The center
contains one of the most remarkable neural science groups in the world.
Many of the ideas discussed in these essays evolved out of interactions with
my colleagues, and it has been one of the great joys and privileges of my career
to have matured scientifically in this heady intellectual environment.
In 1984, Richard Axel, James H. Schwartz, and I were invited by Donald
Fredrickson, president of the Howard Hughes Medical Institute, to develop
a Howard Hughes Medical Institute program in neuroscience at Columbia.
This allowed us to recruit Thomas Jessell from Harvard and to keep Steve
Siegelbaum at Columbia. I was appointed senior investigator. The leadership
of the Howard Hughes Medical Institute has consistently encouraged
Hughes investigators to have a long-term perspective on their work so they
will tackle challenging problems. Research on the molecular biology of
learning and memory certainly meets both of those criteria, especially for
someone who came to this problem from psychoanalysis!
Eric R. Kandel, M.D.
Judith L. Rapoport, M.D.
“Psychotherapy and the Single Synapse: The Impact of Psychiatric Thought
on Neurobiologic Research,” written in 1979, presents a lucid and remarkably
timely review of advances in understanding the impact of experience on
biological structure and function. From research on early adverse rearing experiences
possibly mediated by sensory deprivation, to data from Spitz’s
early clinical observations, to Harlow’s primate rearing manipulations, to
Hubel and Wiesel’s elegant experiments on visual deprivation, Eric Kandel
shows how crucial the right experience at the right time can be for normal
psychologic and neurobiologic development.
Eric Kandel’s own work was based on the habituation and sensitization
training of Aplysia californica, taking advantage of its limited wiring system
that made relevant neural cells easily identifiable. Using electrophysiological
single cell recording, Kandel and his students showed long-term changes in
the form of decreased sensory motor excitation occurring during habituation.
In sensitization, a parallel and opposite change took place, documenting
that presynaptic facilitation now heightened the transmitter release
following exposure to a noxious stimulus.
Kandel has since extended this work remarkably and in doing so has en2
Psychiatry, Psychoanalysis, and the New Biology of Mind
hanced our understanding of behavioral change at a molecular level with
widespread implications for learning and memory. There has indeed been a
great shift in the field of psychiatry: academic psychiatric centers are research
focused and various combinations of brain imaging, molecular genetics,
and epidemiology provide the mainstay of most medical school–based
clinical psychiatric research (for excellent examples, see Caspi et al. 2003
and Hariri 2002). To accelerate this progress, it would be relatively simple to
merge research facilities for neurology and psychiatry departments at many
medical centers.
The 1979 message of this paper, highlighting the duality of our mental
health practitioners, still stands today. I too recall the duality of our Massachusetts
Mental Health Care residency experience with Kandel, although I
differ with his recollection in that it never seemed leisurely! We were indeed
focused on our personal clinical experience, and those of a hoard of supervisors
so numerous that I sped or ran to assorted private offices to dissect my
clinical exchanges. Unlike my Swarthmore College undergraduate education,
where critique of primary sources was the core teaching vehicle, the
sole focus at Massachusetts Mental Health Center was one’s own person as
the therapeutic tool. As such, it was a combined support group and initiation
ceremony. There was a monthly seminar with Ives Hendricks in his home on
Beacon Hill; his clinical teaching was superb and eccentric, and the food was
superb! The Hendricks seminar experience was balanced by Sam Horenstein’s
Saturday morning neurology rounds. Sam usually contented himself
with documenting subtle neurologic signs in our psychiatric patients. With
limited tools, both seminars were essentially descriptive. The real winds of
change came from the growing use of antipsychotics and antidepressants.
Even though we knew we were in a new age, senior nursing staff still showed
us where the hot packs and cold packs were, in case we ever were to need
them. Thanks to neuroleptics, we didn’t.
Now back to the future. The practice of mental health therapy today
shows an even greater duality, and a troubled one. It would be impossible to
merge treatment staffs of psychiatry and neurology facilities. The dramatic
changes in psychopharmacology of the 50s and 60s have provided medications
that are now part of the general medical armamentarium and are (statistically)
less likely to be prescribed by psychiatrists. Neuroscience has
influenced the treatment of neurological disorders such as Alzheimer’s disease,
but major new medical treatments for this severe psychiatric illness
have been slow to arrive, and we still do not understand the mechanism of
important older drugs such as lithium or the basis for the unique efficacy of
clozapine. The daily work of a psychopharmacologist in managed care is almost
a caricature of our 1979 therapeutic duality; the heavy caseload in today’s
medication clinics prohibits all but the most superficial interpersonal
Psychotherapy and the Single Synapse 3
experience. (This fuels the current crisis in psychiatric training, as such jobs
provide little career satisfaction.)
In fairness, we already have some clinical evidence for therapy-induced
change in brain circuitry. The best documented therapy in our field is behavior
therapy, which is also where these neurobiological changes have been
shown (Schwartz et al. 1996). By extension, one might easily envision behavioral
treatments of anxiety disorders, monitored by fMRI “office checks”
on amygdala activation.
In contrast, more psychodynamic therapy/psychoanalysis is now practiced
primarily by psychologists who have no neuroscience training. There
have been a few advances in evaluating the efficacy of focused, interpersonally
oriented treatment (Weissman et al. 1979). The attempt to develop a
unified biological basis for understanding and furthering the psychiatric
treatment has not been hampered by a lack of willingness of neuroscientists
to take on the biological strata for complex social behaviors (Insel and
Young 2001). Here too, one might envision neurobiological aspects of
“bonding” applied in future therapies. But in 2004, most would agree that
we still have a long way to go in reconciling the relationship between biology
and psychiatry, and many would debate whether to even go there. Certainly
across all of medicine, even for conditions for which a specific biological
cause is known, short of an absolute cure, there remains a crucial need for caring
clinicians who can help the patient to understand and deal with his or
her illness.
Caspi A, Sugden K, Moffitt T, et al: Influence of life stress on depression: moderation
by a polymorphism in the 5-HTT gene. Science 301:386–389, 2003
Hariri A, Mattay VS, Tessitore A, et al: Serotonin transporter genetic variation and the
response of the human amygdala. Science 297:400–403, 2002
Insel T, Young LJ: The neurobiology of attachment. Nat Rev Neurosci 2:129–136,
Kandel E: Psychotherapy and the single synapse. N Engl J Med 301:1028–1037, 1979
Schwartz JM, Stoessel PW, Baxter LR, et al: Systematic changes in cerebral glucose
metabolic rate after successful behavior modification treatment of obsessivecompulsive
disorder. Arch Gen Psychiatry 53:109–113, 1996
Weissman M, Prousoff B, Dimascio A, et al: The efficacy of drugs and psychotherapy
in the treatment of acute depressive episodes. Am J Psychiatry 136:555–558,
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C H A P T E R 1
The Impact of Psychiatric Thought
on Neurobiologic Research
Eric R. Kandel, M.D.
This article was originally published in the New England Journal of Medicine, Volume
301, Number 19, 1979, pp. 1028–1037.
From the Division of Neurobiology and Behavior, Departments of Physiology and
Psychiatry, Columbia University, College of Physicians and Surgeons, and the New
York State Psychiatric Institute.
Supported by a Research Scientist Award (MH-18558) and by grants (MH-26212
and NS-12744) from the National Institutes of Health.
Based on the first annual Elvin V. Semrad Memorial Lecture, given at the Harvard
Club of Boston, June 9, 1978. Dr. Semrad was born in 1909, in Abie, Nebraska. Educated
in Nebraska, he trained in psychiatry at the Boston Psychopathic Hospital, at
the McLean Hospital, and at the Boston Psychopathic Institute. In 1952 he was appointed
to the faculty of Harvard Medical School and became clinical director of the
Massachusetts Mental Health Center. Dr. Semrad had recently retired from his position
as professor of clinical psychiatry at Harvard Medical School when he died suddenly
on October 7, 1976.
6 Psychiatry, Psychoanalysis, and the New Biology of Mind
The title of this lecture is at best premature and more likely absurd, but
I have adopted it for two reasons. In the first place, I want to emphasize the
continuing tension within psychiatry between biologic and psychologic explanations
of behavior. Secondly, I want to consider the simplistic but perhaps
useful idea that the ultimate level of resolution for understanding how
psychotherapeutic intervention works is identical with the level at which we
are currently seeking to understand how psychopharmacologic intervention
works—the level of individual nerve cells and their synaptic connections.
I will discuss the second issue later. First, I should like to consider the
tension within psychiatry. Although this tension is long-standing and almost
universal, I first encountered it in 1960, when I entered psychiatric residency
training at the Massachusetts Mental Health Center. In looking about
I was struck by the fact that our residency cohort, a very congenial and intelligent
group, was nonetheless split in a fundamental way on one basic issue:
the degree to which we accepted the current psychoanalytic view of the
mind as providing the adequate conceptual framework for future work in
psychiatry. On this issue we were divided into two groups: the hard-nosed
and the soft-nosed.
The hard-nosed residents, many of whom were attracted to the humane
and existential aspects of the analytic perspective, thought that the psychoanalytic
view of the mind was slightly vague, difficult to verify (or discredit),
and therefore limited in its powers. The hard-nosed yearned for more substantial
knowledge and were drawn to new ways of thought. In particular,
many were drawn to biology. By contrast, most soft-nosed residents had little
direct interest in the biology of the brain, which they thought had promised
much to psychiatry but delivered little. The soft-nosed saw the future of psychiatry
not simply in the development of a better body of knowledge but in
the development of better therapists—therapists qualified to provide more
effective treatment to very disturbed patients. Needless to say, this distinction
is drawn too boldly. Many residents then held, and probably still hold,
aspects of both views. But the distinction does draw attention to a fundamental
tension, a difference in worldview that existed in the psychiatric
world around us as well as in ourselves. I think that most of us at that time
simply failed to appreciate two aspects of the relation between biology and
psychiatry: we failed to appreciate that the conflicted relation between biology
and psychiatry is not unique but is characteristic of the interaction between
closely related fields of science, and we did not know that in other
fields of science this relation has often aided the advancement of knowledge.
People (and noses) may fall by the wayside, but the related scientific disciplines
usually profit and move on.
As pointed out by a number of students of science, most recently by the
biologist E.O. Wilson (1977), there exists for most parent disciplines in sciPsychotherapy
and the Single Synapse 7
ence an antidiscipline. The antidiscipline generates creative tension within
the parent discipline by challenging the precision of its methods and its
claims. For example, for my own parent discipline, cellular neurobiology,
there stands at a more fundamental level the antidiscipline of molecular biology,
and for molecular biology there stands at a more fundamental level
structural (physical) chemistry. In this context it is clear that neurobiology
is the new antidiscipline for which psychology in general and psychiatry in
particular are the parent disciplines.
I say “new” antidiscipline because as knowledge advances and scientific
disciplines change, so do the disciplines impinging on them. In the period
from 1920 to 1960, psychiatry derived its main intellectual impetus from
psychoanalysis. During this phase, its most powerful antidisciplines were
philosophy and the social sciences (Hook 1959). Since 1960, psychiatry has
begun (again) to derive its main intellectual challenge from biology, with the
result that neurobiology has been thrust into the position of the new antidiscipline
for psychiatry. Modern neurobiology had its first impact on psychiatry
when it provided insights into the actions of psychotherapeutic drugs.
But most of us believe that this is only the beginning and that in the near
future, neurobiology will address a matter of more general and fundamental
importance: the biology of human mental processes. When it comes to mental
function, however, biologists are badly in need of guidance. It is here that
psychiatry, as guide and tutor of its antidiscipline, can make a particularly
valuable contribution to neurobiology. Psychology and psychiatry can illuminate
and define for biology the mental functions that need to be studied
if we are to have a meaningful and sophisticated understanding of the biology
of the human mind.
Given the potential power of neurobiology and the vision of psychiatry,
we may well ask why this type of complementarity was not viable before. The
answer to that question is surprisingly simple. The relevant branches of biology—
ethology and neurobiology—were, until recently, simply not mature
enough, either technically or philosophically, to address higher-order problems
related to mental processes. On the appropriate level of resolution, the
cellular level, neurobiology has only recently become capable of accomplishing
for psychology and psychiatry what other antidisciplines have traditionally
accomplished for their parent disciplines—to expand and enlighten the
discipline by providing a new level of mechanistic understanding.
I hasten to emphasize that I do not mean “to displace.” As Wilson has
pointed out, an antidiscipline is usually narrower in scope than its parent
discipline. The antidiscipline can succeed in revitalizing and reorienting the
parent discipline. It forces a new set of approaches, new methodologies and
new insights, but it does not provide a broader, more coherent framework;
it does not produce richer paradigms. Although neurobiology can provide
8 Psychiatry, Psychoanalysis, and the New Biology of Mind
key insights into the human mind, psychology and psychoanalysis are potentially
deeper in content. The hard-nosed propositions of neurobiology, although
scientifically more satisfying, have considerably less existential
meaning than do the soft-nosed propositions of psychiatry. If neurobiology
is at all equal to the task, the sciences of the mind are likely to absorb the
relevant techniques and ideas generated by neurobiology and, having absorbed
them, move on.
This very dichotomy of antidiscipline and parent discipline indicates
how the two disciplines can most fruitfully interact. In this interaction, psychiatry
has a double role. On the one hand, it must seek answers to questions
on its own level—questions related to the diagnosis and treatment of
mental disorders. On the other hand, psychiatry must pose the questions
that its antidiscipline need answer. One of the powers of psychology and
psychiatry, it seems to me, lies in their perspective and, most of all, in their
paradigms, their specific views of certain interrelated variables.
I would like to consider the synergistic interaction between psychiatry
and biology by describing two paradigms that psychology and psychiatry
have defined for neurobiology and that are now being addressed on the cellular
level: the effects on later development of certain types of social and sensory
deprivation in early life, and the mechanisms of learning.
These two classes of studies are paradigmatic in several senses. In purely
behavioral terms, the studies represent examples of the sorts of issues that
behavioral science in general and psychiatry in particular must summarize
and call to the attention of neurobiology. In addition, the studies are interesting
from a methodologic point of view because they illustrate how behavioral
models must be simplified and redefined so that they can be effectively
tackled on progressively more mechanistic levels.
Deprivation in Early Childhood
Experiments ranging from complex ones in the human infant to simple ones
in laboratory animals have documented the existence of a set of critical
stages for normal psychologic development. During these stages, the subject
must interact with a normal social and perceptual environment if development
is to proceed normally. Unless animals and human beings are raised for
the first year (or longer) in what the psychoanalyst Heinz Hartmann (1958)
first called “an average expectable environment,” later social and sensory development
is disrupted, sometimes disastrously.
Before formal studies on maternal deprivation were performed, a few anecdotal
examples of social isolation were collected by anthropologists and
clinicians. From time to time, children had been discovered living in an attic
or a cellar, with minimal social contact, perhaps spending only a few minutes
Psychotherapy and the Single Synapse 9
a day with a caretaker, a nurse, or a parent. Children so deprived in early
childhood are often later found to be speechless and lacking in social responsiveness.
It is difficult, however, to analyze exactly what went wrong
with these children. One often does not know whether the child was severely
retarded mentally from the beginning. In addition, one does not know the
nature or degree of social isolation. But further information on isolation has
been gained from studies of children reared in public institutions.
In a classic series of studies, the psychoanalyst René Spitz compared the
development of infants raised in a foundling home for abandoned children
with the development of infants raised in a nursing home attached to a
women’s prison (Spitz 1945, 1946; Spitz and Wolf 1947). Both institutions
were reasonably clean and provided adequate food and medical care. The babies
in the nursing home were all cared for by their mothers. Because they
were in prison and away from their families, the mothers tended to pour affection
onto their infants in the time allotted each day. By contrast, in the
foundling home, the infants were cared for by nurses, each of whom was responsible
for seven infants. As a result, the children in the foundling home
had much less contact with other human beings than did those in the nursing
home. The two institutions also differed in another respect. In the nursing
home the cribs were open, and the infants could readily watch the
activity in the ward. They could see other babies playing and observe the
mothers and staff going about their business. In the foundling home, the
bars of the cribs were covered with sheets that prevented the infants from
seeing outside and thus dramatically reduced the sensory environment. In
short, the children in the foundling home lived under conditions of sensory,
as well as social, deprivation.
Spitz followed a group of infants at the two institutions from birth
through their early years. At the end of the first 4 months of life, the children
in the foundling home scored better than those in the nursing home on a
number of developmental indices. This difference suggested to Spitz that genetic
factors did not favor the infants in the nursing home. However,
8 months later, at the end of the first year, the children in the foundling
home had fallen far below those in the nursing home, and syndromes developed
that Spitz, like Eckstein-Schlossmann (1926) before him, called “hospitalism”
(now often called “anaclitic depression”). The children were
withdrawn, they showed little curiosity or gaiety, and they were highly susceptible
to infection. In the second and third years of life, when the children
in the nursing home were walking and talking like family-reared children,
the children in the foundling home were retarded in their development and
showed slowed reactions to external stimuli. Only two of 26 children in the
foundling home were able to walk, only these two spoke out at all, and even
they could say only a few words. Normal children at this age are fairly agile,
10 Psychiatry, Psychoanalysis, and the New Biology of Mind
speak hundreds of words, and can construct sentences (Bloom 1970).
Although Spitz’s studies have been criticized for their methodologic
weakness (Pinneau 1955), several aspects of the studies have been confirmed
(Bowlby 1975; Dennis 1960; Engel and Reichsman 1956; Provence
and Lipton 1962). For example, in a study of an orphanage in Teheran where
social and sensory stimulation were minimal, Dennis (1960) found that 60%
of the 2-year-olds were not capable of sitting up unassisted, and 85% of the
4-year-olds were not yet walking on their own. The studies of Spitz thus
stand as a landmark; they define a paradigm that has since been studied repeatedly
and profitably.
The next step was to develop an animal model of infant social isolation.
This step was taken accidentally by Margaret and Harry Harlow, two psychologists
working at the University of Wisconsin. In an attempt to raise a
stock of sturdy and disease-free monkeys for experimental work, the Harlows
separated the infant monkeys from their mothers a few hours after
birth, to feed them a special formula and rear them with special hygienic precautions.
The newborn monkeys were fed daily by remote control and observed
through one-way mirrors. Monkeys reared in isolation for a year
proved to be seriously impaired socially and psychologically. When returned
to the monkey colony, an isolated monkey did not play with other monkeys,
and its grooming and other social interactions were minimal. When attacked,
the monkey did not defend itself. Much of its activity was selfdirected
and consisted of self-clasping, self-mouthing, and self-mutilating
acts, such as chewing on its fingers and toes. It also tended to crouch in a
corner and rock back and forth in a manner reminiscent of autistic children.
When these monkeys reached sexual maturity they did not mate, and several
mature females that were artificially inseminated ignored their offspring.
This profound social and psychologic damage resulted from only 6 months
of total isolation during the first years. Comparable periods of isolation in
later life had little effect on social behavior. These findings suggest that in
monkeys, as in human beings, there is a critical period for social development
(Harlow 1958; Harlow et al. 1965; Suomi and Harlow 1975).
The Harlows next sought to determine what ingredients had to be introduced
into the isolation experience to prevent the development of the isolation
syndrome. They found that giving the isolated monkey a surrogate
mother, a cloth-covered wooden dummy, elicited clinging behavior in the
isolate but was insufficient to allow the emergence of normal social behavior.
Social development occurred normally only if, in addition to a surrogate
mother, the isolated monkey had contact, for a few hours each day, with a
peer who spent the rest of its day in the monkey colony. Recently, Suomi and
Harlow (1975) found that the syndrome can sometimes be fully reversed by
certain monkey psychotherapists—monkeys with certain specific characterPsychotherapy
and the Single Synapse 11
ologic traits. However, unlike the traits that Dr. Semrad nurtured in his residents,
the characteristics of a successful monkey psychotherapist include
an obstinate and truculent pursuit, an unmitigated insistence on continued
interaction with the socially withdrawn monkey, until the isolate responds,
after 6 months of “therapy,” with an apparent flight into health—almost, as
it were, out of desperation.
Even restricted sensory deprivation has dire consequences, again, initially
revealed through clinical studies. In 1932, von Senden summarized the
literature on children born with congenital cataracts that were removed
much later in life. The cataracts deprived these children of patterned visual
experience but allowed them to see diffuse light. Tested after removal of the
cataracts in the teenage years or later, they could not discriminate patterns
well. They learned readily to recognize color but had only a limited ability
to discriminate forms. Some required months to distinguish a square from a
circle. Some never learned to recognize people whom they saw daily (Wertheimer
Similar results were later obtained in monkeys by Austin Riesen and his
colleagues, who reared newborn chimpanzees in the dark: by 3–4 months of
age, the normal chimpanzee readily learns to discriminate among visual
stimuli and between friends and strangers (Riesen 1958). The infant chimpanzee
recognizes and welcomes its caretaker but shows fear and avoidance
of strangers. A chimpanzee reared in the dark for over a year and then restored
to a normal environment does not learn readily to recognize and
avoid objects and cannot discriminate vertical from horizontal lines. Only
after weeks of living in a normal environment does the animal learn to distinguish
friend from foe. These abnormal responses are not due simply to the
absence of sensory stimulation early in life but are due to the absence of patterns
of stimulation. A chimpanzee brought up with sensory stimulation in
the form of an unbroken field of light, produced by enclosing the head in a
translucent dome of plastic that permits normal intensity of stimulation
without the contours of the normal visual environment, is just as blind as
the animal reared in darkness. Thus, the development of normal perception—
that is, the capacity to distinguish between objects in the visual
world—requires exposure to patterned visual stimulation early in infancy.
How is this accomplished? Can we begin to relate the interaction between
the perceptual environment and the brain during the critical period
to the function of individual nerve cells? In an imaginative series of studies
in newborn kittens and monkeys, Hubel and Wiesel examined the effects of
visual deprivation on cellular responses in the primary visual (striate) cortex
(Hubel 1967; Hubel and Wiesel 1977; Hubel et al. 1977; Wiesel and Hubel
1963). They found that a normal adult monkey has good binocular interaction.
Most cells in the cortex respond to an appropriate stimulus presented
12 Psychiatry, Psychoanalysis, and the New Biology of Mind
to either the left or right eye; only a small proportion respond exclusively to
one eye or the other (Figure 1–1 and Figure 1–2). However, if a monkey is
raised from birth to 3 months with one eyelid sutured closed, the animal will
be permanently blind in that eye. Electrical recordings made from single
nerve cells in the striate cortex after removal of the occluding sutures show
that the affected eye has lost its ability to control cortical neurons. Only a
very few cells can be driven from the deprived eye. Similar visual deprivation
in an adult has no effect on vision.
Hubel and Wiesel next found that visual deprivation in newborn monkeys
profoundly alters the organization of the ocular-dominance columns.
Normally, the fibers from the lateral geniculate nucleus for each eye end in
separate and alternating areas of the cortex, giving rise to equal-sized columns
dominated alternately by one or the other eye (Figure 1–3A). The radioautographic
data of Hubel and Wiesel show that after deprivation, the
columns receiving input from the normal eye are much widened at the expense
of those receiving input from the deprived eye (Figure 1–3B). As indicated
in Figure 1–3, these changes may occur because the geniculate cells
that receive input from the closed eye regress and lose their connections
with cortical cells, whereas the geniculate cells that receive input from the
opened eye sprout and connect to cortical cells previously occupied by input
from the other eye.
These studies have provided direct evidence that sensory deprivation
early in life can alter the structure of the cerebral cortex. What I find particularly
interesting is that Hubel and Wiesel had physiologic evidence for the
effect of sensory deprivation in 1965. Using standard techniques, they failed
at that time to find any evidence of structural changes in the cortex. Only in
1970, with the development of new radioautographic labeling techniques
for mapping connections among neurons (Cowan et al. 1972), were they
able to demonstrate the disturbance anatomically. Thus, in a larger sense,
their studies make us realize that we are just beginning to explore the structural
organization of the brain and the alterations that may be caused by experience
and by disease. It is no wonder that an understanding of the
biologic basis of most forms of mental illness has been beyond our reach until
It will be interesting, in the future, to see whether social deprivation of
the sort studied by Harlow leads to deterioration or distortion of connections
in other areas of the brain.
Learning in the Adult
The effect of patterning of environmental experience on brain function is, of
course, not limited to early development. Sensory and social stimuli conPsychotherapy
and the Single Synapse 13
stantly impinge on the brain and produce consequences of varying intensity
and duration. The most clear-cut and best understood of these consequences
is learning. Learning is defined as a prolonged or even relatively permanent
change in behavior that results from repeated exposure to a pattern of stimulation
(Thorpe 1956). I use learning as my second example of the effects of
patterning because I believe that the mechanisms of learning represent a key
FIGURE 1–1. Diagram of the retinal geniculocortical pathway in
higher mammals, showing that the input from the two eyes is segregated
until integration is achieved by neurons in the visual cortex.
The left half of each retina is indicated by a solid line for the right eye and a dotted
line for the left eye. The axons of cells in the lateral geniculate body form synaptic
connections with neurons in the striate (visual) cortex. These cortical neurons are organized
into separate columns and receive input from only one eye, but their axons
are sent to adjacent columns as well as along their own column. This effect creates a
mixing of inputs and allows most cells in the cortex to receive input from both eyes.
14 Psychiatry, Psychoanalysis, and the New Biology of Mind
Psychotherapy and the Single Synapse 15
to an understanding of character development and of the amelioration of
characterologic disorders produced by psychotherapeutic intervention.
The ability to learn from experience is certainly the most remarkable aspect
of human behavior. We are in many ways the embodiment of what we
have learned. In man as well as other animals, most forms of behavior involve
some aspects of learning and memory. Moreover, many psychologic
and emotional problems are thought to be learned—that is, they are thought
to result, at least in part, from experience. And insofar as psychotherapeutic
intervention is successful in treating mental disorders, it presumably succeeds
by creating an experience that allows people to change.
As in studies of social and sensory deprivation, the major questions in
biologic studies of behavior and learning were first posed 70 years ago, but
the ability to answer them was gained only recently. Here, as in investigations
of the critical developmental period, this ability came with progressively
simpler experimental systems. The most consistent progress has
FIGURE 1–2. Binocular interaction and plasticity in the monkey’s
visual cortex (opposite page).
Part A shows a receptive field of a typical neuron in the visual (striate) cortex as
mapped from the left eye (1a) and from the right eye (2a). The neuron responds with
a train of action potentials to a diagonal bar of light moving to the left. Each diagram
shows the visual field as seen by one eye. Although the two are superimposed, they
are drawn separately here for clarity. The fields in the two eyes are similar in orientation,
position, shape, and size and respond to the same form of stimulus, in this case,
a moving bar. The cell responds more effectively when the stimulus is presented to
the ipsilateral eye (A2b) than to the contralateral eye (A1b). F denotes the location
of the foveal region in the visual field.
On the basis of the responses illustrated in A, Hubel and Wiesel divided the response
properties of cortical neurons into the seven ocular-dominance groups in B. If a cell
(small circles) in the visual cortex is influenced only by the contralateral eye (c), it
falls into Group 1. If it receives input only from the ipsilateral eye (i), it falls into
Group 7. For the intermediate groups, one eye may influence the cell much more
than the other (Groups 2 and 6), or the differences may be slight (Groups 3 and 5).
According to these criteria, the cell in A would fall into Group 6.
Part C shows ocular-dominance histograms in normal and monocular monkeys. The
histogram in C1 is based on 1,256 cells recorded from area 17 in normal adult and
juvenile monkeys. The cells in layer 4 were excluded. The histogram in C2 was obtained
from one monkey in which the right eye was closed for 2 weeks to 18 months,
and recordings were made from the left hemisphere. The shadings in the histogram
indicate cells with abnormal responses.
Source. Adapted from Hubel 1967, Hubel and Wiesel 1977, Hubel et al. 1977, and
Wiesel and Hubel 1963.
16 Psychiatry, Psychoanalysis, and the New Biology of Mind
resulted from studies of two simple forms of nonassociative learning: habituation
and sensitization. Each of these forms is evident in human beings but
can also be explored effectively in a variety of simple animal models. I will
first consider habituation.
Habituation, perhaps the simplest form of learning, is a decrease in a behavioral
response resulting from repeated presentation of the initiating stimulus.
A common example is the habituation of an “orienting response” to a new
stimulus. When a novel stimulus such as a loud noise is presented for the first
time, one’s attention is immediately drawn to it, and one’s heart rate and respiratory
rate increase. If the same noise is repeated, one rapidly learns to recognize
the sound and one’s attention and bodily responses gradually diminish
(that is why one can become accustomed to working in a noisy office). In this
sense, habituation is learning to recognize and to ignore stimuli that have lost
novelty or meaning. Besides being important in its own right, habituation is
frequently involved in more complex learning, which includes not only acquiring
new responses but also eliminating incorrect responses.
The first approach to an animal model of habituation was made by Sherrington
in 1906. In the course of studying the behavior underlying posture
FIGURE 1–3. Diagram showing changes in the dimensions of the
cortical columns for eye preference after closure of the left eye.
After deprivation, the columns receiving input from the normal (right) eye are widened
at the expense of those receiving input from the deprived (left) eye.
Psychotherapy and the Single Synapse 17
and locomotion, he observed that habituation of certain reflex forms of behavior,
such as the flexion withdrawal of a limb to stimulation of the skin,
occurred with repeated stimulation and that recovery occurred only after
many seconds of rest. With characteristic prescience, Sherrington suggested
that the habituation of the withdrawal reflex was due to a functional decrease
in the effectiveness of the set of synapses through which the motor
neurons for the behavior were repeatedly activated. This problem was subsequently
reinvestigated by Spencer, Thompson, and Neilson, who found
close parallels between habituation of the spinal reflexes in the cat and habituation
of more complex behavioral responses in man (Spencer et al.
1966). Moreover, by recording intracellularly from motor neurons, Spencer
and his colleagues began the modern study of habituation. They found, as
Sherrington had suggested, that the depression of the behavior was due to a
decrease in the synaptic convergence onto the motor cells. However, the central
synaptic pathways of the flexion-withdrawal reflex in the cat are complex,
involving many as yet unspecified connections through interneurons.
As a result, further analysis of habituation has required still simpler systems
in which the behavioral response can be reduced to one or a series of monosynaptic
My colleagues and I have extended the analyses of habituation and sensitization
in studies of the marine snail Aplysia californica. This animal has
a defensive withdrawal reflex of its respiratory organ, the gill, which is similar
to the defensive reflexes of mammals, and habituation of this reflex
shows all the features that characterize habituation in vertebrates, including
man (Kandel 1976; Pinsker et al. 1970). Moreover, the wiring diagram of
this behavior is remarkably simple, consisting of 6 identified motor neurons
that mediate the behavior and a group of 24 sensory neurons that connect
directly onto the motor neurons. There are also several interneurons that receive
input from the sensory neurons and converge on the motor neurons
(Figure 1–4). Activity in a sensory neuron leads to release of a chemical
transmitter substance that interacts with the receptors on the external membrane
of the motor cell and reduces its membrane potential. If the membrane
potential is reduced sufficiently, the motor cell will fire an action potential.
The synaptically produced reduction in membrane potential is therefore
called an excitatory synaptic potential (Eccles 1964). In response to the first
stimulus, the sensory neurons produce large excitatory synaptic potentials
in the motor cells, causing these cells to discharge rapidly and produce a
brisk withdrawal. With habituation training, the synaptic potential in the
motor cell gradually becomes smaller; it produces fewer spikes, and the behavior
is reduced. Finally, the synaptic potential becomes very small, at
which point no behavior is produced. After a single training session involving
10 stimuli, the memory for this event (as evidenced by a reduced synap18
Psychiatry, Psychoanalysis, and the New Biology of Mind
tic potential and behavior) is short, persisting for only minutes or hours.
However, after four repeated training sessions spaced over consecutive days,
the memory for habituation is prolonged, persisting for more than 3 weeks.
The critical change underlying short-term habituation occurs at the excitatory
chemical synapses that the sensory neurons make on the motor neurons.
With repeated stimulation, these synapses become less effective
functionally because they release progressively less transmitter. Transmitter
release depends on the influx of calcium into the terminals with each action
potential. Analyses of the mechanisms that produce habituation indicate
that the reduced output of neurotransmitter and the resultant depression of
synaptic transmission is caused by a prolonged decrease in calcium influx
(Klein and Kandel 1978).
What are the limits of this plasticity? How much can the effectiveness of
a given synapse change, and how long can such a change endure? Can longterm
habituation produce a complete and prolonged inactivation of a previously
functioning synapse? In an effort to answer these questions, the connections
between the sensory neurons and a given motor neuron were
compared in control animals and animals examined after the acquisition of
long-term habituation (Castellucci et al. 1978). In the control animals, 90%
of sensory neurons produced detectable connections to the major motor
FIGURE 1–4. Diagram indicating the neural circuit for the gillwithdrawal
reflex in Aplysia californica.
Of about 24 mechanoreceptor sensory neurons that innervate the siphon skin, only
one is shown for the purpose of simplification. In this reflex, the site of the plasticity
(hatched triangles) underlying habituation is at the terminals of the sensory neurons
on the central target cells—the interneurons and the motor neurons.
Psychotherapy and the Single Synapse 19
cells (Figure 1–5). By contrast, after long-term habituation, only 30% of the
sensory neurons produced detectable connections onto the motor cell, and
this effect lasted for over a week; these connections were only partially restored
at 3 weeks. Thus, fully functioning synaptic connections were inactivated
for over a week as a result of a simple learning experience—several
brief sessions of habituation training of 10 trials each.
Thus, whereas short-term habituation involves a transient decrease in
synaptic efficacy, long-term habituation leads to prolonged and profound
functional inactivation of a previously existing connection. These data provide
direct evidence that long-term change in synaptic efficacy can underlie
a specific instance of long-term memory. Moreover, at a critical synapse such
as this one, relatively few stimuli produce long-term synaptic depression.
Sensitization, the opposite of habituation, is the process whereby an animal
learns to increase a given reflex response as a result of a noxious or novel
stimulus. Thus, sensitization requires the animal to attend to stimuli that potentially
produce painful or dangerous consequences. Like habituation, sensitization
can last from minutes to days and weeks, depending on the pattern
of stimulation (Pinsker et al. 1973). In this discussion, I will focus on the
short-term form.
At the cellular level, sensitization also involves altered transmission at
the synapses made by the sensory neurons on their central target cells. Specifically,
sensitization involves a mechanism called presynaptic facilitation,
whereby the neurons mediating sensitization end on the terminals of the
sensory neurons and enhance their ability to release transmitter (Figure 1–6).
Thus, the same synaptic locus is regulated in opposite ways by opposing
forms of learning: it is depressed by habituation and enhanced by sensitization.
The transmitter released by the neurons that mediate presynaptic facilitation
(which is thought to be serotonin) acts on the terminals of the
sensory neurons to increase the level of cyclic AMP (cAMP). Cyclic AMP, in
turn, acts (perhaps through phosphorylation of a membrane channel) to increase
calcium influx and thereby enhance transmitter release (Brunelli et al.
1976; Cedar and Schwartz 1972; Cedar et al. 1972; Hawkins et al. 1976;
Klein and Kandel 1978; Schwartz et al. 1971) (Figure 1–7).
How effective a restoring force is sensitization? Can it restore the completely
inactivated synaptic connections produced by long-term habituation?
We have found that study sensitization not only reversed the depressed
behavior but restored the effectiveness of synapses that had been functionally
disconnected and would have remained so for over a week (Carew et al.
1979) (Figure 1–6B).
20 Psychiatry, Psychoanalysis, and the New Biology of Mind
Psychotherapy and the Single Synapse 21
Thus, in these simple instances, learning does not involve a dramatic
anatomic rearrangement in the nervous system. No nerve cells or even synapses
are created or destroyed. Rather, learning of habituation and sensitization
changes the functional effectiveness of previously existing chemical
synaptic connections and, in these instances, does so simply by modulating
calcium influx in the presynaptic terminals. Thus, a new dimension is introduced
in thinking about the brain. These complex pathways, which are
genetically determined, appear to be interrupted not by disease but by experience,
and they can also be restored by experience.
Implications for the Classification and
Understanding of Psychiatric Disorders
The finding that dramatic and enduring alterations in the effectiveness of
connections result from sensory deprivation and learning leads to a new way
of viewing the relation between social and biologic processes in the generation
of behavior. There is a tendency in psychiatry to think that biologic determinants
of behavior act on a different “level of the mind” than do social
and functional determinants. For example, it is still customary to classify
psychiatric illnesses into two major categories: organic and functional. The
organic mental illnesses include the dementias and the toxic psychoses; the
functional illnesses include the various depressive syndromes, the schizophrenias,
and the neuroses. This distinction stems from studies in the nineteenth
century, when neuropathologists examined the brains of patients at
autopsy and found a disturbance in brain architecture in some diseases and
a lack of disturbance in others. The diseases that produced clear (gross) ev-
FIGURE 1–5. Long-term habituation (opposite page).
In A, a synaptic connection between a sensory neuron (S.N.) and the motor neuron
(M.N.) L7 is compared in control (untrained) animals and in animals that have been
subjected to long-term habituation training. In control animals, the synaptic connections
produce a large excitatory synaptic potential. The synaptic connection in habituated
animals is undetectable. The sensory neuron was depolarized intracellularly to
trigger a single action potential and evoke a synaptic potential in the gill motor neuron
In B, the mean percentage of detectable connections is shown in control and habituated
animals tested at three intervals after long-term habituation training. The error
bars indicate the S.E.M.
Source. Adapted from Castellucci VF, Carew TJ, Kandel ER: “Cellular Analysis of
Long-Term Habituation of the Gill-Withdrawal Reflex of Aplysia californica.” Science
202:1306–1308, 1978. Used with permission.
22 Psychiatry, Psychoanalysis, and the New Biology of Mind
Psychotherapy and the Single Synapse 23
idence of brain lesions were called organic, and those that lacked these features
were called functional. Studies of the critical developmental period and
of learning have shown that this distinction is artificial. Sensory deprivation
and learning have profound biologic consequences, causing effective disruption
of synaptic connections under some circumstances and reactivation of
connections under others. Instead of distinguishing between mental disorders
along biologic and nonbiologic lines, it might be more appropriate to
ask, in each type of mental illness, to what degree is this biologic process determined
by genetic and developmental factors, to what degree is it due to
infectious or toxic agents, and to what degree is it socially determined? In
each case, even in the most socially determined neurotic illness, the end result
is biologic. Ultimately, all psychologic disturbances reflect specific alterations
in neuronal and synaptic function. And insofar as psychotherapy
works, it works by acting on brain functions, not on single synapses, but on
synapses nevertheless. Clearly, a shift is needed from a neuropathology also
based only on structure to one based on function.
An Overview
Cellular studies of the critical stages of development and of learning have
shown that genetic and developmental processes determine the connections
between neurons; what they leave unspecified is the strength of the connections.
It is this factor—the long-term efficacy of synaptic connections—that
is played on by environmental effects such as learning. What learning accomplishes
in the instances so far studied is to alter the effectiveness of preexisting
pathways, thereby leading to the expression of new patterns of
behavior. As a result, when I speak to someone and he or she listens to me,
we not only make eye contact and voice contact but the action of the neu-
FIGURE 1–6. Scheme of circuit for presynaptic facilitation (A)
and restoration of synaptic transmission and behavior by a sensitizing
stimulus after long-term habituation (B) (opposite page).
In A, stimuli to the head activate neurons that excite facilitative interneurons (Fac.
Int.). The facilitating cells, in turn, end on the synaptic terminals of the sensory neurons
(S.N.), where they modulate transmitter release. Exc. Int. denotes excitatory interneurons,
and M.N. motor neuron.
In B, a typical undetectable excitatory synaptic potential from a habituated animal
and a typical detectable excitatory postsynaptic potential from a sensitized animal are
Source. Adapted from Carew T, Castellucci VF, Kandel ER: “Sensitization in Aplysia:
Restoration of Transmission in Synapses Inactivated by Long-Term Habituation.” Science
205:417–419, 1979. Used with permission.
24 Psychiatry, Psychoanalysis, and the New Biology of Mind
ronal machinery in my brain is having a direct and, I hope, long-lasting effect
on the neuronal machinery in his or her brain, and vice versa. Indeed, I
would argue that it is only insofar as our words produce changes in each
other’s brains that psychotherapeutic intervention produces changes in patients’
minds. From this perspective, the biologic and psychologic approaches
are joined. I would hope that the deep-seated dualism that once
caused psychiatry and neurobiology to split into hard-nosed and soft-nosed
attitudes will prove to be only a transient interlude in the history of psychiatry.
Certainly, in their day, Meynert, Wagner-Jauregg, and Freud had little
difficulty in appreciating philosophically what my residency cohort and
I lost sight of and what we can now again assert, perhaps with slightly more
sophistication: what we conceive of as our mind is an expression of the functioning
of our brain.
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Thomas R. Insel, M.D.
In “A New Intellectual Framework for Psychiatry,” Eric Kandel aims to integrate
psychiatry with the biological insights of 1998, specifically addressing
the relationship of cognition and behavior to brain processes (Kandel 1998).
He notes the need to enhance psychiatric training with neuroscientific expertise
and describes the importance of biology for a comprehensive understanding
of mental processes. Kandel provides five principles that frame this
understanding, some of which may have seemed provocative in 1998: 1) all
mental processes are neural, 2) genes and their protein products determine
neural connections, 3) experience alters gene expression, 4) learning changes
neural connections, and 5) psychotherapy changes gene expression. He concludes
this thoughtful paper with a description of “unconscious” processing
in patients with hippocampal lesions, noting that neuroscience might provide
a new framework for psychoanalysis as well as psychiatry in general.
In the 7 years since Kandel’s paper, biology has been transformed by several
landmark events and discoveries, rendering Kandel’s call for integration
28 Psychiatry, Psychoanalysis, and the New Biology of Mind
even more important. The most historic event occurred in 2003 when the
Human Genome Project published the full sequence of the human genome,
mapping 30,000 genes across nearly 3 billion bases of DNA. The human sequence
not only provides an unprecedented opportunity to study how our
species differs from its mammalian relatives, it also demonstrates the remarkable
sequence similarity across humans, with 99.9% homology between
individuals. A current project, the International Haplotype Mapping
Project, is working to describe the nature of human variation, identifying
where the 0.1% of difference between individuals emerges across the
3 billion bases of DNA (The International HapMap Consortium 2003). With
the advent of new technologies for high-throughput sequencing, projects
that in 1998 required tens of thousands of hours (such as the sequencing of
a new microbe) now are routinely completed by a single postdoctoral fellow
in a day.
The past 7 years can also be considered an era of biological pluralism,
sometimes noted as the era of systems biology. Decades of studying a single
gene or a single neurotransmitter have given way to techniques that permit
the measurement of thousands of RNAs or proteins simultaneously. Recall
that the entire body of scientific literature in this field prior to 1998 focused
on roughly 1% of the genome. Indeed, the few neurotransmitters, receptors,
and transporters studied in neuroscience totaled perhaps 30 amines and proteins,
products of less than 0.1% of the genome. We now suspect that 20,000
genes are expressed in the brain, with as many as 6,000 expressed exclusively
in the brain. Not surprisingly, in the past 6 years, much of biology has
moved into a discovery phase, exploring which genes are expressed in the
brain, where and when they are expressed, and how they respond to experience.
Neuroanatomic maps of cytoarchitecture can now be redrawn based
on molecular fingerprints of individual cells and brain nuclei (Zirlinger et
al. 2001). There is no doubt that, as Kandel stated in 1998, 1) genes and proteins
determine neural connections and 2) experience, including psychotherapy,
alters gene expression. The molecular players and the cellular rules
by which neural systems develop and experience alters gene expression are
just being revealed. One thing is already clear: serotonin and dopamine will
be only two of hundreds of important factors that future psychiatrists will
need to know about.
Systems neuroscience has also advanced beyond the study of single electrodes
and single brain regions to the widespread use of multielectrode arrays
and various new imaging techniques to visualize multiple brain regions
simultaneously. The simplistic (and even the complex) network diagrams of
hierarchical organization in the brain have given way to dynamic models of
neural activity, involving abundant recursive connections between brain regions
and subtle temporal and state changes that have been hypothesized to
A New Intellectual Framework for Psychiatry 29
underlie mental function (Abbott 2001). While there is no question that, as
Kandel stated, “all mental processes are neural,” we are now beginning to
understand how neural activity measured in ensembles of cells or in field potentials
of millions of cells binds information together to create memory, attention,
or consciousness (Reynolds and Desimone 2003).
While molecular, cellular, and systems neuroscience have advanced so
rapidly over the past 7 years, has psychiatry embraced or ignored this progress?
Anyone reading the American Journal of Psychiatry during this time will recognize
the abundant findings of psychiatric genetics and the increasing impact
of neuroimaging. The human genome map, the haplotype map, and
rapid genotyping are already beginning to revolutionize our approach to
psychiatric genetics, allowing gene findings from linkage studies and highthroughput
studies of variations in candidate genes associated with psychiatric
illness. While almost no one expects that genetics will discover a Mendelian
“cause” for any of the major mental illnesses, the discovery of
variations associated with vulnerability should reveal the architecture for
each of these illnesses that predisposes for risk, just as we have seen for hypertension
and other genetically complex medical disorders. Similarly, the
profile of gene expression in schizophrenia and bipolar disorder can be investigated
by interrogating thousands of genes in select brain areas (Middleton
et al. 2002).
Neuroimaging of regional function, in vivo neurochemistry, and connectivity
have allowed psychiatric researchers to peer inside the “black box” of
the brain. In this research area, part of the integration with neuroscience that
Kandel hoped for in 1998 has arrived, although thus far cognitive scientists,
not psychiatric patients, have been the chief beneficiaries. Studies with fMRI
have provided remarkable insights into how the brain parses language, recognizes
faces, and encodes emotion. Recent studies have described the neurobiology
of repression (Anderson et al. 2004), romantic love (Bartels and
Zeki 2000), and the unconscious (Henson 2003). But the technology, remarkable
as it is, remains correlational with an unclear relationship to the
millisecond world of neural function. PET studies of receptors and transporters
may be more easily interpreted, but the field lacks many of the radioligands
needed. And Kandel’s call for studies measuring changes in regional
activity with psychotherapy or psychopharmacological treatment remains
largely unanswered (note, however, Goldapple et al. 2004).
While research in psychiatry has begun to embrace the power of molecular,
cellular, and systems neuroscience, this scientific excitement has not
yet influenced clinical practice by refining diagnosis or informing treatment.
Furthermore, these advances have been conspicuously ignored by training
programs. Most psychiatry residency programs remain focused on psychodynamic
psychotherapy or applied psychopharmacology with little expo30
Psychiatry, Psychoanalysis, and the New Biology of Mind
sure to the revolutions occurring in neurobiology or cognitive science.
While many of America’s best colleges have developed departments or majors
in neuroscience, medical schools continue to divide the mind from the
brain, forcing students to choose between psychiatry and neurology. Judging
from recent recruiting statistics, both psychiatry and neurology are stalled,
in spite of the enormous interest in neuroscience from students entering
medical school. The intellectual framework Kandel foresees for psychiatry
may ultimately require that both psychiatry and neurology are reframed as
clinical neuroscience disciplines. Patients with mental disorders—autism,
Tourette’s syndrome, schizophrenia, and bipolar disorder—have brain illnesses.
And patients with Parkinson’s disease, Alzheimer’s disease, and most
neurologic disorders have mental symptoms as core features of their illness.
As Kandel predicted, neuroscience can bring intellectual excitement
back to psychiatry. This is even more evident and more necessary in 2005
than in 1998. The neurobiological tools are available to study the most mysterious
aspects of mental life, including unconscious processes, emotion,
and drives. Genetics may bring validity, not just reliability, to psychiatric diagnosis
helping clinicians to understand the many subtypes of psychosis and
ultimately predicting which treatment is most suitable for each patient. Just
as important, psychiatry can bring to biology and to the rest of medicine an
appreciation for the complexity of mental life. But for Kandel’s vision to be
realized, psychiatry will need to embrace neuroscience, not just as a research
tool but as the scientific basis for clinical training and everyday practice.
Martin Luther King Jr. once remarked that the sad part of the Rip van Winkle
story was not that he awoke to a world that did not recognize him, but that
he slept through the American Revolution (King 1959). Let us hope, along
with Eric Kandel, that modern psychiatry does not sleep through one of the
most exciting periods of progress in understanding the biological basis of
cognition and behavior.
Abbott LF: The timing game. Nat Neurosci 4:115–116, 2001
Anderson MC, Ochsner KN, Kuhl B, et al: Neural systems underlying the suppression
of unwanted memories. Science 303:232–235, 2004
Bartels A, Zeki S: The neural basis of romantic love. Neuroreport 11:3829–3834,
Goldapple K, Segal Z, Garson C, et al: Modulation of cortical-limbic pathways in major
depression. Arch Gen Psychiatry 61:34–41, 2004
Henson RN: Neuroimaging studies of priming. Prog Neurobiol 70:53–81, 2003
The International HapMap Consortium: The International HapMap Project. Nature
426:789–796, 2003
A New Intellectual Framework for Psychiatry 31
Kandel ER: A new intellectual framework for psychiatry. Am J Psychiatry 155:457–
469, 1998
King ML Jr: “Remaining awake through a great revolution.” Morehouse College
Commencement, June 2, 1959. Available at:
King/liberation_curriculum (document 590602–005). Accessed February 15,
Middleton FA, Mirnics K, Pierri JN, et al: Gene expression profiling reveals alterations
of specific metabolic pathways in schizophrenia. J Neurosci 22:2718–
2729, 2002
Reynolds JH, Desimone R: Interacting roles of attention and visual salience in V4.
Neuron 37:853–863, 2003
Zirlinger M, Kreiman G, Anderson DJ: Amygdala-enriched genes identified by microarray
technology are restricted to specific amygdaloid subnuclei. Proc Natl
Acad Sci USA 98:5270–5275, 2001
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C H A P T E R 2
Eric R. Kandel, M.D.
When historians of science turn their attention to the emergence of molecular
medicine in the last half of the twentieth century, they will undoubtedly
note the peculiar position occupied throughout this period by psychiatry. In
the years following World War II, medicine was transformed from a practicing
art into a scientific discipline based on molecular biology (Pauling et al.
1949). During that same period, psychiatry was transformed from a medical
discipline into a practicing therapeutic art. In the 1950s and in some academic
centers extending into the 1960s, academic psychiatry transiently
This article was originally published in the American Journal of Psychiatry,
Volume 155, Number 4, 1998, pp. 457–469.
This paper is an extended version of an address given on the hundredth anniversary
of the New York State Psychiatric Institute of Columbia University. Received
July 21, 1997; revision received November 4, 1997; accepted November 11, 1997.
From the Howard Hughes Medical Institute and Center for Neurobiology and Behavior,
Departments of Psychiatry and Biochemistry and Molecular Biophysics, Columbia
University College of Physicians and Surgeons.
The author thanks James H. Schwartz and Thomas Jessell for discussions of ideas
considered in this article in the course of work on our joint textbook, Principles of
Neural Science.
34 Psychiatry, Psychoanalysis, and the New Biology of Mind
abandoned its roots in biology and experimental medicine and evolved into
a psychoanalytically based and socially oriented discipline that was surprisingly
unconcerned with the brain as an organ of mental activity.
This shift in emphasis had several causes. In the period after World
War II, academic psychiatry began to assimilate the insights of psychoanalysis.
These insights provided a new window on the richness of human
mental processes and created an awareness that large parts of mental life, including
some sources of psychopathology, are unconscious and not readily
accessible to conscious introspection. Initially, these insights were applied
primarily to what were then called neurotic illnesses and to some disorders
of character. However, following the earlier lead of Eugen Bleuler (1911/
1950) and Carl Jung (1906/1936), the reach of psychoanalytic therapy soon
extended to encompass almost all of mental illness, including the major psychoses:
schizophrenia and the major depressions (Day and Semrad 1978;
Fromm-Reichmann 1948, 1959; Rosen 1963; Rosenfeld 1965).
Indeed, the extension of psychoanalytic psychiatry did not stop here; it
next expanded to include specific medical illnesses (Alexander 1950; Sheehan
and Hackett 1978). Influenced in part by their experience in World
War II, many psychiatrists came to believe that the therapeutic efficacy of
psychoanalytic insights might solve not only the problems of mental illness
but also otherwise intractable medical illnesses such as hypertension,
asthma, gastric ulcers, and ulcerative colitis—diseases that did not readily
respond to the pharmacological treatments available in the late 1940s. These
illnesses were thought to be psychosomatic and to be induced by unconscious
Thus, by 1960 psychoanalytically oriented psychiatry had become the
prevailing model for understanding all mental and some physical illnesses.
When in 1964 Harvard Medical School celebrated the twentieth year of the
psychoanalytically oriented Department of Psychiatry at Beth Israel Hospital,
Ralph Kahana, a member of the faculty of that department, summarized
the leadership role of psychoanalytically oriented psychiatry in the following
way: “In the past 40 years, largely under the impact of psychoanalysis,
dynamic psychotherapy has become the principal and essential curative skill
of the American psychiatrist and, increasingly, a focus of his training” (Kahana
By merging the descriptive psychiatry of the period before World War II
with psychoanalysis, psychiatry gained a great deal in explanatory power
and clinical insight. Unfortunately, this was achieved at the cost of weakening
its ties with experimental medicine and with the rest of biology.
The drift away from biology was not due simply to changes in psychiatry;
it was in part due to the slow maturation of the brain sciences. In the late
1940s, the biology of the brain was neither technically nor conceptually maA
New Intellectual Framework for Psychiatry 35
ture enough to deal effectively with the biology of most higher mental processes
and their disorders. The thinking about the relationship between
brain and behavior was dominated by a view that different mental functions
could not be localized to specific brain regions. This view was espoused by
Karl Lashley (1929), who argued that the cerebral cortex was equipotential;
all higher mental functions were presumed to be represented diffusely
throughout the cortex. To most psychiatrists and even to many biologists,
the notion of the equipotentiality of the cerebral cortex made behavior seem
intractable to empirical biological analysis.
In fact, the separation of psychiatry from biology had its origins even earlier.
When Sigmund Freud (1954) first explored the implications of unconscious
mental processes for behavior, he tried to adopt a neural model of
behavior in an attempt to develop a scientific psychology. Because of the immaturity
of brain science at the time, he abandoned this biological model for
a purely mentalistic one based on verbal reports of subjective experiences.
Similarly, in the 1930s B.F. Skinner rejected neurological theories in his
studies of operant conditioning in favor of objective descriptions of observable
acts (Skinner 1938).
Initially, this separation may have been as healthy for psychiatry as it was
for psychology. It permitted the development of systematic definitions of behavior
and of disease that were not contingent on still-vague correlations
with neural mechanisms. Moreover, by incorporating the deep concern of
psychoanalysis for the integrity of an individual’s personal history, psychoanalytic
psychiatry helped develop direct and respectful ways for physicians
to interact with mentally ill patients, and it led to a less stigmatized social
perspective on mental illness.
However, the initial separation of psychoanalysis from neural science advocated
by Freud was stimulated by the realization that a merger was premature.
As psychoanalysis evolved after Freud—from being an investigative
approach limited to a small number of innovative thinkers to becoming the
dominant theoretical framework in American psychiatry—the attitude toward
neural science also changed. Rather than being seen as premature, the
merger of psychoanalysis and biology was seen as unnecessary, because neural
science was increasingly considered irrelevant.
Moreover, as the limitations of psychoanalysis as a system of rigorous,
self-critical thought became apparent, rather than confronting these limitations
in a systematic, questioning, experimental manner, and perhaps
rejoining biology in searching for newer ways of exploring the brain, psychoanalytic
psychiatry spent most of the decades of its dominance—the period
from 1950 to 1980—on the defensive. Although there were important
individual exceptions, as a group, psychoanalysts devalued experimental inquiry.
Consequently, psychoanalysis slid into an intellectual decline that has
36 Psychiatry, Psychoanalysis, and the New Biology of Mind
had a deleterious effect on psychiatry, and because it discouraged new ways
of thought, it has had a particularly deleterious effect on the training of psychiatrists.
Let me illustrate with a personal example the extent to which this unquestioning
attitude came to influence my own psychiatry training. In the
summer of 1960, I left my postdoctoral training in neural science at the National
Institutes of Health (NIH) to begin residency training at the Massachusetts
Mental Health Center, the major psychiatric teaching hospital of
Harvard Medical School. I entered training together with 20-odd other
young physicians, many of whom went on to become leaders in American
psychiatry: Judith Livant Rapoport, Anton Kris, Dan Buie, Ernest Hartmann,
Paul Wender, Joseph Schildkraut, Alan Hobson, and George Vaillant. Yet in
the several years in which this outstanding group of physicians was in training,
at a time when training was leisurely and there was still a large amount
of spare time, there were no required or even recommended readings. We
were assigned no textbooks; rarely was there a reference to scientific papers
in conferences or in case supervision. Even Freud’s papers were not recommended
reading for residents.
Much of this attitude came from our teachers, from the heads of the residency
program. They made a point of encouraging us not to read. Reading,
they argued, interfered with a resident’s ability to listen to patients and therefore
biased his or her perception of the patients’ life histories. One famous,
much quoted remark was that “there are those who care about people and
there are those who care about research.” Through the efforts of the heads of
the residency program, the whole thrust of psychoanalytic psychiatry at the
Massachusetts Mental Health Center, and perhaps at Harvard Medical School
in general, was not simply to develop better psychiatrists but to develop better
therapists—therapists prepared to understand and empathize with the
patients’ existential problems.
This view was summarized in 1978 by Day and Semrad in the following
The essence of therapy with the schizophrenic patient is the interaction between
the creative resources of both therapist and patient. The therapist
must rely on his own life experience and translate his knowledge of therapeutic
principles into meaningful interaction with the patient while recognizing,
evoking, and expanding the patient’s experience and creativity; both
then learn and grow from the experience.
In order to engage a schizophrenic patient in therapy, the therapist’s basic
attitude must be an acceptance of the patient as he is—of his aims in life, his
values, and his modes of operating, even when they are different and very often
at odds with his own. Loving the patient as he is, in his state of decompensation,
is the therapist’s primary concern in approaching the patient. As
a result the therapist must find his personal satisfactions elsewhere. His job
A New Intellectual Framework for Psychiatry 37
is extremely taxing in its contradictions, for he must love the patient, expect
him to change, and yet derive his additional satisfactions elsewhere and tolerate
In small measure this advice was sound, even in retrospect. A humane
and compassionate perspective taught one to listen carefully and insightfully
to one’s patients. It helped us to develop the empathy essential for all aspects
of a therapeutic relationship. But as a framework for a psychiatric education
designed to train leaders in academic psychiatry, it was incomplete. For almost
all residents it was intellectually limiting, and for some talented residents
it proved stifling.
The almost unrealistic demand for empathy left little room for intellectual
content. There were, for example, no grand rounds at the Massachusetts
Mental Health Center. No outside speakers were invited to address the house
officers on a regular basis to discuss current clinical or scientific issues. The
major coordinated activity for the residents was a weekly group therapy session
(with a wonderful and experienced group leader) in which the residents
constituted the members of the group—the patients, so to speak.
It was only through the insistence of the house staff and their eagerness for
knowledge that the first grand rounds were established at the Massachusetts
Mental Health Center in 1965. To initiate these rounds, several of us tried to
recruit a psychiatrist in the Boston area to speak about the genetic basis of
mental illness. We could find no one; not a single psychiatrist in all of Boston
was concerned with or even had thought seriously about that issue. We finally
imposed on Ernst Mayr, the great Harvard biologist and a friend of Franz Kallmann,
a founder of psychiatric genetics, to come and talk to us.
I am providing here an oversimplified description of the weakness of an
environment that had many excellent qualities and many strengths. The intellectual
quality of the house officers was remarkable, and the commitment of
the faculty to the training of the house staff and to the treatment of the patients
was admirable. Moreover, I am describing the predominant trend at the center;
there were countervailing ones. While the heads of the training program
actively discouraged both reading and research, the director of the center, Jack
Ewalt, strongly encouraged research. Moreover, I have been assured that during
this period Harvard psychiatry was remarkably out of step with the rest of
the country, and that a lack of scholarly concern was not universal within academic
psychiatry nationally. Clearly, scholarly concerns were not lacking at
Washington University under Eli Robins, at a number of other centers in the
Midwest, or at Johns Hopkins University under Seymour Kety (1959). But a
lack of critical questioning seemed to be widespread in Boston and at many
other institutions on the east and west coasts of the country.
Our residency years—the decade of the 1960s—marked a turning point
in American psychiatry. To begin with, new and effective treatments, in the
38 Psychiatry, Psychoanalysis, and the New Biology of Mind
form of psychopharmacological drugs, began to be available. Initially, a
number of supervisors discouraged us from using them, believing that they
were designed more to aid our anxiety than that of the patients. By the mid-
1970s, the therapeutic scene had changed so dramatically that psychiatry
was forced to confront neural science if only to understand how specific
pharmacological treatments were working.
With the advent of psychopharmacology, psychiatry was changed, and
that change brought it back into the mainstream of academic medicine.
There were three components to this progress. First, whereas psychiatry
once had the least effective therapeutic armamentarium in medicine, it now
had effective treatments for the major mental illnesses and something that
began to approach a practical cure for two of the three most devastating diseases:
depression and manic-depressive illness. Second, led first by Eli Robins
at Washington University and then by Robert Spitzer at Columbia
University’s New York State Psychiatric Institute, new clinically validated
and objective criteria were established for diagnosing mental illness. Third,
Seymour Kety used his leadership position at NIH to spark a renewed interest
in the biology of mental illness and specifically in the genetics of schizophrenia
and depression.
In parallel, the years since 1980 have witnessed major developments in
brain sciences, in particular in the analysis of how different aspects of mental
functioning are represented by different regions of the brain. Thus, psychiatry
is now presented with a new and unique opportunity. When it comes to
studying mental function, biologists are badly in need of guidance. It is here
that psychiatry, and cognitive psychology, as guide and tutor, can make a
particularly valuable contribution to brain science. One of the powers of
psychiatry, of cognitive psychology, and of psychoanalysis lies in their perspectives.
Psychiatry, cognitive psychology, and psychoanalysis can define
for biology the mental functions that need to be studied for a meaningful and
sophisticated understanding of the biology of the human mind. In this interaction,
psychiatry can play a double role. First, it can seek answers to questions
on its own level, questions related to the diagnosis and treatment of
mental disorders. Second, it can pose the behavioral questions that biology
needs to answer if we are to have a realistically advanced understanding of
human higher mental processes.
A Common Framework for
Psychiatry and the Neural Sciences
As a result of advances in neural science in the last several years, both psychiatry
and neural science are in a new and better position for a rapprochement,
a rapprochement that would allow the insights of the psychoanalytic
A New Intellectual Framework for Psychiatry 39
perspective to inform the search for a deeper understanding of the biological
basis of behavior. As a first step toward such a rapprochement, I here outline
an intellectual framework designed to align current psychiatric thinking and
the training of future practitioners with modern biology.
This framework can be summarized in five principles that constitute, in
simplified form, the current thinking of biologists about the relationship of
mind to brain.
Principle 1. All mental processes, even the most complex psychological
processes, derive from operations of the brain. The central tenet of this view
is that what we commonly call mind is a range of functions carried out by
the brain. The actions of the brain underlie not only relatively simple motor
behaviors, such as walking and eating, but all of the complex cognitive actions,
conscious and unconscious, that we associate with specifically human
behavior, such as thinking, speaking, and creating works of literature, music,
and art. As a corollary, behavioral disorders that characterize psychiatric
illness are disturbances of brain function, even in those cases where the
causes of the disturbances are clearly environmental in origin.
Principle 2. Genes and their protein products are important determinants
of the pattern of interconnections between neurons in the brain and the details
of their functioning. Genes, and specifically combinations of genes, therefore
exert a significant control over behavior. As a corollary, one component contributing
to the development of major mental illnesses is genetic.
Principle 3. Altered genes do not, by themselves, explain all of the variance
of a given major mental illness. Social or developmental factors also
contribute very importantly. Just as combinations of genes contribute to behavior,
including social behavior, so can behavior and social factors exert actions
on the brain by feeding back upon it to modify the expression of genes
and thus the function of nerve cells. Learning, including learning that results
in dysfunctional behavior, produces alterations in gene expression. Thus all
of “nurture” is ultimately expressed as “nature.”
Principle 4. Alterations in gene expression induced by learning give rise
to changes in patterns of neuronal connections. These changes not only contribute
to the biological basis of individuality but presumably are responsible
for initiating and maintaining abnormalities of behavior that are induced by
social contingencies.
Principle 5. Insofar as psychotherapy or counseling is effective and produces
long-term changes in behavior, it presumably does so through learning,
by producing changes in gene expression that alter the strength of
synaptic connections and structural changes that alter the anatomical pattern
of interconnections between nerve cells of the brain. As the resolution
of brain imaging increases, it should eventually permit quantitative evaluation
of the outcome of psychotherapy.
40 Psychiatry, Psychoanalysis, and the New Biology of Mind
I now consider each of these principles in turn and illustrate the experimental
basis of this new framework and its implications for the theory and
practice of psychiatry.
All Functions of Mind Reflect Functions of Brain
This principle is so central in traditional thinking in biology and medicine
(and has been so for a century) that it is almost a truism and hardly needs
restatement. This principle stands as the basic assumption underlying neural
science, an assumption for which there is enormous scientific support.
Specific lesions of the brain produce specific alterations in behavior, and specific
alterations in behavior are reflected in characteristic functional changes
in the brain (Kandel et al. 1991). Nevertheless, two points deserve emphasis.
First, although this principle is now accepted among biologists, the details
of the relationship between the brain and mental processes—precisely
how the brain gives rise to various mental processes—is understood poorly,
and only in outline. The great challenge for biology and psychiatry at this
point is to delineate that relationship in terms that are satisfying to both the
biologist of the brain and the psychiatrist of the mind.
Second, the relationship of mind to brain becomes less obvious, more
nuanced, and perhaps more controversial when we appreciate that biologists
apply this principle to all aspects of behavior, from our most private
thoughts to our most public expression of emotion. The principle applies to
behaviors by single individuals, to behaviors between individuals, and to social
behavior in groups of individuals. Viewed in this way, all sociology must
to some degree be sociobiology; social processes must, at some level, reflect
biological functions. I hasten to add that formulating a relationship between
social processes (or even psychological processes) and biological functions
might not necessarily prove to be optimally insightful in elucidating social
dynamics. For many aspects of group or individual behavior, a biological
analysis might not prove to be the optimal level or even an informative level
of analysis, much as subatomic resolution is often not the optimal level for
the analysis of biological problems. Nevertheless, it is important to appreciate
that there are critical biological underpinnings to all social actions.
This aspect of the principle has not been readily accepted by all, especially
not by all sociologists, as can be illustrated by one example from the
Center for Advanced Studies in the Behavioral Sciences in Palo Alto, California,
probably the country’s premier think tank in the social sciences. In its
annual report of 1996, the center described the planning of a special project
entitled Culture, Mind, and Biology. As plans for this project progressed, it
became clear that many social scientists had a deep and enduring antipathy
toward the biological sciences because they equated biological thinking with
A New Intellectual Framework for Psychiatry 41
a view of human nature that they found simplistic, misguided, and socially
and ethically dangerous. Since two earlier and influential biological approaches
to the social sciences—scientifically argued racism and social Darwinism—
had proven to be intellectually sterile and socially destructive,
many social scientists objected to the idea. They objected to the notion
that a living organism’s properties (not only its physical form but also its behavioral
inclinations, abilities, and life prospects) are material and hence reducible
to its genes. The conception of human nature that many social
scientists associate with biological thinking asserts that individual and group
differences as well as individual and group similarities in physical form, behavioral
inclination, abilities, and life prospects can similarly be understood
and explained by genes. . . . As a result of this understanding, many disclaim
the relevance of biological thinking for behavior and instead embrace some
type of radical mind-body dualism in which it is assumed that the processes
and products of the mind have very little to do with the processes and products
of the body. (Annual Report, Center for Advanced Studies in the Behavioral
Sciences, 1996; italics added)
What is the basis of this unease among social scientists? Like all knowledge,
biological knowledge is a double-edged sword. It can be used for ill as
well as for good, for private profit or public benefit. In the hands of the misinformed
or the malevolent, natural selection was distorted to social Darwinism,
and genetics was corrupted into eugenics. Brain sciences have also
been and can again be misused for social control and manipulation. How can
we ensure that the advances of the brain sciences will serve to enrich our
lives and to elevate our understanding of ourselves and each other? The only
way to encourage the responsible use of this knowledge is to base the uses
of biology in social policy on an understanding of biology.
The unease of social scientists derives in part from two misapprehensions
(not unique to social scientists): first, that biologists think that biological processes
are strictly determined by genes, and second, that the sole function of
genes is the inexorable transmission of hereditary information from one generation
to another. These profoundly wrong ideas lead to the notion that invariant,
unregulated genes, not modifiable by external events, exert an
inevitable influence on the behavior of individuals and their progeny. In this
view, social forces as such have little influence on human behavior. They are
powerless in the face of the predetermined, relentless actions of the genes.
This fatalistic and fundamentally wrong view was behind the eugenics
movements of the 1920s and 1930s. As a basis for social policy, this view justifiably
elicits fear and distrust in clear-thinking people. However, this view
is based on a fundamental misconception of how genes work, which even
some psychiatrists may not fully appreciate. The key concept of importance
here is that genes have dual functions.
42 Psychiatry, Psychoanalysis, and the New Biology of Mind
First, genes serve as stable templates that can replicate reliably. This template
function is exercised by each gene, in each cell of the body, including
the gametes. It is this function that provides succeeding generations with
copies of each gene. The fidelity of the template replication is high. Moreover,
the template is not regulated by social experience of any sort. It can
only be altered by mutations, and these are rare and often random. This
function of the gene, its template (transmission) function, is indeed beyond
our individual or social control.
Second, genes determine the phenotype; they determine the structure,
function, and other biological characteristics of the cell in which they are expressed.
This second function of the gene is referred to as its transcriptional
function. Although almost every cell of the body has all of the genes that are
present in every other cell, in any given cell type (be it a liver cell or a brain
cell) only a fraction of genes, perhaps 10%–20%, are expressed (transcribed).
All of the other genes are effectively repressed. A liver cell is a liver
cell and a brain cell is a brain cell because each of these cell types expresses
only a particular subset of the total population of genes. When a gene is expressed
in a cell, it directs the phenotype of that cell: the manufacture of specific
proteins that specify the character of that cell.
Whereas the template function, the sequence of a gene—and the ability
of the organism to replicate that sequence—is not affected by environmental
experience, the transcriptional function of a gene—the ability of a given gene
to direct the manufacture of specific proteins in any given cell—is, in fact,
highly regulated, and this regulation is responsive to environmental factors.
A gene has two regions (Figure 2–1). A coding region encodes mRNA,
which in turn encodes a specific protein. A regulatory region usually lies upstream
of the coding region and consists of two DNA elements. The promoter
element is a site where an enzyme, called RNA polymerase, will begin to read
and transcribe the DNA coding region into mRNA. The enhancer element
recognizes protein signals that determine in which cells, and when, the coding
region will be transcribed by the polymerase. Thus, a small number of
proteins, or transcriptional regulators, that bind to different segments of the
enhancer element determine how often RNA polymerase binds to the promoter
element and transcribes the gene. Internal and external stimuli—
steps in the development of the brain, hormones, stress, learning, and social
interaction—alter the binding of the transcriptional regulators to the enhancer
element, and in this way different combinations of transcriptional
regulators are recruited. This aspect of gene regulation is sometimes referred
to as epigenetic regulation.
Stated simply, the regulation of gene expression by social factors makes
all bodily functions, including all functions of the brain, susceptible to social
influences. These social influences will be biologically incorporated in the
A New Intellectual Framework for Psychiatry 43
altered expressions of specific genes in specific nerve cells of specific regions
of the brain. These socially influenced alterations are transmitted culturally.
They are not incorporated in the sperm and egg and therefore are not transmitted
genetically. In humans, the modifiability of gene expression through
learning (in a nontransmissible way) is particularly effective and has led to
a new kind of evolution: cultural evolution. The capability of learning is so
highly developed in humans that humankind changes much more by cultural
evolution than by biological evolution. Measurements of skulls found
in the fossil record suggest that the size of the human brain has not changed
since Homo sapiens first appeared approximately 50,000 years ago; yet
clearly, human culture has evolved dramatically in that same time.
FIGURE 2–1. Genetic transcriptional control.
A: The typical eukaryotic gene has two regions. The coding region is transcribed by
RNA polymerase II into an mRNA and is then translated into a specific protein. The
regulatory region, consisting of enhancer elements and a promoter element, which
contains the TATA box (T=thymidine, A=adenine), regulates the initiation of transcription
of the structural gene.
Transcriptional regulatory proteins bind both the promoter and the enhancer regions.
B1: A set of proteins (such as TATA box factors IIA, IIB, IID, and others) binds
to the TATA box, to the promoter, and to the distal enhancer regions. B2: Proteins that
bind to the enhancer region cause looping of the DNA, thereby allowing the regulatory
proteins that bind to distal enhancers to contact the polymerase.
Source. Adapted from Schwartz and Kandel 1995.
44 Psychiatry, Psychoanalysis, and the New Biology of Mind
Genes Contribute Importantly to Mental
Function and Can Contribute to Mental Illness
Let us consider the contribution of the template functions of DNA—the heritable
aspects of gene action. Here we first need to ask, How do genes contribute
to behavior? Clearly, genes do not code for behavior in a direct way.
A single gene encodes a single protein; it cannot by itself encode for a single
behavior. Behavior is generated by neural circuits that involve many cells,
each of which expresses specific genes that direct the production of specific
proteins. The genes expressed in the brain encode proteins that are important
in one or another step of the development, maintenance, and regulation
of the neural circuits that underlie behavior. A wide variety of proteins—
structural, regulatory, and catalytic—are required for the differentiation of a
single nerve cell, and many cells and many more genes are required for the
development and function of a neural circuit.
To account for what we now appreciate as variations in the template
functions of a gene, Darwin and his followers first postulated that variations
in human behavior may, in part, be due to natural selection. If this is so,
some element of the behavioral variation in any population will necessarily
have a genetic basis. Some portion of this variation in turn should show up
as clearly heritable differences. Control studies of heritable factors in human
behavior have proven difficult to devise, because it is not possible or desirable
to control an individual’s environment for experimental purposes except
in some very limited situations. Thus, behavioral studies of identical
twins provide important information not otherwise available.
Identical twins share an identical genome and are therefore as alike genetically
as is possible for two individuals. Similarities between identical
twins who have been separated early in life and raised in different households,
as occasionally happens, will therefore be more attributable to genes
than to environment. Identical twins, compared with a group of individuals
matched in age, sex, and socioeconomic status, share a remarkable number
of behavioral traits. These include tastes, religious preferences, and vocational
interests that are commonly considered to be socially determined and
distinctive features of an individual. These findings argue that human behavior
has a significant hereditary component. But the similarity is far from perfect.
Twins can and do vary a great deal. Thus, twin studies also emphasize
the importance of environmental influences; they indicate quite clearly that
environmental factors are very important (Kandel et al. 1991).
A similar situation applies to disturbances of behavior and to mental illness.
The first direct evidence that genes are important in the development of
schizophrenia was provided in the 1930s by Franz Kallmann (1938). Kallmann
was impressed with the fact that the incidence of schizophrenia
A New Intellectual Framework for Psychiatry 45
throughout the world is uniformly about 1%, even though the social and environmental
factors vary dramatically. Nevertheless, he found that the incidence
of schizophrenia among parents, children, and siblings of patients with
the disease is 15%, strong evidence that the disease runs in families. However,
a genetic basis for schizophrenia cannot simply be inferred from the increased
incidence in families. Not all conditions that run in families are necessarily genetic:
wealth and poverty, habits, and values also run in families, and in earlier
times even nutritional deficiencies such as pellagra ran in families.
To distinguish genetic from environmental factors, Kallmann turned to
twin studies and compared the rates of illness in identical (monozygotic)
and fraternal (dizygotic) twins. As we have seen, monozygotic twins share
almost all of each other’s genes. By contrast, dizygotic twins share only 50%
of their genes and are genetically equivalent to siblings. Therefore, if schizophrenia
is caused entirely by genetic factors, monozygotic twins should be
identical in their tendency to develop the disease. Even if genetic factors
were necessary but not sufficient for the development of schizophrenia, because
environmental factors were involved, a monozygotic twin of a patient
with schizophrenia should be at substantially higher risk than a dizygotic
twin. The tendency for twins to have the same illness is called concordance.
Studies on twins have established that the concordance for schizophrenia in
monozygotic twins is about 45%, compared to only about 15% in dizygotic
twins, which is about the same as for other siblings.
To disentangle further the effects of nature and nurture, Heston (1970)
studied patients in the United States and Rosenthal and colleagues (1971)
studied patients in Denmark. In both sets of studies, the rate of schizophrenia
was higher among the biological relatives of adopted children who had
schizophrenia than among those of adopted children who were normal. The
difference in rate, about 10%–15%, was the same as that observed earlier by
This familial pattern of schizophrenia is most dramatically evident in an
analysis of the data from Denmark by Gottesman (1991). Gottesman examined
the data from 40 Danish patients with schizophrenia, identifying all relatives
with schizophrenia for whom good family pedigrees were available.
He then ranked the relatives in terms of the percentage of genes shared with
the schizophrenic patient. He found a higher incidence of schizophrenia
among first-order relatives—those who share 50% of the patient’s genes, including
siblings, parents, and children—than among second-order relatives—
those who share 25% of the patient’s genes, including aunts, uncles,
nieces, nephews, and grandchildren. Even the third-degree relatives, who
share only 12.5% of the patient’s genes, had a higher incidence of schizophrenia
than the 1% found in the population at large. These data strongly
suggest a genetic contribution to schizophrenia.
46 Psychiatry, Psychoanalysis, and the New Biology of Mind
If schizophrenia were caused entirely by genetic abnormalities, the concordance
rate for monozygotic twins, who share almost all of each other’s
genes, would be nearly 100%. The fact that the rate is 45% clearly indicates
that genetic factors are not the only cause. Multiple causality is also evident
from studies of the genetic transmission of the disease. Relatively routine
studies of pedigrees are sufficient to pinpoint whether a disease is transmitted
by dominant or recessive Mendelian inheritance, but this has not proven
to be the mode of transmission of schizophrenia. The most likely explanation
for the unusual genetic transmission of schizophrenia is that it is a multigenic
disease involving allelic variations in perhaps as many as 10–15 loci
in the population worldwide, and that perhaps combinations of three to five
loci are needed to cause the disease in an individual. Moreover, these several
genes can vary in the degree of penetrance.
In a natural population, any gene at any locus will exist in a number of
different, clearly related forms called alleles. The penetrance of an allele depends
on the interaction between that allele and the remainder of the genome,
as well as with environmental factors. One twin can inherit a set of
genes that program tall growth, but without good nutrition that twin may
never grow tall. Similarly, not all people with the same dominant and abnormal
Huntington’s disease gene will have the full-blown movement disorders
and accompanying cognitive disturbances; a few may have a more moderate
form of the disease.
As in other polygenic diseases, such as diabetes and hypertension, most
forms of schizophrenia are thought to require not only the accumulation of
several genetic defects but also the actions of developmental and environmental
factors. To understand schizophrenia, it will be essential to learn how
several genes combine to predispose an individual to a disease and to determine
how the environment influences the expression of these genes.
The fact that many genes are involved does not mean, however, that in
some cases single genes are not essential for the expression of a behavior. The
importance of specific genes to behavior can best be demonstrated in simple
animals, such as fruit flies or mice, in which mutations in a single gene can be
more easily studied. Mutations of single genes in Drosophila or in mice can
produce abnormalities in a variety of behaviors, including learned behavior as
well as innate behavior such as courtship and locomotion.
Behavior Itself Can Also Modify Gene Expression
I have considered the template function of the gene, which is transmissible
but not regulated. I now turn to that aspect of genetic function that is regulated
but not transmitted. Studies of learning in simple animals provided the
first evidence that experience produces sustained changes in the effectiveA
New Intellectual Framework for Psychiatry 47
ness of neural connections by altering gene expression. This finding has profound
ramifications that should revise our view of the relationship between
social and biological processes in the shaping of behavior.
To appreciate the importance of this relationship, consider for a moment
the situation in American psychiatry as recently as 1968, when DSM-II appeared.
A common view in psychiatry at that time was that biological and
social determinants of behavior act on separate levels of the mind: one level
had a clear empirical basis, and the other was unspecified. As a result, until
the 1970s psychiatric illnesses were traditionally classified into two major
categories: organic and functional. Thus, Seltzer and Frazier wrote in 1978,
“organic brain syndrome is a general term used to describe those conditions
of impaired function of the nervous system that are manifest by psychiatric
symptoms. This contrasts with the majority of psychiatric syndromes called
These organic mental illnesses included the dementias, such as Alzheimer’s
disease, and the toxic psychoses, such as those that follow the chronic
use of cocaine, heroin, and alcohol. Functional mental illnesses included not
only the neurotic illnesses but also the depressive illnesses and the schizophrenias.
This distinction originally derived from the observations of nineteenthcentury
neuropathologists, who examined the brains of patients at autopsy
and found gross and readily demonstrable distortions in the architecture of
the brain in some psychiatric diseases but not in others. Diseases that produced
anatomical evidence of brain lesions were called organic; those lacking
these features were called functional.
This distinction, now clearly outdated, is no longer tenable. There can
be no changes in behavior that are not reflected in the nervous system and
no persistent changes in the nervous system that are not reflected in structural
changes on some level of resolution. Everyday sensory experience, sensory
deprivation, and learning can probably lead to a weakening of synaptic
connections in some circumstances and a strengthening of connections in
others. We no longer think that only certain diseases, the organic diseases,
affect mentation through biological changes in the brain and that others, the
functional diseases, do not. The basis of the new intellectual framework for
psychiatry is that all mental processes are biological, and therefore any alteration
in those processes is necessarily organic.
As is now evident in DSM-IV, the classification of mental disorders must
be based on criteria other than the presence or absence of gross anatomical
abnormalities. The absence of detectable structural changes does not rule
out the possibility that more subtle but nonetheless important biological
changes are occurring. These changes may simply be below the level of detection
with the still-limited techniques available today. Demonstrating the
48 Psychiatry, Psychoanalysis, and the New Biology of Mind
biological nature of mental functioning requires more sophisticated anatomical
methodologies than the light-microscopic histology of nineteenthcentury
pathologists. To clarify these issues it will be necessary to develop a
neuropathology of mental illness that is based on anatomical function as
well as anatomical structure. Imaging techniques such as positron emission
tomography and functional magnetic resonance imaging have opened the
door to the noninvasive exploration of the human brain at a level of resolution
that begins to approach that which is required to understand the physical
mechanisms of mentation and therefore of mental disorders. This
approach is now being pursued in the study of schizophrenia, depression,
obsessive-compulsive disorders, and anxiety disorders (Jones 1995).
We now need to ask, How do the biological processes of the brain give
rise to mental events, and how in turn do social factors modulate the biological
structure of the brain? In the attempt to understand a particular mental
illness, it is more appropriate to ask, To what degree is this biological process
determined by genetic and developmental factors? To what degree is it environmentally
or socially determined? To what degree is it determined by a
toxic or infectious agent? Even the mental disturbances that are considered
to be most heavily determined by social factors must have a biological component,
since it is the activity of the brain that is being modified.
A New View of the Relationship Between
Inherited and Acquired Mental Illnesses
In the few instances where it has been possible to examine rigorously the
persistent changes in mental functions, these functions have been shown to
involve alterations in gene expression. Thus, in studying the specific
changes that underlie persistent mental states, normal as well as disturbed,
we should also look for altered gene expression. As we have seen, there is
now substantial evidence that the susceptibility to major psychotic illnesses
(schizophrenia and manic-depressive disorders) is heritable. These illnesses
in part reflect alterations in the template function of the gene—in the nucleotide
sequence of a number of different genes—leading to abnormal mRNAs
and abnormal proteins. It is therefore tempting to think that insofar as psychiatric
illnesses such as posttraumatic stress syndrome are acquired by experience,
they are likely to involve alterations in the transcriptional function
of the gene—in the regulation of gene expression. Nonetheless, some individuals
may be much more susceptible to this syndrome because of the combination
of genes they have inherited.
Development, stress, and social experience are all factors that can alter
gene expression by modifying the binding of transcriptional regulators to
each other and to the regulatory regions of genes. It is likely that at least
A New Intellectual Framework for Psychiatry 49
some neurotic illnesses (or components of them) result from reversible defects
in gene regulation, which may be due to altered binding of specific proteins
to certain upstream regions that control the expression of certain genes
(Figure 2–2).
Maintenance of Learned Alterations in Gene Expression
by Structural Alterations in Neural Circuits of the Brain
How does altered gene expression lead to the stable alterations of a mental
process? Animal studies of alterations in gene expression induced by learning
indicate that one major consequence of such alterations in gene activation
is the growth of synaptic connections. This growth was first delineated
by studies in simple invertebrate animals such as the snail Aplysia (Bailey
and Kandel 1993). Animals subjected to controlled learning that gave rise to
long-term memory had twice as many presynaptic terminals as untrained
animals. Some forms of learning, such as long-term habituation, produce the
opposite changes; they lead to a regression and pruning of synaptic connections.
These morphological changes seem to be a signature of the long-term
memory process. They do not occur with short-term memory.
In mammals, and especially in humans, each functional component of
the nervous system is represented by hundreds of thousands of nerve cells.
In such complex systems a specific instance of learning is likely to lead to
alterations in a large number of nerve cells insofar as the interconnections of
the various sensory and motor systems involved in the learning are changed.
Indeed, studies have shown that such vast changes do occur. The most detailed
evidence has come from studies of the somatic sensory system.
The primary somatic sensory cortex contains four separate maps of the
surface of the body in four areas in the postcentral gyrus (Brodmann’s areas
1, 2, 3a, and 3b). These cortical maps differ among individuals in a manner
that reflects their use. Moreover, the cortical maps for somatic sensations are
dynamic, not static, even in mature animals (Merzenich et al. 1988). The
distribution of these functional connections can expand and retract, depending
on the particular uses or activities of the peripheral sensory pathways.
Since each of us is brought up in a somewhat different environment,
exposed to different combinations of stimuli, and we develop motor skills in
different ways, each brain is modified in unique ways. This distinctive modification
of brain architecture, along with a unique genetic makeup, constitutes
the biological basis for individuality.
Two studies provide evidence for this view (Merzenich et al. 1988). One
study found that the somatosensory maps vary considerably among normal
animals. However, this study did not separate the effects of different experiences
from the consequences of different genetic endowment. Another study
50 Psychiatry, Psychoanalysis, and the New Biology of Mind
FIGURE 2–2. There is a genetic component to both inherited and
acquired psychiatric illness.
Genetic and acquired illnesses both have a genetic component. Genetic illnesses
(e.g., schizophrenia) are expressions of altered genes, whereas illnesses acquired as
learned behavior (neuroses) involve the modulation of gene expression by environmental
stimuli, leading to the transcription of a previously inactive gene. The gene is
illustrated as having two segments. A coding region is transcribed into an mRNA by
an RNA polymerase. The mRNA in turn is translated into a specific protein. A regulatory
segment consists of an enhancer region and a promoter region. In this example
the RNA polymerase can transcribe the gene when the regulatory protein binds to the
enhancer region. For gene activation to occur, the regulatory protein must first be
A(1): Under normal conditions the phosphorylated regulatory protein binds to the
enhancer region, thereby activating the transcription of the gene, leading to the production
of the protein (P=phosphorus, A=adenine, C=cytosine, G=guanine, T=thymidine).
A(2): A mutant form of the coding region of the structural gene, in which a
T has been substituted for a C, leads to transcription of an altered mRNA. This in
turn produces an abnormal protein, giving rise to the disease state. This alteration in
gene structure becomes established in the germ line and is heritable.
B(1): If the regulatory protein for a normal gene is not phosphorylated, it cannot bind
to the enhancer site, and thus gene transcription cannot be initiated. B(2): In this
case a specific experience leads to the activation of serotonin (5-HT) and cAMP,
which activate the cAMP-dependent protein kinase. The catalytic unit phosphorylates
the regulatory protein, which then can bind to the enhancer segment and thus
initiate gene transcription. By this means, an abnormal learning experience could
lead to the expression of a protein that gives rise to symptoms of a neurotic disorder.
Source. Adapted from Kandel 1995.
A New Intellectual Framework for Psychiatry 51
was conducted to see whether activity is important in determining the topographic
organization of the somatosensory cortex. Adult monkeys were encouraged
to use three middle fingers at the expense of two other fingers of the
hand to obtain food. After several thousand trials, the area of cortex devoted
to the three fingers was greatly expanded at the expense of the area normally
devoted to the other fingers (Figure 2–3). Practice alone, therefore, may not
only strengthen the effectiveness of existing patterns of connections but also
change cortical connections to accommodate new patterns of actions.
Psychotherapy and Pharmacotherapy May
Induce Similar Alterations in Gene Expression
and Structural Changes in the Brain
As these arguments make clear, it is intriguing to suggest that insofar as psychotherapy
is successful in bringing about substantive changes in behavior,
it does so by producing alterations in gene expression that produce new
structural changes in the brain. This obviously should also be true of psy-
FIGURE 2–3. The representation of the body on the surface of
the cerebral cortex is modified by experience.
A: Penfield’s somatic-sensory homunculus redrawn as a complete body, showing the
overrepresentation of certain parts of the skin surface.
B: Training expands existing afferent inputs in the cortex. A monkey was trained for
1 hour per day to perform a task that required repeated use of the tips of fingers 2, 3,
and occasionally 4 (dark shading).
C1: Representation of the tips of the digits of an adult monkey in Brodmann’s cortical
area 3b three months before training. C2: After a period of repeated stimulation, the
portion of area 3b representing the tips of the stimulated fingers is substantially enlarged
(dark shading).
Source. (A) Adapted from Blakemore 1977. (B) Adapted from Jenkins et al. 1990.
52 Psychiatry, Psychoanalysis, and the New Biology of Mind
chopharmacological treatment. Treatment of neurosis or character disorders
by psychotherapeutic intervention should, if successful, also produce functional
and structural changes. We face the interesting possibility that as
brain imaging techniques improve, these techniques might be useful not
only for diagnosing various neurotic illnesses but also for monitoring the
progress of psychotherapy. The joint use of pharmacological and psychotherapeutic
interventions might be especially successful because of a potentially
interactive and synergistic—not only additive—effect of the two
interventions. Psychopharmacological treatment may help consolidate the
biological changes caused by psychotherapy.
One example of this congruence is now evident in obsessive-compulsive
disorder (OCD). This common debilitating psychiatric illness is characterized
by recurrent unwanted thoughts, obsessions, and conscious ritualized
acts and compulsions that are usually attributed to attempts to deal with the
anxiety generated by the obsessions. Medications that are selective serotonin
reuptake inhibitors (SSRIs) and specific behavioral therapies that use the
principles of deconditioning, involving exposure and response prevention,
are effective in reducing the symptoms of many patients with OCD.
Many investigators have postulated a role for the cortical-striatalthalamic
brain system in the mediation of OCD symptoms. OCD is associated
with functional hyperactivity of the head of the right caudate nucleus.
After effective treatment of OCD with either an SSRI (such as fluoxetine)
alone or with behavioral modification alone (with exposure and response
prevention techniques), there is a substantial decrease in activity (measured
as glucose metabolic rate) in the head of the right caudate nucleus. In one
study (J.M. Schwartz et al. 1996), patients who responded to behavior therapy
had a significant decrease in glucose metabolic rate in the caudate nucleus
bilaterally compared to those who did not respond to treatment.
These arguments suggest that when a therapist speaks to a patient and
the patient listens, the therapist is not only making eye contact and voice
contact, but the action of neuronal machinery in the therapist’s brain is having
an indirect and, one hopes, long-lasting effect on the neuronal machinery
in the patient’s brain; and quite likely, vice versa. Insofar as our words
produce changes in our patient’s mind, it is likely that these psychotherapeutic
interventions produce changes in the patient’s brain. From this perspective,
the biological and sociopsychological approaches are joined.
Implications of a New Framework for
the Practice of Psychiatry
The biological framework that I have outlined here is not only important
conceptually; it is also important practically. To function effectively in the fuA
New Intellectual Framework for Psychiatry 53
ture, the psychiatrists we are training today will need more than just a nodding
familiarity with the biology of the brain. They will need the knowledge
of an expert, a knowledge perhaps different from but fully comparable to
that of a well-trained neurologist. In fact, it is likely that in the decades ahead
we will see a new level of cooperation between neurology and psychiatry.
This cooperation is likely to have its greatest impact on patients for whom
the two approaches—neurological and psychiatric—overlap, such as those
in treatment for autism, mental retardation, and the cognitive disorders due
to Alzheimer’s and Parkinson’s diseases.
It can be argued that an intellectual framework so fully embedded in biology
and aligned with neurology is premature for psychiatry. In fact, we are
only beginning to understand the simplest mental functions in biological
terms; we are far from having a realist neurobiology of clinical syndromes
and even farther from having a neurobiology of psychotherapy. These arguments
have some validity. Thus, the decision for psychiatry revolves around
the question, When will the time be optimal for a more complete rapprochement
between psychiatry and biology? Is it when the problem is still premature—
when the biology of mental illness still confronts us as deep
mysteries—or is it when the problem is already postmature—when mental
illness is on the way to being understood? If psychiatry will join the intellectual
fray in full force only when the problems are largely solved, then psychiatry
will deprive itself of one of its main functions, which is to provide
leadership in the attempts to understand the basic mechanisms of mental
processes and their disorders. Since the presumed function of academic psychiatry
is to train people who advance knowledge—people who can not only
benefit from the insights of the current biological revolution but also contribute
to it—psychiatry must take its commitment to the training of biological
scientists more seriously. It must put its own oars into the water and pull
its own weight. If the biology of mental processes continues to be solved by
others without the active participation of psychiatrists, we may well ask,
What is the purpose of a psychiatric education?
While psychiatrists debate the degree to which they should immerse
themselves in modern molecular biology, most of the remaining scientific
community has resolved that issue for itself. Most biologists sense that we
are in the midst of a remarkable scientific revolution, a revolution that is
transforming our understanding of life’s processes—the nature of disease
and of medical therapeutics. Most biologists believe that this revolution will
have a profound impact on our understanding of mind. This view is shared
by students just beginning their scientific training. Many of the very best
graduate students in biology and the best M.D.-Ph.D. students are drawn to
neural science and particularly to the biology of mental processes for this
very reason. If the progress of the past few years and the continued influx of
54 Psychiatry, Psychoanalysis, and the New Biology of Mind
talented people are any guide, we can expect a major growth in our understanding
of mental processes.
We thus are confronting an interesting paradox. While the scientific
community at large has become interested in the biology of mental processes,
the interest of medical students in a psychiatric career is declining.
Thus, from an educational point of view, psychiatry is in a trough. One reason
for the loss of interest, beyond the economic issue of managed care, is
the current intellectual scene in psychiatry. Medical students realize that insofar
as the teaching of psychiatry is often based primarily on doing psychotherapy,
a major component of psychiatry as it is now taught does not
require a medical education. As Freud so clearly emphasized, psychotherapy
can be carried out effectively by nonmedical specialists. Why, then, go to
medical school?
As a greater emphasis on biology begins to change the nature of psychiatry,
it also is likely to draw an increasing number of talented medical
students into psychiatry. In addition, it will make psychiatry a more technologically
sophisticated and more scientifically rigorous medical discipline. A
biological orientation can help revitalize the teaching and practice of psychiatry
by bringing to bear on the problems of mental illness a critical understanding
of brain processes, a familiarity with therapeutics, and an
understanding of both neurological and psychiatric diseases—in short, an
ability to encompass mental and emotional life within a framework that includes
biological as well as social determinants. A renewed involvement of
psychiatry with biology and with neurology, therefore, not only is scientifically
important but also emphasizes the scientific competence that, I would
argue, should be the basis for the clinical specialty of psychiatry in the
twenty-first century.
Biology and the Possibility of a
Renaissance of Psychoanalytic Thought
It would be unfortunate, even tragic, if the rich insights that have come from
psychoanalysis were to be lost in the rapprochement between psychiatry and
the biological sciences. With the perspective of time, we can readily see what
has hindered the full intellectual development of psychoanalysis during the
last century. To begin with, psychoanalysis has lacked any semblance of a
scientific foundation. Even more, it has lacked a scientific tradition, a questioning
tradition based not only on imaginative insights but on creative and
critical experiments designed to explore, support, or, as is often the case, falsify
those insights. Many of the insights from psychoanalysis are derived
from clinical studies of individual cases. Insights from individual cases can
be powerful, as we have learned from Paul Broca’s study of the patient LebA
New Intellectual Framework for Psychiatry 55
orgne (Schiller 1992). The analysis of this patient is a historical landmark; it
marks the origin of neuropsychology. Study of this one patient led to the discovery
that the expression of language resides in the left hemisphere and
specifically in the frontal cortex of that hemisphere. But as Broca’s cases illustrate,
clinical insights, especially those based on individual cases, need to
be supported by independent and objective methods. Broca achieved this by
studying Leborgne’s brain at autopsy and by subsequently discovering eight
other patients with similar lesions and similar symptoms. It is, I believe, the
lack of a scientific culture more than anything else that led to the insularity
and anti-intellectualism which characterized psychoanalysis in the last
50 years and which in turn influenced the training of psychiatrists in the period
of World War II, the period in which psychoanalysis was the dominant
mode of thought in American psychiatry.
But the sins of the fathers (and mothers) need not be passed on to succeeding
generations. Other disciplines have recovered from similar periods
of decline. American psychology, for example, went through a period of insularity
and myopia in the 1950s and 1960s despite its being a rigorous and
experimental discipline. Under the leadership of Hull, Spence, and Skinner,
the behaviorist tradition they espoused focused only on the reflexive and observable
aspects of behavior and dealt with these as if they represented all
there is to mental life.
With the emergence of computers to model and test ideas about mind,
and with the development of more controlled ways of examining human
mental processes, psychology reemerged in the 1970s in its modern form as
a cognitive psychology that has explored language, perception, memory, motivation,
and skilled movements in ways that have proven stimulating, insightful,
and rigorous. Modern psychology is still evolving. The recent
merger of cognitive psychology with neural science—the discipline we now
call cognitive neural science—is proving to be one of the most exciting areas
in all of biology. What is the aspiration of psychoanalysis if not to be the
most cognitive of neural sciences? The future of psychoanalysis, if it is to
have a future, is in the context of an empirical psychology, abetted by imaging
techniques, neuroanatomical methods, and human genetics. Embedded
in the sciences of human cognition, the ideas of psychoanalysis can be
tested, and it is here that these ideas can have their greatest impact.
The following is but one example from my own field, the cognitive neural
science of memory. One of the great insights of modern cognitive neural
science in the study of memory is the realization that memory is not a unitary
function of mind but has at least two forms, called explicit and implicit:
a memory for what things are as compared to a memory for how to do something.
Explicit memory encodes conscious information about autobiographical
events and factual knowledge. It is a memory about people, places, facts,
56 Psychiatry, Psychoanalysis, and the New Biology of Mind
and objects, and it requires for its expression the hippocampus and the medial
temporal lobe. Implicit memory involves for its recall an unconscious
memory for motor and perceptual strategies. It depends on the specific sensory
and motor systems as well as on the cerebellum and the basal ganglia.
Patients with lesions of the medial temporal lobe—or the hippocampus,
which lies deep in it—cannot acquire new explicit memories for people,
places, and objects. But they are fully able to learn motor skills and are also
able to improve their performance on perceptual tasks. Implicit memory is
not limited to simple tasks. It also includes a sophisticated form of memory
called priming, in which recognition of words or objects is facilitated by prior
exposure to the words or visual clues. Thus, a subject can recall the cued
item better than other items for which no cues have been provided. Similarly,
when shown the first few letters of previously studied words, a subject with
temporal lobe lesions often responds by selecting correctly the previously
presented word, even though he cannot remember ever seeing the word before!
The tasks that patients who lack explicit memory are capable of learning
have in common that they do not require conscious awareness. The patient
need not deliberately remember anything. Thus, when given a highly complex
mechanical puzzle to solve, the patient may learn it as quickly as a normal
person, but on questioning will not remember seeing the puzzle or
having worked on it previously. When asked why his performance on a task
is much better after several days of practice than on the first day, the patient
may respond, “What are you talking about? I’ve never done this task before.”
What a momentous discovery! Here we have, for the first time, the neural
basis for a set of unconscious mental processes. Yet this unconscious
bears no resemblance to Freud’s unconscious. It is not related to instinctual
strivings or to sexual conflicts, and the information never enters consciousness.
These sets of findings provide the first challenge to a psychoanalytically
oriented neural science. Where, if it exists at all, is the other unconscious?
What are its neurobiological properties? How do unconscious strivings become
transformed to enter awareness as a result of analytic therapy?
There are other challenges, of course. But at the very least, a biologically
based psychoanalysis would redefine the usefulness of psychoanalysis as an
effective perspective on certain specific disorders. At its best, psychoanalysis
could live up to its initial promise and help revolutionize our understanding
of mind and brain.
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Arnold M. Cooper, M.D.
Today more than ever before in its 100-year history, psychoanalysis is in a
state of theoretical and clinical excitement, uncertainty, and open debate.
Under the term theoretical pluralism psychoanalysts have acknowledged that
there are multiple competing views concerning the nature of mental life, the
origins of psychopathology, the centrality of intrapsychic conflict, the
sources of the resistance to change, and the relationship of present to past.
There is also a sharp continuing debate over whether psychoanalysis should
aspire to accommodate any variety of scientific methodology or whether it
should confine itself to being a hermeneutic discipline. In this setting, the
attempts to adjudicate the superiority of one or another viewpoint by detailed
reporting of analyst-patient interactions have failed. Each of the various
schools of analytic thought—for example, Kleinian, ego-psychological,
relational, and self-psychological—finds little difficulty in claiming its point
of view as the superior explanatory base for clinical observation. From the
hermeneutic viewpoint, psychoanalysis cannot and will not advance greatly
beyond the initial discoveries of Freud and their later elaboration and enrichment
by others. In contrast, Eric Kandel calls upon psychoanalysis to
find ways to invigorate itself, to become a source of new ideas, and to enrich
60 Psychiatry, Psychoanalysis, and the New Biology of Mind
the neurosciences by becoming part of the neuroscientific community, while
preserving and expanding its knowledge and skill in mapping the conscious
and unconscious mental life of human beings.
Psychoanalysis may be following a destiny typical of many sciences: an
early period of discovery and innovation followed by a decline to a baseline
level of scientific activity. If that is the case, psychoanalysis can surely benefit
by being a partner of neuroscience, which has only begun its upward arc.
Kandel has provided a brief course in neurobiology for psychoanalysts in
this remarkable paper filled with suggestions for future combined research.
He vividly describes the advances of neuroscience that converge with psychoanalytic
interests. The psychoanalytic map of the mind—the most complete
and interesting map available—helps to set an agenda for neurobiology.
After all, what is most interesting about the brain is how it generates mental
life. What is the biology of subjectivity, consciousness, selfhood, and conflict?
Kandel points to promising starts in these directions. Simultaneously,
the advances in neurobiology have begun to demonstrate aspects of what
psychoanalytic treatment must achieve biologically if its effects are to be significant.
As has been demonstrated, talking cures are reflected in brain
changes, as are pharmacologic cures. Neuroscience has embarked on an
amazing voyage of discovery and psychoanalysis has an opportunity and obligation
to participate and contribute.
There can be no question that another century of neuroscience will produce
advances that seem unimaginable today, including a richer, more nuanced
understanding of such human qualities as emotional responsiveness,
unconscious mental processing, chronic resentment, self-damaging behaviors,
self-pity, persistent avoidance of loving and gratifying relationships,
and resistance to change. Some fear that this is a road to an Orwellian world
where a pill will make us all feel good and that it will reduce individuality
and the quest for knowledge. Psychoanalysis can play an important role in
ensuring that neuroscience does not go down that path but joins the psychoanalytic
effort for expanded self-awareness and choice. Kandel offers multiple
examples of why analysts should interest themselves in and avail
themselves of newer neuroscience findings. While at the moment the two
enterprises are in many respects parallel, we can be certain that the continuing
advances of neuroscience are likely to demonstrate that certain psychoanalytic
ideas are wrong (as is already the case for infantile amnesia, once
attributed to repression and now known to be the result of the lack of necessary
memory pathways in a young child), while other ideas are better understood;
for example, the understanding of implicit memory and its
extraordinary fixity and ubiquity place the concepts of repetition-compulsion
and resistance in a new light. Shifts in philosophy of mind may be required
on both sides of the current divide: an acceptance of mind-brain as a single
Biology and the Future of Psychoanalysis 61
entity that can be investigated from different perspectives, rejection of a
computational model in favor of nonlinear complexity, and full recognition
of the power of both environment and molecular alteration to influence
complex social behaviors.
The psychoanalytic enterprise has suffered hugely from its isolation from
the academic setting. To my knowledge, no analytic institute gives a priority
to empirical scientific research in the way that is routine in medical schools.
Few analytic institutes are even in a position to begin to muster the resources
that are required to provide their students with research experience. The International
Psychoanalytical Association has been making a major and successful
effort to recruit and train researchers, and there is now a thriving
psychoanalytic empirical research effort in such areas as the development of
mentalization, the effects of early mother-infant attunement, the consequences
of different attachment patterns, outcome studies of short-term dynamic
psychotherapies, among many others. However, this is a small
beginning and does not touch upon the problem of institutes that are often
satisfied with their clinical expertise, untested though it is. An appropriate
task for psychoanalytic educators is to accomplish what medical education
is finding so difficult: inculcating the necessary reductionism of scientific
thought while retaining the humanism required for empathic understanding
of another’s experience.
For all of these reasons, Kandel’s views have aroused both fervent support
and opposition among psychoanalysts. I look forward to an era of enhanced
cooperation of psychoanalysis and neuroscience and can imagine
the possibility that interpretation may be accompanied by imaging techniques
that will demonstrate differences between one interpretive pathway
and another and that analytic progress may be checked against brain
changes, and we will know better what must change if pathology is being
successfully dealt with. It would be similar to the internist’s use of laboratory
findings to check the progress of a treatment. The advent of pharmacologic
agents for depression, anxiety, tics, and obsessional symptoms, to mention
just a few syndromes, was initially regarded by many psychoanalysts as an
interference and obstruction to the conduct of analytic work. Time has
shown that these agents often make analysis possible for patients whose
symptom predominance overwhelms their capacity for free associative
exploration of their emotional lives. Relief from overwhelming anxiety, depression,
or obsession opens the possibilities for a search for a better understanding
or a reconstruction of one’s selfhood, one’s history, and one’s
decision making. The problem for psychoanalysts is how to absorb the findings
of neuroscience, whose precision concerns very limited parts of human
mental function, into the theories of psychoanalysis, which are concerned
with much larger, less precisely defined areas of mind.
62 Psychiatry, Psychoanalysis, and the New Biology of Mind
Psychoanalysts are, or should be, grateful to Kandel for his invitation to
us to bring our knowledge of the mind to the neuroscientists in their astonishing
journey through the brain. Eric Kandel has offered a challenge to psychoanalysis
that we must meet.
C H A P T E R 3
A New Intellectual Framework
for Psychiatry Revisited
Eric R. Kandel, M.D.
We must recollect that all of our provisional ideas in
psychology will presumably one day be based on an
organic substructure.
—Sigmund Freud,
“On Narcissism” (S. Freud 1914/1957)
The deficiencies in our description would probably
vanish if we were already in a position to replace the
psychological terms with physiological or chemical
ones.…We may expect [physiology and chemistry]
to give the most surprising information and we cannot
guess what answers it will return in a few dozen
years of questions we have put to it. They may be of
a kind that will blow away the whole of our artificial
structure of hypothesis.
—Sigmund Freud,
“Beyond the Pleasure Principle” (S. Freud 1920/1955)
This article was originally published in the American Journal of Psychiatry, Volume
156, Number 4, 1999, pp. 505–524.
64 Psychiatry, Psychoanalysis, and the New Biology of Mind
The American Journal of Psychiatry has received a number of letters in response
to my earlier “Framework” article (Kandel 1998). Some of these are
reprinted elsewhere in this issue, and I have answered them briefly there.
However, one issue raised by some letters deserves a more detailed answer,
and that relates to whether biology is at all relevant to psychoanalysis. To my
mind, this issue is so central to the future of psychoanalysis that it cannot be
addressed with a brief comment. I therefore have written this article in an attempt
to outline the importance of biology for the future of psychoanalysis.
During the first half of the twentieth century, psychoanalysis revolutionized
our understanding of mental life. It provided a remarkable set of new
insights about unconscious mental processes, psychic determinism, infantile
sexuality, and, perhaps most important of all, about the irrationality of
human motivation. In contrast to these advances, the achievements of psychoanalysis
during the second half of this century have been less impressive.
Although psychoanalytic thinking has continued to progress, there have
been relatively few brilliant new insights, with the possible exception of certain
advances in child development (for a review of recent progress, see Isenstadt
1998; Levin 1998; Shapiro and Emde 1995; Shevrin 1998). Most
important, and most disappointing, psychoanalysis has not evolved scientifically.
Specifically, it has not developed objective methods for testing the exciting
ideas it had formulated earlier. As a result, psychoanalysis enters the
twenty-first century with its influence in decline.
This decline is regrettable, since psychoanalysis still represents the most
coherent and intellectually satisfying view of the mind. If psychoanalysis is
to regain its intellectual power and influence, it will need more than the
stimulus that comes from responding to its hostile critics. It will need to be
engaged constructively by those who care for it and who care for a sophisticated
and realistic theory of human motivation. My purpose in this article is
to suggest one way that psychoanalysis might reenergize itself, and that is by
developing a closer relationship with biology in general and with cognitive
neuroscience in particular.
A closer relationship between psychoanalysis and cognitive neuroscience
would accomplish two goals for psychoanalysis, one conceptual and
the other experimental. From a conceptual point of view, cognitive neuroscience
could provide a new foundation for the future growth of psychoanalysis,
a foundation that is perhaps more satisfactory than metapsychology.
David Olds has referred to this potential contribution of biology as “rewriting
metapsychology on a scientific foundation.” From an experimental point
of view, biological insights could serve as a stimulus for research, for testing
specific ideas about how the mind works.
Others have argued that psychoanalysis should be satisfied with more
modest goals; it should be satisfied to strive for a closer interaction with cogBiology
and the Future of Psychoanalysis 65
nitive psychology, a discipline that is more immediately related to psychoanalysis
and more directly relevant to clinical practice. I have no quarrel
with this argument. It seems to me, however, that what is most exciting in
cognitive psychology today and what will be even more exciting tomorrow
is the merger of cognitive psychology and neuroscience into one unified discipline,
which we now call cognitive neuroscience (for one example of this
merger, see Milner et al. 1998). It is my hope that by joining with cognitive
neuroscience in developing a new and compelling perspective on the mind
and its disorders, psychoanalysis will regain its intellectual energy.
Meaningful scientific interaction between psychoanalysis and cognitive
neuroscience of the sort that I outline here will require new directions for
psychoanalysis and new institutional structures for carrying them out. My
purpose in this article, therefore, is to describe points of intersection between
psychoanalysis and biology and to outline how those intersections
might be investigated fruitfully.
The Psychoanalytic Method and the
Psychoanalytic View of the Mind
Before I outline the points of congruence between psychoanalysis and biology,
it is useful to review some of the factors that have led to the current crisis
in psychoanalysis, a crisis that has resulted in good part from a restricted
methodology. Three points are relevant here.
First, at the beginning of the twentieth century, psychoanalysis introduced
a new method of psychological investigation, a method based on free
association and interpretation. Freud taught us to listen carefully to patients
and in new ways, ways that no one had used before. Freud also outlined a
provisional schema for interpretation, for making sense out of what otherwise
seemed to be unrelated and incoherent associations of patients. This
approach was so novel and powerful that for many years, not only Freud but
also other intelligent and creative psychoanalysts could argue that psychotherapeutic
encounters between patient and analyst provided the best context
for scientific inquiry. In fact, in the early years, psychoanalysts could
and did make many useful and original contributions to our understanding
of the mind simply by listening to patients, or by testing ideas from the analytic
situation in observational studies, a method that has proved particularly
useful for studying child development. This approach may still be
useful clinically because, as Anton Kris has emphasized, one listens differently
now. Nevertheless, it is clear that as a research tool this particular
method has exhausted much of its novel investigative power. One hundred
years after its introduction, there is little new in the way of theory that can
be learned by merely listening carefully to individual patients. We must, at
66 Psychiatry, Psychoanalysis, and the New Biology of Mind
last, acknowledge that at this point in the modern study of mind, clinical observation
of individual patients, in a context like the psychoanalytic situation
that is so susceptible to observer bias, is not a sufficient basis for a
science of mind.
This view is shared even by senior people within the psychoanalytic
community. Thus, Kurt Eissler (1969) wrote, “the decrease in momentum of
psychoanalytic research is due not to subjective factors among the analysts,
but rather to historical facts of wider significance: the psychoanalytic situation
has already given forth everything it contains. It is depleted with regard
to research possibilities, at least as far as the possibility of new paradigms is
Second, as these arguments make clear, although psychoanalysis has historically
been scientific in its aim, it has rarely been scientific in its methods;
it has failed over the years to submit its assumptions to testable experimentation.
Indeed, psychoanalysis has traditionally been far better at generating
ideas than at testing them. As a result of this failure, it has not been able to
progress as have other areas of psychology and medicine.
The concerns of modern behavioral science for controlling experimenter
bias by means of blind experiments have largely escaped the concern of psychoanalysts
(for important exceptions, see Dahl 1974; Luborsky and Luborsky
1995; Teller and Dahl 1995). With rare exception, the data gathered in
psychoanalytic sessions are private: the patient’s comments, associations, silences,
postures, movements, and other behaviors are privileged. In fact, the
privacy of communication is central to the basic trust engendered by the
psychoanalytic situation. Here is the rub. In almost all cases, we have only
the analysts’ subjective accounts of what they believe has happened. As the
research psychoanalyst Hartvig Dahl (1974) has long argued, hearsay evidence
of this sort is not accepted as data in most scientific contexts. Psychoanalysts,
however, are rarely concerned that their account of what happened
in a therapy session is bound to be subjective and biased.
As a result, what Boring (1950) wrote, nearly 50 years ago, still stands:
“We can say, without any lack of appreciation for what has been accomplished,
that psychoanalysis has been prescientific. It has lacked experiments,
having developed no techniques for control. In the refinement of
description without control it is impossible to distinguish semantic specification
from fact.”
Thus, in the future, psychoanalytic institutes should strive to have at
least a fraction of all supervised analyses be accessible to this sort of scrutiny.
This is important not only for the psychoanalytic situation but also for other
areas of investigation. Insights gained in therapy sessions have importantly
inspired other modes of investigation outside the psychoanalytic situation.
A successful example is the direct observation of children and the experiBiology
and the Future of Psychoanalysis 67
mental analysis of attachment and parent-child interaction. Basing future
experimental analyses on insights gained from the psychoanalytic situation
makes it all the more important that the scientific reliability of these situations
be optimized.
Third, unlike other areas of academic medicine, psychoanalysis has a serious
institutional problem. The autonomous psychoanalytic institutes that
have persisted and proliferated over the last century have developed their
own unique approaches to research and training, approaches that have become
insulated from other forms of research. With some notable exceptions,
the psychoanalytic institutes have not provided their students or faculty
with appropriately academic settings for questioning scholarship and empirical
To survive as an intellectual force in medicine and in cognitive neuroscience,
and indeed in society as a whole, psychoanalysis will need to adopt
new intellectual resources, new methodologies, and new institutional arrangements
for carrying out its research. Several medical disciplines have
grown by incorporating the methodologies and concepts of other disciplines.
By and large, psychoanalysis has failed to do so. Because psychoanalysis
has not yet recognized itself as a branch of biology, it has not
incorporated into the psychoanalytic view of the mind the rich harvest of
knowledge about the biology of the brain and its control of behavior that has
emerged in the last 50 years. This, of course, raises the question, Why has
psychoanalysis not been more welcoming of biology?
The Current Generation of Psychoanalysts
Have Raised Arguments for and Against a
Biology of Mind
In 1894, Freud argued that biology had not advanced enough to be helpful
to psychoanalysis. It was premature, he thought, to bring the two together.
One century later, a number of psychoanalysts have a far more radical view.
Biology, they argue, is irrelevant to psychoanalysis. To give an example, Marshall
Edelson in his book Hypothesis and Evidence in Psychoanalysis wrote:
Efforts to tie psychoanalytic theory to a neurobiological foundation, or to
mix hypotheses about mind and hypotheses about brain in one theory,
should be resisted as expressions of logical confusion.
I see no reason to abandon the position Reiser takes despite his avowed
belief in the “functional unity” of mind and body, when he considers the
mind-body relation:
“The science of the mind and the science of the body utilize different languages,
different concepts (with differing levels of abstraction and complexity),
and different sets of tools and techniques. Simultaneous and parallel
68 Psychiatry, Psychoanalysis, and the New Biology of Mind
psychological and physiological study of a patient in an intense anxiety state
produces of necessity two separate and distinct sets of descriptive data, measurements,
and formulations. There is no way to unify the two by translation
into a common language, or by reference to a shared conceptual framework,
nor are there as yet bridging concepts that could serve…as intermediate templates,
isomorphic with both realms. For all practical purposes, then, we deal
with mind and body as separate realms; virtually, all of our psychophysiological
and psychosomatic data consist in essence of covariance data, demonstrating
coincidence of events occurring in the two realms within specified
time intervals at a frequency beyond chance.” (Reiser 1975, p. 479)
I think it is at least possible that scientists may eventually conclude that
what Reiser describes does not simply reflect the current state of the art,
methodologically, or the inadequacy of our thought but represents, rather,
something that is logically or conceptually necessary, something that no
practical or conceptual developments will ever be able to mitigate. (Edelson
In my own numerous interactions with Reiser, I have never sensed him
to have difficulty relating brain to mind. Nevertheless, I have quoted Edelson
at length because his view is representative of that shared by a surprisingly
large number of psychoanalysts, and even by Freud in some of his later
writings. This view, often referred to as the hermeneutic as opposed to the
scientific view of psychoanalysis, reflects a position that has hindered psychoanalysis
from continuing to grow intellectually (M.S. Roth 1998; Shapiro
Now, psychoanalysis could, if it wanted to do so, easily rest on its hermeneutic
laurels. It could continue to expound on the remarkable contributions
of Freud and his students, on the insights into the unconscious mental
processes and motivations that make us the complex, psychologically nuanced
individuals we are (Bowlby 1960; Erikson 1963; A. Freud 1936;
S. Freud 1933[1932]/1964; Hartmann 1939/1958; Klein 1957; Kohut 1971;
Spitz 1945; Winnicott 1954/1958). Indeed, in the context of these contributions,
few would challenge Freud’s position as the great modern thinker on
human motivation or would deny that our century has been permanently
marked by Freud’s deep understanding of the psychological issues that historically
have occupied the Western mind from Sophocles to Schnitzler.
But if psychoanalysis is to rest on its past accomplishments, it must remain,
as Jonathan Lear (1998) and others have argued, a philosophy of
mind, and the psychoanalytic literature—from Freud to Hartmann to Erikson
to Winnicott—must be read as a modern philosophical or poetic text
alongside Plato, Shakespeare, Kant, Schopenhauer, Nietzsche, and Proust.
On the other hand, if the field aspires, as I believe most psychoanalysts do
aspire, to be an evolving, active contributor to an emerging science of the
mind, then psychoanalysis is falling behind.
Biology and the Future of Psychoanalysis 69
I therefore agree with the sentiment expressed by Lear (1998): “Freud
is dead. He died in 1939, after an extraordinary productive and creative
life.…It is important not to get stuck on him, like some rigid symptom, either
to idolize him or to denigrate him.”
Biology in the Service of Psychoanalysis
My focus in this article is on ways that biology might reinvigorate the psychoanalytic
exploration of mind. I should say at the outset that although we
have the outlines of what could evolve into a meaningful biological foundation
for psychoanalysis, we are very much at the beginning. We do not yet
have an intellectually satisfactory biological understanding of any complex
mental processes. Nevertheless, biology has made remarkable progress in
the last 50 years, and the pace is not slacking. As biologists come to focus
more of their efforts on the brain-mind, most of them have become convinced
that the mind will be to the biology of the twenty-first century what
the gene has been to the biology of the twentieth century. Thus, Francois
Jacob (1998) writes, “the century that is ending has been preoccupied with
nucleic acids and proteins. The next one will concentrate on memory and
desire. Will it be able to answer the questions they pose?”
My key argument is that the biology of the next century is, in fact, in a
good position to answer some of the questions about memory and desire,
that these answers will be all the richer and more meaningful if they are
forged by a synergistic effort of biology and psychoanalysis. In turn, answers
to these questions, and the very effort of providing them in conjunction with
biology, will provide a more scientific foundation for psychoanalysis.
In the next century, biology is likely to make deep contributions to the
understanding of mental processes by delineating the biological basis for the
various unconscious mental processes, for psychic determinism, for the role
of unconscious mental processes in psychopathology, and for the therapeutic
effect of psychoanalysis. Now, biology will not immediately enlighten
these deep mysteries at their core. These issues represent, together with the
nature of consciousness, the most difficult problems confronting all of biology—
in fact, all of science. Nevertheless, one can begin to outline how biology
might at least clarify some central psychoanalytic issues, at least at their
margins. Here I outline eight areas in which biology could join with psychoanalysis
to make important contributions: 1) the nature of unconscious
mental processes, 2) the nature of psychological causality, 3) psychological
causality and psychopathology, 4) early experience and the predisposition to
mental illness, 5) the preconscious, the unconscious, and the prefrontal cortex,
6) sexual orientation, 7) psychotherapy and structural changes in the
brain, and 8) psychopharmacology as an adjunct to psychoanalysis.
70 Psychiatry, Psychoanalysis, and the New Biology of Mind
1. Unconscious Mental Processes
Central to psychoanalysis is the idea that we are unaware of much of our
mental life. A great deal of what we experience—what we perceive, think,
dream, fantasize—cannot be directly accessed by conscious thought. Nor
can we explain what often motivates our actions. The idea of unconscious
mental processes not only is important in its own right, but it is critical for
understanding the nature of psychic determinism. Given the centrality of
unconscious psychic processes, what can biology teach us about them?
In 1954 Brenda Milner made the remarkable discovery, based on studies
of the amnestic patient H.M., that the medial temporal lobe and the hippocampus
mediate what we now call declarative (explicit) memory storage, a
conscious memory for people, objects, and places (Scoville and Milner
1957). In 1962 she made the further discovery that even though H.M. had
no conscious recall of new memories about people, places, and objects, he
was nonetheless fully capable of learning new perceptual and motor skills
(for a recent review, see Milner et al. 1998). These memories—what we now
call procedural or implicit memory—are completely unconscious and are
evident only in performance rather than in conscious recall.
Using the two memory systems together is the rule rather than the exception.
These two memory systems overlap and are commonly used together
so that many learning experiences recruit both of them. Indeed,
constant repetition can transform declarative memory into a procedural
type. For example, learning to drive an automobile at first involves conscious
recollection, but eventually driving becomes an automatic and nonconscious
motor activity. Procedural memory is itself a collection of
processes involving several different brain systems: priming, or recognition
of recently encountered stimuli, is a function of sensory cortices; the acquisition
of various cued feeling states involves the amygdala; formation of new
motor (and perhaps cognitive) habits requires the neostriatum; learning new
motor behavior or coordinated activities depends on the cerebellum. Different
situations and learning experiences recruit different subsets of these and
other procedural memory systems, in variable combination with the explicit
memory system of the hippocampus and related structures (Squire and Kandel
1999; Squire and Zola-Morgan 1991) (Figure 3–1).
In procedural memory, then, we have a biological example of one component
of unconscious mental life. How does this biologically delineated unconscious
relate to Freud’s unconscious? In his later writings, Freud used
the concept of the unconscious in three different ways (for a review of
Freud’s ideas on consciousness, see Solms 1997). First, he used the term in
a strict or structural way to refer to the repressed or dynamic unconscious.
This unconscious is what the classical psychoanalytic literature refers to as
Biology and the Future of Psychoanalysis 71
the unconscious. It includes not only the id but also that part of the ego
which contains unconscious impulses, defenses, and conflicts and therefore
is similar to the dynamic unconscious of the id. In this dynamic unconscious,
information about conflict and drive is prevented from reaching consciousness
by powerful defensive mechanisms such as repression.
Second, in addition to the repressed parts of the ego, Freud proposed that
still another part of the ego is unconscious. Unlike the unconscious parts of
the ego that are repressed and therefore resemble the dynamic unconscious,
the unconscious part of the ego that is not repressed is not concerned with
unconscious drives or conflicts. Moreover, unlike the preconscious unconscious,
this unconscious part of the ego is never accessible to consciousness
even though it is not repressed. Since this unconscious is concerned with
habits and perceptual and motor skills, it maps onto procedural memory.
I shall therefore refer to it as the procedural unconscious.
Finally, Freud used the term descriptively, in a broader sense—the preconscious
unconscious—to refer to almost all mental activities, to most thoughts
and all memories that enter consciousness. According to Freud, an individual
FIGURE 3–1. A taxonomy of the declarative and procedural
memory systems.
This taxonomy lists the brain structures and connections thought to be especially important
for each kind of declarative and nondeclarative memory.
Source. Reprinted from Milner B, Squire LR, Kandel ER: “Cognitive Neuroscience
and the Study of Memory.” Neuron 20:445–468, 1998. Used with permission of Cell
72 Psychiatry, Psychoanalysis, and the New Biology of Mind
is not aware of almost all of the mental processing events themselves yet can
have ready conscious access to many of them by an effort of attention. From
this perspective, most of mental life is unconscious much of the time and becomes
conscious only as sensory percepts: as words and images.
Of these three unconscious mental processes, only the procedural unconscious,
the unconscious part of the ego that is not conflicted or repressed,
appears to map onto what neuroscientists call procedural memory
(for a similar argument, see also Lyons-Ruth 1998). This important correspondence
between cognitive neuroscience and psychoanalysis was first recognized
in a thoughtful article by Robert Clyman (1991), who considered
procedural memory in the context of emotion and its relevance for transference
and for treatment. This idea has been developed further by Louis
Sander, Daniel Stern, and their colleagues in the Boston Process of Change
Study Group (1998), who have emphasized that many of the changes that
advance the therapeutic process during an analysis are not in the domain of
conscious insight but rather in the domain of unconscious procedural (nonverbal)
knowledge and behavior. To encompass this idea, Sander (1998),
Stern (1998), and their colleagues have developed the idea that there are moments
of meaning—moments in the interaction between patient and therapist—
that represent the achievement of a new set of implicit memories that
permits the therapeutic relationship to progress to a new level. This progression
does not depend on conscious insights; it does not require, so to speak,
the unconscious becoming conscious. Rather, moments of meaning are
thought to lead to changes in behavior that increase the patient’s range of
procedural strategies for doing and being. Growth in these categories of
knowledge leads to strategies for action that are reflected in the ways in
which one person interacts with another, including ways that contribute to
Marianne Goldberger (1996) has extended this line of thought by emphasizing
that moral development also is advanced by procedural means.
She points out that people do not generally remember, in any conscious way,
the circumstances under which they assimilated the moral rules that govern
their behavior; these rules are acquired almost automatically, like the rules
of grammar that govern our native language.
I illustrate this distinction between procedural and declarative memory
that comes from cognitive neuroscience to emphasize the utility for psychoanalytic
thought of a fundamentally neurobiological insight. But in addition,
I would suggest that as applied to psychoanalysis, these biological ideas are
still only ideas. What biology offers is the opportunity to carry these ideas
one important step further. We now know a fair bit about the biology of this
procedural knowledge, including some of its molecular underpinnings (Milner
et al. 1998).
Biology and the Future of Psychoanalysis 73
The interesting convergence of psychoanalysis and biology on the problem
of procedural memory confronts us with the task of testing these ideas
in a systematic way. We will need to examine, from both a psychoanalytic
and a biological perspective, the range of phenomena we have subsumed under
the term procedural memory and see how they map onto different neural
systems. In so doing we will want to examine, in behavioral, observational,
and imaging studies, to what degree different components of a given moment
of meaning or different moments of this sort recruit one or another anatomical
subsystem of procedural memory.
As these arguments make clear, one of the earlier limitations to the study
of unconscious psychic processes was that no method existed for directly
observing them. All methods for studying unconscious processes were indirect.
Thus, a key contribution that biology can now make—with its ability
to image mental processes and its ability to study patients with lesions in different
components of procedural memory—is to change the basis of the
study of unconscious mental processes from indirect inference to direct observation.
By these means we might be able to determine which aspects of
psychoanalytically relevant procedural memory are mediated by which of
the subcortical systems concerned. In addition, imaging methods may also
allow us to discern which brain systems mediate the two other forms of unconscious
memory, the dynamic unconscious and the preconscious unconscious.
Before I turn to the preconscious unconscious and its possible relation to
the prefrontal cortex, I first want to consider three other features related to
the procedural unconscious: its relation to psychic determinism, to conscious
mental processes, and to early experience.
2. The Nature of Psychological Determinacy:
How Do Two Events Become Associated in the Mind?
In Freud’s mind, unconscious mental processes provided an explanatory
mechanism for psychic determinism. The fundamental idea of psychic determinism
is that little, if anything, in one’s psychic life occurs by chance.
Every psychic event, whether procedural or declarative, is determined by an
event that precedes it. Slips of the tongue, apparently unrelated thoughts,
jokes, dreams, and all images within each dream are related to preceding
psychological events and have a coherent and meaningful relationship to the
rest of one’s psychic life. Psychological determinacy is similarly important in
psychopathology. Every neurotic symptom, no matter how strange it may
seem to the patient, is not strange in the unconscious mind but is related to
preceding mental processes. The connections between symptoms and causative
mental processes or between the images of a dream and their preceding
74 Psychiatry, Psychoanalysis, and the New Biology of Mind
psychically related events are obscured by the operation of ubiquitous and
dynamic unconscious processes.
The development of many ideas within psychoanalytic thought and its
core methodology, free association, derives from the concept of psychic determinism
(Kris 1982). The purpose of free association is to have the patient
report to the psychoanalyst all thoughts that come to mind and to refrain
from exercising over them any degree of censorship or direction (Brenner
1978; Kris 1982). The key idea of psychic determinism is that any mental
event is causally related to its preceding mental event. Thus, Brenner (1978)
wrote, “In the mind, as in physical nature about us, nothing happens by
chance, or in a random way. Each psychic event is determined by the ones
which precede it.”
Although we do not have a rich biological model of psychic declarative
explicit knowledge, we have in biology a good beginning of an understanding
of how associations develop in procedural memory (for a review, see
Squire and Kandel 1999). Insofar as aspects of procedural knowledge are relevant
to moments of meaning, these biological insights should prove useful
for understanding the procedural unconscious.
In the last decade of the nineteenth century, at the time that Freud was
working on his theory of psychological determinacy, Ivan Pavlov was developing
an empirical approach to a particular instance of psychic determinism
at the level of what we now call procedural knowledge: learning by association.
Pavlov sought to elucidate an essential feature of learning that had been
known since antiquity. Western thinkers since Aristotle had appreciated that
memory storage requires the temporal association of contiguous thoughts, a
concept later developed systematically by John Locke and the British empiricist
philosophers. Pavlov’s brilliant achievement was to develop an animal
model of learning by association that could be studied rigorously in the laboratory.
By changing the timing of two sensory stimuli and observing
changes in simple reflex behavior, Pavlov (1927) established a procedure
from which reasonable inferences could be made about how changes in the
association between two stimuli could lead to changes in behavior—to
learning (for more recent reviews, see Dickinson 1980; Domjan and
Burkhard 1986; Rescorla 1988; Squire and Kandel 1999). Pavlov thus developed
powerful paradigms for associative learning that led to a permanent
shift in the study of behavior, moving it from an emphasis on introspection
to an objective analysis of stimuli and responses. This is exactly the sort of
shift we are looking for in psychoanalytic investigations of psychic determinism.
I have described this familiar paradigm because I want to emphasize
three points relevant to psychoanalytic thought. First, in learning to associate
two stimuli, a subject does not simply learn that one stimulus precedes
Biology and the Future of Psychoanalysis 75
the other. Instead, in learning to associate two stimuli, a subject learns that
one stimulus comes to predict the other (for a discussion of this point, see
Fanselow 1998; Rescorla 1988). Second, as we shall see below, classical conditioning
is a superb paradigm for analyzing how knowledge can move from
being unconscious to entering consciousness (Shevrin et al. 1996). Finally,
classical conditioning can be used to acquire not only appetitive responses
but also aversive ones and thus can give us insight into the emergence of psychopathology.
I now turn to each of these points.
The psychic determinism of classical conditioning is probabilistic
For many years psychologists thought that classical conditioning followed
rules of psychic determinism similar to those outlined by Freud. They
thought that classical conditioning depended only on contiguity, on a critical
minimum interval between the conditioned and the unconditioned stimulus,
so that the two were experienced as connected. According to this view,
each time a conditioned stimulus is followed by a reinforcing or unconditioned
stimulus, a neural connection is strengthened between the stimulus
and the response or between one stimulus and another, until eventually the
bond becomes strong enough to change behavior. The only relevant variable
determining the strength of conditioning was thought to be the number of
pairings of the conditioned stimulus and unconditioned stimulus. In 1969,
Leon Kamin made what now is generally considered the most significant
empirical discovery in conditioning since Pavlov’s initial findings at the turn
of the century. Kamin found that animals learn more than contiguity; they
learn contingencies. They do not simply learn that the conditioned stimulus
precedes the unconditioned stimulus but rather that the conditioned stimulus
predicts the unconditioned stimulus (Kamin 1969). Thus, associative
learning does not depend on a critical number of pairings of conditioned
stimulus and unconditioned stimulus but on the power of the conditioned
stimulus to predict a biologically significant unconditioned stimulus (Rescorla
These considerations suggest why animals and people acquire classical
conditioning so readily. Classical conditioning, and perhaps all forms of associative
learning, likely evolved to enable animals to learn to distinguish
events that regularly occur together from those that are only randomly associated.
In other words, the brain seems to have evolved a simple mechanism
that “makes sense” out of events in the environment by assigning a predictive
function to some events. What environmental conditions might have
shaped or maintained a common learning mechanism in a wide variety of
species? All animals must be able to recognize and avoid danger; they must
search out rewards such as food that is nutritious and avoid food that is
76 Psychiatry, Psychoanalysis, and the New Biology of Mind
spoiled or poisoned. An effective way to achieve this knowledge is to be able
to detect regular relationships between stimuli or between behavior and
stimuli. It is possible that by examining this relationship in cell biological
terms, we may well be looking at the elementary mechanism of psychic determinism.
Classical conditioning and the relationship of conscious
procedural to unconscious declarative mental processes
Conventional classical conditioning is usually carried out in a form called
delay conditioning, in which the onset of the conditioned stimulus typically
precedes the onset of the unconditioned stimulus by about 500 msec, and
both the conditioned stimulus and the unconditioned stimulus terminate together
(Figure 3–2). This form of conditioning is prototypically procedural
(Clark and Squire 1998; Squire and Kandel 1999). When a normal human
subject learns an eyeblink response to a weak tactile stimulus on his brow,
that subject is unaware that he or she is being conditioned. Patients with
damage to the hippocampus and the medial temporal neocortex, who therefore
lack explicit (declarative) memory altogether, can be conditioned like
normal subjects in a delay-conditioning paradigm.
A slight variation, trace conditioning, converts implicit conditioning into
explicit memory. With trace conditioning the conditioned stimulus terminates
before the unconditioned stimulus occurs, so that the conditioned
stimulus is brief, and there is a 500-msec gap between the termination of the
conditioned stimulus and the onset of the unconditioned stimulus (Figure
3–2). Richard Thompson and his colleagues found that trace conditioning
depends on the hippocampus and is eliminated in experimental animals
with lesions of the hippocampus (Kim et al. 1995; Solomon et al. 1986).
Clark and Squire (1998) extended these experiments to humans and found
that trace conditioning requires conscious recall. In the course of trace
conditioning, normal subjects usually become consciously aware of the temporal
gap in the relationship between the conditioned stimulus and unconditioned
stimulus. Those subjects who do not become aware of this gap do
not acquire trace conditioning. Moreover, this task cannot be mastered by
people who suffer from amnesia—from a defect in declarative memory—as
a result of lesions to the medial temporal lobe.
Thus, a small shift in temporal sequence changes an instance of psychic
determinism from being unconscious to being conscious! This is consistent
with the idea that the two memory systems, procedural and declarative, are
often jointly recruited by a common task and encode different aspects of the
sensory pattern of stimuli (or of the external world) present to the subject.
Where in the medial temporal lobe is this shift from one type of memory
Biology and the Future of Psychoanalysis 77
storage to the other occurring? Eichenbaum (1998) has argued that the hippocampus
functions to associate noncontiguous events over space and time.
We in fact now know that trace conditioning recruits the hippocampus and
the circuitry of the medial temporal lobe. Which parts of the hippocampal
circuitry are key for trace conditioning? Do other regions become involved?
Does the prefrontal cortex (which we shall consider below)—an area concerned
with working memory that is thought to represent an aspect of the
FIGURE 3–2. The different temporal relationships between the
conditioned stimulus (CS) and the unconditioned stimulus (US) for
delay conditioning and trace conditioning.
During delay conditioning, a tone-conditioned stimulus is presented and remains on
until a 100-msec air puff to the eye (the unconditioned stimulus) is presented, and
both stimuli terminate together. The word delay refers to the interval between the onset
of the conditioned stimulus and the onset of the unconditioned stimulus (in this
example, about 700 msec). During trace conditioning, the presentation of the conditioned
stimulus and the presentation of the unconditioned stimulus are separated by
an interval (in this example, 500 msec) during which no stimulus is present.
Source. Reprinted from Clark RE, Squire LR: “Classical Conditioning and Brain Systems:
The Role of Awareness.” Science 280:77–81, 1998. Used with permission of the
American Association for the Advancement of Science.
78 Psychiatry, Psychoanalysis, and the New Biology of Mind
preconscious unconscious—mediate associations between unconscious and
conscious memories that are the subject of analysis?
3. Psychological Causality and Psychopathology
We have seen that one point of convergence between biology and psychoanalysis
is the relevance of procedural memory for early moral development,
for aspects of transference, and for moments of meaning in psychoanalytic
therapy. We have considered a second point of convergence in examining the
relationship between the associative characteristic of classical conditioning
and psychological determinacy. Here, I want to illustrate a third point of
convergence: that between Pavlovian fear conditioning, a form of procedural
memory mediated by the amygdala, signal anxiety, and posttraumatic stress
syndromes in humans.
Early in his work on classical conditioning, Pavlov appreciated that conditioning
is appetitive when the unconditioned stimulus is rewarding, but
the same procedure will produce defensive conditioning when the unconditioned
stimulus is aversive. Pavlov next found that defensive conditioning
provides a particularly good experimental model of signal anxiety, a form of
learned fear that can be advantageous.
It is pretty evident that under natural conditions the normal animal must respond
not only to stimuli which themselves bring immediate benefit or
harm, but also to other physical or chemical agencies…which in themselves
only signal the approach of these stimuli; though it is not the sight or the
sound of the beast of prey which is itself harmful to smaller animals, but its
teeth and claws. (Pavlov 1927, p. 14)
A similar proposal was made independently by Freud. Because painful
stimuli are often associated with neutral stimuli, symbolic or real, Freud
postulated that repeated pairing of neutral and noxious stimuli can cause the
neutral stimulus to be perceived as dangerous and to elicit anxiety. Placing
this argument in a biological context, Freud wrote:
The individual will have made an important advance in his capacity for selfpreservation
if he can foresee and expect a traumatic situation of this kind
which entails helplessness, instead of simply waiting for it to happen. Let us
call a situation which contains the determinant for such expectation a danger
situation. It is in this situation that the signal of anxiety is given. (S. Freud
1926/1959, p. 166; italics added)
Thus, both Pavlov and Freud appreciated that it is biologically adaptive
to have the ability to respond defensively to danger signals before the real
danger is present. Signal or anticipatory anxiety prepares the individual for
Biology and the Future of Psychoanalysis 79
fight or flight if the signal is from the environment. Freud suggested that
mental defenses substitute for actual flight or withdrawal in response to internal
danger. Signal anxiety therefore provides an opportunity for studying
how mental defenses are recruited: how psychic determinism gives rise to
We know that the amygdala is important for emotionally charged memory,
as in classical conditioning of fear by pairing a neutral tone with a shock
(LeDoux 1996). The amygdala coordinates the flow of information between
the areas of the thalamus and the cerebral cortex that process the sensory
cues and areas that process the expression of fear: the hypothalamus, which
regulates the autonomic response to fear, and the limbic neocortical association
areas, the cingulate cortex and prefrontal cortex, which are thought to
be involved in evaluating the conscious evaluation of emotion. LeDoux has
argued that in anxiety, the patient experiences the autonomic arousal as
something threatening happening, an arousal mediated by the amygdala.
LeDoux attributes the absence of awareness to a shutting down of the hippocampus
by stress, a mechanism considered below. We now have excellent
methods for imaging these structures in both experimental animals and humans
in order to address the question of how these linkages are established
and, once established, how they are maintained (Breiter et al. 1996; LeDoux
1996; Whalen et al. 1996).
4. Early Experience and Predisposition to Psychopathology
Signal anxiety represents a simple example of an acquired psychopathology.
But, as is the case with all things acquired, some people have a greater constitutional
disposition than others to acquire neurotic anxiety. What factors
predispose an individual to associate a variety of neutral stimuli with threatening
In “Mourning and Melancholia” and in his other writings, Freud emphasized
two components in the etiology of acquired psychopathology: constitutional
(including genetic) predispositions and early experiential factors,
especially loss. Indeed, there is evidence in the development of many forms
of mental illness for both genetic components and experiential factors (both
early developmental factors and later acute precipitating factors). As one example,
while there is a clear genetic contribution to susceptibility to depression,
many patients with major depression have experienced stressful life
events during childhood, including abuse or neglect, and these stressors are
important predictors of depression (Agid et al. 1999; Bremner et al. 1995;
Brown et al. 1997; Heim et al. 1997a, 1997b; Kendler et al. 1992). The case
is most clear for posttraumatic stress disorder (PTSD), which requires for its
diagnosis the presence of stressful experience so severe as to be outside the
80 Psychiatry, Psychoanalysis, and the New Biology of Mind
range of usual human experience. About 30% of individuals traumatized in
this way subsequently develop the full syndrome of PTSD (Heim et al.
1997a, 1997b). This incomplete penetrance raises the question, What (besides
genes) predisposes people to developing PTSD and other stress-related
The component of the early environment thought to be most important
for humans, and in fact for all mammals, is the infant’s major caretaker, usually
the mother. Psychoanalysis has long argued that the manner in which a
mother and her infant interact creates within the child’s mind the first internal
representation not only of another person but of an interaction, of a relationship.
This initial representation of people and of relationships is
thought to be critical for the subsequent psychological development of the
child. The interaction goes both ways. The way the infant behaves toward
the mother exerts a considerable influence on the mother’s behavior. Secure
attachment of mother and infant is thought to foster in the infant comfort
with itself and basic trust in others, whereas insecure attachment is thought
to foster anxiety.
One of the key initial ideas to emerge from both cognitive and neurobiological
study of development is that the development of these internal representations
can only be induced during certain early and critical periods in
the infant’s life. During these critical periods, and only during these periods,
the infant (and its developing brain) must interact with a responsive environment
(an “average expectable environment,” to use Heinz Hartmann’s term)
if the development of the brain and of the personality is to proceed satisfactorily.
The first compelling evidence for the importance of early relationships
between parents and offspring came from Anna Freud’s studies on the traumatic
effects of family disruption during World War II (A. Freud and Burlingham
1973). The importance of family disruption was further developed
by René Spitz (1945), who compared two groups of infants separated from
their mothers. One group was raised in a foundling home where the infants
were cared for by nurses, each of whom was responsible for seven infants;
the other group was in a nursing home attached to a women’s prison, where
the infants were cared for daily by their mothers. By the end of the first year,
the motor and intellectual performance of the children in the orphanage had
fallen far below that of the children in the nursing home; those children were
withdrawn and showed little curiosity or gaiety.
Harry Harlow extended this work one important step further by developing
an animal model of infant development (Harlow 1958; Harlow et al.
1965). He found that when newborn monkeys were isolated for 6 months to
1 year and then returned to the company of other monkeys, they were physically
healthy but behaviorally devastated. These monkeys crouched in a
Biology and the Future of Psychoanalysis 81
corner of their cages and rocked back and forth like severely disturbed or autistic
children. They did not interact with other monkeys, nor did they fight,
play, or show any sexual interest. Isolation of an older animal for a comparable
period was innocuous. Thus, in monkeys, as in humans, there is a critical
period for social development. Harlow next found that the syndrome
could be partially reversed by giving the isolated monkey a surrogate
mother, a cloth-covered wooden dummy. This surrogate elicited clinging behavior
in the isolated monkey but was insufficient for the development of
fully normal social behavior. Normal social development could only be rescued
if, in addition to a surrogate mother, the isolated animal had contact for
a few hours each day with a normal infant monkey who spent the rest of the
day in the monkey colony.
The work of Anna Freud, Spitz, and Harlow was importantly extended
by John Bowlby, who began to think about the interaction of the infant and
its caregiver in biological terms. Bowlby (1960, 1969) formulated the idea
that the defenseless infant maintains a closeness to its caretaker by means of
a system of emotive and behavioral response patterns that he called the attachment
system. Bowlby conceived of the attachment system as an inborn
instinctual or motivational system, much like hunger or thirst, that organizes
the memory processes of the infant and directs it to seek proximity to
and communication with the mother. From an evolutionary point of view,
the attachment system clearly enhances the infant’s chances for survival by
allowing the immature brain to use the parents’ mature functions to organize
its own life processes. The infant’s attachment mechanism is mirrored in the
parents’ emotionally sensitive responses to the infant’s signals. Parental responses
serve both to amplify and reinforce the infant’s positive emotional
state and attenuate the infant’s negative emotional states by giving the infant
secure protection when upset. These repeated experiences become encoded
in procedural memory as expectations that help the infant feel secure.
It should be noted that during the first 2–3 years of life, when an infant’s
interaction with its mother is particularly important, the infant relies primarily
on its procedural memory systems. Both in humans and in experimental
animals, declarative memory develops later. Thus, infantile amnesia, which
results in the fact that very few memories from early childhood are accessible
to later recall, is evident not only in humans but also in other mammals, including
rodents. This amnesia presumably occurs not because of the powerful
repression of memories during resolution of the oedipal complex, but
because of slow development of the declarative memory system (Clyman
Bowlby described the response to separation as occurring in two phases:
protest and despair. Events that disturb the proximity of the infant to the attachment
object elicit protest: clinging, following, searching, crying, and
82 Psychiatry, Psychoanalysis, and the New Biology of Mind
acute physiological arousal lasting minutes to hours. These behaviors serve
to restore proximity. When contact is regained, these clinging behaviors are
shut off, according to Bowlby, by a feedback mechanism, and alternative behavioral
systems, most notably exploratory behavior, become activated. If
separation is prolonged, despair gradually replaces the early responses as the
infant recognizes that separation may be prolonged or permanent and shifts
from anxiety and anger to sadness and despair. Whereas protest is thought
to be adaptive by increasing the likelihood that the parent and infant find
each other again, despair is thought to prepare the infant for prolonged passive
survival, achieved by conserving energy and withdrawing from danger.
We owe to Levine and colleagues (1957, 1962; Levine et al. 1967), Ader
and Grota (1969), and Hofer (1981, 1994) the discovery that a similar attachment
system exists in rodents. The extension of this research to a rodent
model system, which is much simpler, but still mammalian, holds great
power. For example, in mice, individual genes can be expressed or ablated,
which allows a powerful approach for relating individual genes to behavior.
Levine found that rat pups show an immediate protest to separation, consisting
of repeated high-intensity vocalization, agitated searching, and high
levels of self-grooming. If the mother fails to return and the separation continues,
the protest behaviors wane over a period of hours and are replaced
by a number of slower-developing behaviors—akin to despair—as the pups
become progressively less alert and responsive, and their body temperature
and heart rate drop. Much as Harlow was able to dissect the components of
the caregiver that were essential for normal character development, so Hofer
was able to show that three different aspects of pups’ protest-despair responses
were triggered by three different hidden regulators within the
mother-infant interaction: loss of warmth, loss of food, and loss of tactile
Levine and his colleagues (1967) were the first to carry the analysis to a
molecular level by studying how varying degrees of infant attachment affected
the animals’ subsequent ability to respond to stress. Hans Selye had
pointed out as early as 1936 that humans and experimental animals respond
to stressful experiences by activating their hypothalamic-pituitary-adrenal
(HPA) axis. The end product of the HPA system is the release of glucocorticoid
hormones by the adrenal gland. These hormones serve as major regulators
of homeostasis—of intermediary metabolism, muscle tone, and
cardiovascular function. Together with catecholamines released by the autonomic
nervous system and by the adrenal medulla, the secretion of glucocorticoids
is essential for survival in the face of stress.
Levine therefore asked the question, Can the long-term response of the
HPA system to stress be modulated by experience? If so, is it particularly sensitive
to early experience? Levine discovered that when, during the first
Biology and the Future of Psychoanalysis 83
2 weeks of life, pups were removed from their mothers for only a few minutes,
the pups showed increased vocalization, which elicited increased maternal
care. The mothers responded by licking, grooming, and carrying these
pups around more often than if they had not been removed. This increase in
the mother’s attachment behavior reduced, for the rest of the animal’s life, the
pup’s HPA response—its plasma levels of glucocorticoid—to a variety of
stressors! Concomitantly, it reduced the pup’s fearfulness and vulnerability
to stress-related disease (Liu et al. 1997; Plotsky and Meaney 1993). By contrast,
when, during the same 2-week period of life, pups were separated from
their mothers for prolonged periods of time (3–6 hours per day for 2 weeks),
the opposite reaction ensued. Now the mothers ignored the pups, and the
pups showed an increase in plasma ACTH and glucocorticoid responses
to stress as adults. Thus, differences in an infant’s interactions with its
mother—differences that fall in the range of naturally occurring individual
differences in maternal care—are crucial risk factors for an individual’s future
response to stress. Here we have a remarkable example of how early experience
alters the set point for a biological response to stress.
Studies by Charles Nemeroff and Paul Plotsky have found that these
early adverse life experiences result in increased gene expression for corticotropin-
releasing factor (CRF), the hormone released from the hypothalamus
to initiate the HPA response. Daily maternal separation during the first
2 weeks is associated in the rat with profound and persistent increases in the
expression of the mRNA for CRF, not only in the hypothalamus but also in
limbic areas, including the amygdala and the bed nucleus of the stria terminalis
(Meaney et al. 1991; Nemeroff 1996; Plotsky and Meaney 1993).
However, the biological insights into attachment theory do not stop here.
Bruce McEwen, Robert Sapolsky, and their colleagues have discovered that
the increases in glucocorticoids which follow prolonged separation have adverse
effects on the hippocampus (McEwen and Sapolsky 1995; Sapolsky
1996). There are two types of receptors for glucocorticoids: type 1 (the mineralocorticoid
receptors) and type 2 (the glucocorticoid receptors). The hippocampus
is one of the few sites in the body that has both! Thus, repeated
stress (or exposure to elevated glucocorticoids over a number of weeks)
causes atrophy of neurons of the hippocampus, which is reversible when the
stress or glucocorticoid exposure is discontinued. However, when stress or
elevated glucocorticoid exposure is prolonged over many months or even
years, permanent damage occurs, and there is a loss of hippocampal neurons.
As we might predict from the key role of the hippocampus in declarative
memory, both reversible atrophy and permanent damage result in
significant impairment of memory. This deficit in memory is detectable at
the cellular level; it is evident in a weakening of a process called long-term
potentiation, an intrinsic mechanism that is thought to be critical for learn84
Psychiatry, Psychoanalysis, and the New Biology of Mind
ing-related strengthening of synaptic connections (McEwen and Sapolsky
1995; Squire and Kandel 1999) (Figure 3–3). Thus, what may initially appear
as repression may actually prove to be a true amnesia: damage to the
medial temporal lobe system of the brain.
This set of experiments has deep significance for the relationship of early
unconscious mental processes to later conscious mental processes. Stress
early in life produced by separation of the infant from its mother produces a
reaction in the infant that is stored primarily by the procedural memory system,
the only well-differentiated memory system that the infant has early in
its life, but this action of the procedural memory system leads to a cycle of
changes that ultimately damages the hippocampus and thereby results in a
persistent change in declarative memory.
This rodent model has direct clinical relevance. Patients with Cushing’s
syndrome overproduce glucocorticoids as a result of having a tumor in the
adrenal gland, the pituitary gland, or the part of the hypothalamus that controls
the pituitary. Starkman and her colleagues (1992) have studied these
patients and found that those who have had the disease for over 1 year have
selective atrophy of the hippocampus and concomitant memory loss. Similar
atrophy and memory loss are thought to occur with posttraumatic stress.
Bremner and his colleagues (1995, 1997) have found that patients with combat-
related PTSD have deficits in declarative memory as well as an 8% reduction
in the volume of the right hippocampus (Figure 3–3). Here, however,
the atrophy and memory loss are not secondary to increased glucocorticoids
but are due to some other mechanisms, since in these patients the glucocorticoid
levels are lower than normal.
In the 1970s, Sachar first showed that similar events occur in the hypothalamic-
pituitary axis of patients with depression (Sachar 1976). Over 50%
of depressed patients have sustained levels of glucocorticoids. Subsequent
studies showed that elevated glucocorticoids are associated with a decrease
in the number of glucocorticoid receptors and with resistance to cortisol
suppression by dexamethasone. Consistent with the data from rodents, patients
with depression have a significant reduction in the volume of the hippocampus
and an elevated loss of declarative memory.
Nemeroff and his colleagues (reviewed in Nemeroff 1998) have found
that in depressed patients, the secretion of CRF is markedly increased. This
has suggested the interesting idea that in depressed patients, the neurons in
the brain that secrete CRF are hyperactive. Consistent with this idea, when
CRF is injected directly into the central nervous system of mammals, it produces
many of the signs and symptoms of depression, including decreased
appetite, altered autonomic nervous system activity, decreased libido, and
disrupted sleep. In view of the evidence that early untoward life experience
increases the likelihood in adulthood of suffering from depression or certain
Biology and the Future of Psychoanalysis 85
FIGURE 3–3. Schematic summary of actions of adrenal steroids
that affect hippocampal function and alter cognitive performance.
Left: Do stress-induced glucocorticoids cause brain atrophy? Relation between hippocampal
volume and (top) duration of depression among individuals with a history
of major depression, (middle) extent of cortisol hypersecretion among patients with
Cushing’s syndrome, and (bottom) duration of combat exposure among veterans
with or without a history of posttraumatic stress disorder. Cortisol is another term for
the human glucocorticoid hydrocortisone.
Right: (top): Hippocampal circuitry is diagrammed showing some of the main connections
between entorhinal cortex (ENT), Ammon’s horn (H), and dentate gyrus
(DG). f=fornix; pp=perforant pathway; CA1 and CA3 are subregions of the hippocampus.
(bottom): Moderate-duration stress, acting through both glucocorticoids
and excitatory amino acids (especially glutamate), causes reversible atrophy of apical
dendrites of CA3 pyramidal neurons; severe and prolonged stress causes pyramidal
cell loss that is especially apparent in CA3, but spreads to CA1 as well. The mechanistic
relationship between reversible atrophy and permanent neuron loss is not presently
known, although both glucocorticoids and excitatory amino acids are involved.
Source. (Left): Reprinted from Sapolsky RM: “Why Stress is Bad for Your Brain.”
Science 273:749–750, 1996. Used with permission of the American Association for
the Advancement of Science. (Right): Reprinted from McEwen BS, Sapolsky RM:
“Stress and Cognitive Function.” Curr Opin Neurobiol 5:205–216, 1995. Used with
permission of Elsevier.
86 Psychiatry, Psychoanalysis, and the New Biology of Mind
anxiety disorders, Nemeroff has suggested that this vulnerability is probably
mediated by the hypersecretion of CRF.
These insights are likely to have several applications. First is the development
of progressively more refined animal models for the factors that predispose
to stress and depression, models that may allow one to identify—in
experimental animals and perhaps later in humans—the genes that are activated
by CRF and that predispose to anxiety. Second, drugs that block the
actions of CRF on its receptors in target tissue may prove useful for certain
types of depression. Finally, with increased resolution, one might conceivably
be able to follow the therapeutic responses of patients by imaging the
hippocampus and seeing to what degree anatomical changes are halted, or
even reversed, and by seeing how responses to psychotherapy correlate with
levels of CRF and glucocorticoids.
5. The Preconscious Unconscious and the Prefrontal Cortex
We have so far only considered the implicit unconscious. What about the
preconscious unconscious concerned with all memories and thought capable
of reading consciousness and the repressed or unconscious? We have
reasons to believe that aspects of the preconscious unconscious may be mediated
by the prefrontal cortex. Perhaps the strongest argument is that the
prefrontal cortex is involved in bringing a variety of explicit knowledge to
conscious awareness. The prefrontal association cortex has two major functions:
it integrates sensory information, and it links it to planned movement.
Because the prefrontal cortex mediates these two functions, it is thought to
be one of the anatomical substrates of goal-directed action in long-term
planning and judgment. Patients with damaged prefrontal association areas
have difficulty in achieving realistic goals. As a result, they often achieve little
in life, and their behavior suggests that their ability to plan and organize
everyday activities is diminished (Damasio 1994, 1996).
Over the last two decades, it has become clear that the prefrontal cortex
subserves as one component of a system that serves as a critical short-term
holding function for information, including information that is stored in or
recalled from declarative memory stores. This idea emerged from the discovery
that lesions in the prefrontal cortex produce a specific deficit in a shortterm
component of explicit memory called working memory. The cognitive
psychologist Alan Baddeley (1986), who developed the idea of working
memory, suggested that this type of memory integrates moment-to-moment
perceptions across time, rehearses them, and combines them with stored information
about past experience, actions, or knowledge. This memory
mechanism is crucial for many apparently simple aspects of everyday life:
carrying on a conversation, adding a list of numbers, driving a car. Baddeley’s
Biology and the Future of Psychoanalysis 87
idea was further developed in neurobiological experiments by Joaquin Fuster
(1997) and Patricia Goldman-Rakic (1996), who first suggested that
some aspects of working memory are represented in the prefrontal association
cortex and that the recall of any explicit information from memory—
the recall from preconscious to conscious—requires working memory. A
prediction of this finding is that in trace conditioning, the unconditioned
stimulus might activate the working memory system of the dorsolateral prefrontal
cortex, and thereby it acts, often together with the hippocampus, to
render into consciousness the otherwise procedural associative process.
Clinical studies of patients with lesions suggest that the prefrontal cortex
also seems to represent some aspects of moral judgments; it governs our
ability to plan intelligently and responsibly (Damasio 1996). This raises the
interesting possibility that the recall of explicit knowledge may depend on
an adaptive and realistic evaluation of the information to be recalled. In this
sense the prefrontal cortex may, as suggested by Solms (1998), be involved
in coordinating functions psychoanalysts attribute to the executive functions
of the ego on the one hand and the superego on the other.
6. Sexual Orientation and the Biology of Drives
Freud conceived of drives as the energetic components of mind. A drive, he
argued, leads to a state of tension or excitation, a state that cognitive psychologists
now call the motivational state. Motivational states impel actions
with the goal of reducing tension.
Early in his career, perhaps influenced by Havelock Ellis (1901), Magnus
Hirschfeld (1899), and Richard Krafft-Ebing (1901), Freud believed that a
person’s sexual orientation was significantly influenced by innate developmental
processes and that all humans were constitutionally bisexual. This
constitutional bisexuality was a key factor in both male and female homosexuality.
Later, however, he came to think of sexual orientation as an
acquired characteristic. Freud (1905/1953) specifically thought of male homosexuality
as representing a failure of normal sexual development, a failure
of the developing male child to separate himself adequately from an intense
sexual bond with his mother. As a result, the grown boy identifies with his
mother and seeks to play her role in an attempt to reenact the relationship
that existed between them. Freud proposed that the boy’s failure to separate
from his mother might be the result of several factors, including a close,
binding relationship to a possessive mother and a weak, hostile, or absent
father. In terms of his three phases of psychosexual development, Freud saw
male homosexuality, with its emphasis on anal intercourse, as a failure to
progress normally from the anal to the genital phase. Female homosexuality
was defined less clearly in Freud’s mind, but he thought of it as the mirror
88 Psychiatry, Psychoanalysis, and the New Biology of Mind
image of the process he outlined for men. Freud also saw a latent homosexual
component in the development of paranoia, alcoholism, and drug addiction.
Freud’s views on sexuality are now at least 50 years old, and in some
cases 90 years old. Some have understandably been abandoned by modern
psychoanalytic thought, and all have been modified. But I recount them not
to hold Freud or the psychoanalytic community responsible for outdated
ideas but to illustrate that any psychological or clinical insight into sexuality,
no matter how modern, will almost certainly be clarified by a better biological
understanding of gender identification and sexual orientation, even
though at the moment we know little. As homosexuality has become more
openly accepted by society at large, there has been active discussion within
the homosexual community, the psychoanalytic community, and society
about the degree to which sexual orientation is inborn or acquired. The observation
by Freud and other analysts that some gay men tend to recollect
their fathers as hostile or distant and their mothers as unusually close has
more recent corroboration (LeVay 1997). However, other studies suggest a
genetic contribution to sexual orientation.
This is a complex area, because genotypic gender, phenotypic gender,
gender identification, and sexual orientation are distinct from one another
but interrelated. Indeed, the recognition of this complexity can render standard
terms such as male, female, masculine, and feminine imprecise and in
need of qualification (Bell et al. 1981).
Genotypic gender is determined by the genes, whereas phenotypic gender
is defined by the development of the internal and external genitalia (Bell
et al. 1981; Gorski 2000; Green 1985). Gender identification is more subtle
and complex and refers to the subjective perception of one’s sex. Finally, sexual
orientation refers to the preference for sexual partners. The factors that
contribute to the various aspects of gender are not fully understood, but
I discuss them because historically this is an area that is central to psychoanalysis;
and since the nurture–nature dichotomy is one that biology has repeatedly
confronted and sometimes enlightened, this is an area in which
biology could make a distinctive contribution. Although gender identification
and sexual orientation are complex and have features that are distinctively
human and may well not be amenable to study in experimental
animals, many other aspects of sexual behavior are much like feeding and
drinking behavior—so essential to survival that they are extremely conserved
among mammals, involving common brain and hormonal systems
and even aspects of stereotypic behavior. As a result, we have learned a good
deal about the neural control of sex hormones and behavior from experimental
animals such as rats and mice.
Early embryonic development of the gonad is identical in males and feBiology
and the Future of Psychoanalysis 89
males. Genotypic gender is determined by an individual’s complement of sex
chromosomes: females have two X chromosomes, whereas males have one
X and one Y. Male phenotypic gender is determined by a single gene, called
testis determining factor, on the Y chromosome. This gene initiates the development
of the bisexual early gonad into a testis, which produces testosterone;
in the absence of testis determining factor, the gonad develops into
an ovary and produces estrogen. All of the other phenotypic sexual characteristics
result from the effects of gonadal hormones on other tissues. Of particular
interest both to biologists and to psychoanalysts is that sexual
dimorphism extends to the brain and thereby to behavior.
The behavior of males and females differs, even before puberty. Since
many aspects of sexuality are conserved among all mammals, sexual behavior
relevant to human sexuality can be studied in primates and even in rodents.
Young male monkeys participate in more rough-and-tumble play than
do female monkeys, a difference related to testosterone levels. Human girls
who have been exposed prenatally to unusually high levels of androgens as
a result of congenital adrenal hyperplasia prefer the same play as boys (Gorski
1996, 2000; Schiavi et al. 1988). It seems likely that sex differences in the
play behavior of children are influenced at least in part by the organizational
effects of the level of prenatal androgens.
The level of testosterone has other dramatic effects on behavior (Gladue
and Clemens 1978; Gorski 1996; Imperato-McGinley et al. 1991; Knobil and
Neil 1994). Male rats castrated at or prior to birth fail as adults to show the
mounting behavior typical of males in the presence of receptive females,
even if they are given testosterone. Furthermore, if these rats are given estrogen
and progesterone in adulthood, mimicking the hormonal milieu of the
adult female rats, they display the same sexually receptive posture typical of
females in heat. If castration is performed a few days after birth, neither of
these effects occurs. Thus, like perceptual skills and motor coordination,
sex-typical behavior is organized during a critical period, around the time of
birth, even though the behavior itself is not seen until much, much later.
Sex differences in behavior, to the extent that they manifest differences
in brain function, must at least partly result from sex differences in the structure
of the central nervous system. One possible anatomical site for these
differences is the hypothalamus, which is concerned with sexual behavior as
well as a variety of other homeostatic drives (for a review, see Knobil and
Neil 1994). Electrical stimulation of the hypothalamus in intact, awake
rhesus monkeys and rats generates sex-typical sexual behavior (Perachio et
al. 1979). Biologists have found a striking sexually dimorphic difference in
the medial preoptic area of the hypothalamus in rodents (Allen and Gorski
1992; Allen et al. 1989). Here there are four functional groups of neurons—
of unknown function so far—called the interstitial nuclei of the anterior hy90
Psychiatry, Psychoanalysis, and the New Biology of Mind
pothalamus (INAH-1 to INAH-4). One of these nuclei, INAH-3, is five times
larger in the male rat than in the female. Many cells in this nucleus die during
female development; these cells are rescued in male pups by circulating
testosterone and can be rescued in females by testosterone injections during
a critical developmental window (Davis et al. 1996; Dodson and Gorski
There are also sexual dimorphisms in the thickness of various regions of
the cerebral cortex in the rat. For example, there is greater asymmetry in the
male: the thickness of the left side of a male rat cortex is greater than the
right. Perhaps as a consequence, the splenium of the corpus callosum contains
more neurons in the female. Other brain regions also show sexual dimorphisms,
and doubtless there are more to be found.
The finding of a biological basis for gender genotype and phenotype
raises the question, What is the biological basis for sexual orientation? To
begin with, it is obvious that as the development of gender is multifactorial,
so the etiology of sexual orientation must also be multifactorial; presumably,
it is determined by hormones, genes, and environmental factors. A behavioral
trait such as sexual orientation almost certainly is not caused by a single
gene, a single alteration in a hormone or in brain structure, or a single
life experience. The continuing progress in studies of sexually dimorphic
characteristics will no doubt help psychoanalysts better understand gender
identity and sexual orientation.
Anatomical studies on sexual orientation are just beginning, and we will
need much more information before we can have confidence in the published
findings on anatomical differences. At the moment they should rather
be considered as interesting possibilities. Simon LeVay (1991, 1997) obtained
brains of gay men and presumed heterosexual men, all of whom died
of AIDS, and the brains of women. INAH-3, the most prominent of the sexually
dimorphic nuclei in the rat hypothalamus, was on average two to three
times bigger in the presumed heterosexual men than in the women. However,
in the gay men INAH-3 was on average the same size as in the women.
None of the other three INAH nuclei showed any difference between the
groups. In addition to potential problems with the sample under study, it is
not possible on the basis of LeVay’s observations to say whether the structural
differences are present at birth, whether they influence men to become
gay or straight, or whether the dimorphism is a result of differences in sexual
behavior. But with better sampling and improvements in brain imaging techniques,
it may be possible to answer these questions.
Allen and Gorski (1992) described still another difference between gay
and straight men in the anterior commissure, a pathway between the left and
right sides of the brain that is generally larger in women than in men. Allen
and Gorski found that the anterior commissure is on average larger in gay
Biology and the Future of Psychoanalysis 91
men than in straight men. In fact, it is larger in gay men than in women (see
also Zhou et al. 1995).
Another question that is now being addressed is whether sexual orientation
is inherited or acquired (Bailey and Pillard 1991; Bailey et al. 1993;
Dörner et al. 1991; Eckert et al. 1986; Hamer et al. 1993; Pillard and Weinrich
1986; Whitman et al. 1993). Sexual orientation seems to be influenced
by genes, and this influence is, as one would expect, complex. Sexual orientation
runs in families. If a male is gay, the chances of a twin brother being
gay increase substantially. In the case of monozygotic twins, individuals who
share the same genes, the concordance rate is 50%. For dizygotic twins, the
concordance rate is about 25%. By contrast, in the general population, the
incidence of male homosexuality is less than 10%. For female homosexuality,
the genetic relationship is weaker—about 30% of monozygotic twins and
about 15% of dizygotic twins. These numbers seem roughly similar to those
for other complex traits, indicating that both genetic and important nongenetic
factors operate.
These are all early findings, and their consistency over groups of people,
both heterosexual and homosexual, is still being questioned. But the methods
are at hand for establishing whether there are reliable anatomical differences
between people with different sexual orientations. As I suggested
above, either outcome should greatly influence psychoanalytic thinking
about the dynamics of sexual orientation.
7. Outcome of Therapy and Structural Changes in the Brain
Recent work in experimental animals indicates that long-term memory leads
to alterations in gene expression and to subsequent anatomical changes in the
brain. Anatomical changes in the brain occur throughout life and are likely to
shape the skills and character of an individual. The representation of body
parts in the sensory and motor areas of the cerebral cortex depends on their
use and, thus, on the particular experience of the individual. Edward Taub and
his colleagues scanned the brains of string instrument players. During performance,
string players are continuously engaged in skillful hand movement.
The second to fifth fingers of the left hand, which contact the strings, are manipulated
individually, while the fingers of the right hand, which move the
bow, do not express as much patterned, differentiated movement. Brain images
of these musicians revealed that their brains were different from the
brains of nonmusicians. Specifically, the cortical representation of the fingers
of the left hand, but not of the right, was larger in the musicians (for review,
see Ebert et al. 1995; Squire and Kandel 1999) (Figure 3–4).
Such structural changes are more readily achieved in the early years of
life. Thus, Johann Sebastian Bach was Bach not simply because he had the
92 Psychiatry, Psychoanalysis, and the New Biology of Mind
right genes but probably also because he began practicing musical skills at a
time when his brain was most sensitive to being modified by experience.
Taub and his colleagues found that musicians who learned to play their instruments
by the age of 12 years had a larger representation of the fingers of
the left hand, their important playing hand, than did those who started later
in life (Figure 3–4) (Ebert et al. 1995).
These considerations raise a question central to psychoanalysis: Does
therapy work in this way? If so, where do these psychotherapeutically induced
changes occur? Do the therapeutically induced structural changes
occur at the same sites altered by the mental disorder itself, or are the therapeutically
induced changes independent compensatory changes that occur
at other related sites?
FIGURE 3–4. Larger size of the cortical representation of the
fifth finger of the left hand in string players than in nonmusicians.
The figure shows the size of cortical representations measured by magnetoencephalography
as the dipole strength, which is thought to be an index of total neuronal activity.
Among string players, those who begin musical practice before age 13 have a
larger representation than do those who begin later. Horizontal lines indicate means.
Source. Based on Ebert et al. 1995 as modified by Squire LR, Kandel ER: Memory:
From Mind to Molecules. New York: Scientific American Library, 2000. Figure reprinted
by permission of Scientific American Inc.
Biology and the Future of Psychoanalysis 93
Long-lasting changes in mental functions involve alteration in gene expression
(Ebert et al. 1995; Squire and Kandel 1999). Thus, in studying the
specific changes that underlie persistent mental states, normal as well as disturbed,
we should also look for altered gene expression. How does altered
gene expression lead to long-lasting alteration of a mental process? Animal
studies of alterations in gene expression associated with learning indicate
that such alterations are followed by changes in the pattern of connections
between nerve cells, in some cases the growth and retraction of synaptic
It is intriguing to think that insofar as psychoanalysis is successful in
bringing about persistent changes in attitudes, habits, and conscious and
unconscious behavior, it does so by producing alterations in gene expression
that produce structural changes in the brain. We face the interesting possibility
that as brain imaging techniques improve, these techniques might be
useful not only for diagnosing various neurotic illnesses but also for monitoring
the progress of psychotherapy.
8. Psychopharmacology and Psychoanalysis
As early as 1962, Mortimer Ostow, a psychoanalyst trained in neurology who
had a long interest in the relationship of neurobiology to psychoanalysis
(Ostow 1954a, 1954b), pointed to the utility of using drugs in the course of
psychoanalysis (Ostow 1962). He argued even then that in addition to its
therapeutic value, pharmacological intervention can serve as a biological
tool for investigating aspects of affective function. Ostow observed that one
of the principal effects of psychopharmacological agents is on affect, which
led him to argue that affect often is a more important determinant of behavior
and of illness than ideation or conscious interpretation. This idea reinforces
that of Sander, Stern, and the Boston Process of Change Study Group
on the relative importance of unconscious affect over conscious insight, and
stresses once again the importance of changes in unconscious procedural
knowledge (such as those that occur during the moments of meaning considered
above) as indices of therapeutic progress, indices that the Boston
group considers as important as conscious insight. Both the arguments of
Ostow and those of the Boston group make clear that changes in the patient’s
unconscious internal representations can be beneficial for progress even
without reaching consciousness. Perhaps, in these cases, the unconscious is
more important than even Freud appreciated! Thus, the theme that emerges
from Ostow’s study on the actions of psychopharmacological agents on the
psychoanalytic process echoes the ideas of Sanders and Stern, which stress
that progress in psychotherapy has an important procedural component and
that much of what happens in therapy need not be directly related to insight.
94 Psychiatry, Psychoanalysis, and the New Biology of Mind
A Genuine Dialogue Between Biology and
Psychoanalysis Is Necessary If We Are to
Achieve a Coherent Understanding of Mind
As I have suggested earlier, most biologists believe that the mind will be to
the twenty-first century what the gene was to the twentieth century. I have
briefly discussed how the biological sciences in general and cognitive neuroscience
in particular are likely to contribute to a deeper understanding of
a number of key issues in psychoanalysis. An issue that is often raised is that
a neurobiological approach to psychoanalytic issues would reduce psychoanalytic
concepts to neurobiological ones. If that were so, it would deprive
psychoanalysis of its essential texture and richness and change the character
of therapy. Such a reduction is not simply undesirable but impossible. The
agendas for psychoanalysis, cognitive psychology, and neural science overlap,
but they are by no means identical. The three disciplines have different
perspectives and aims and would converge only on certain critical issues.
The role of biology in this endeavor is to illuminate those directions that
are most likely to provide deeper insights into specific paradigmatic processes.
Biology’s strength is its rigorous way of thinking and its depth of analysis.
Our understanding of heredity, gene regulation, the cell, antibody
diversity, the development of the body plan and of the brain, and the generation
of behavior has been profoundly expanded as biology has probed progressively
deeper into the molecular dynamics of life processes. The
strengths of psychoanalysis are its scope and the complexity of the issues it
addresses, strengths that cannot be diminished by biology. Just as medicine
has time and again provided direction to biology, and psychiatry to neuroscience,
so can psychoanalysis serve as a skillful and reality-oriented tutor
for a sophisticated understanding of the mind-brain.
During the past half century, we have repeatedly seen successful unifications
within the biological sciences without the disappearance of the core
disciplines. For example, classical genetics and molecular biology have
merged into a common discipline, molecular genetics. We now know that
the traits that Gregor Mendel described and the genes on specific locations
on chromosomes that Thomas Hunt described are stretches of doublestranded
DNA. This insight has allowed us to understand how genes replicate
and how they control cellular function. These insights have revolutionized
biology, but this has hardly abolished the discipline of genetics. To the
contrary, with the human genome sequence expected to be completed in the
year 2003, genetics is flourishing. It has used the powerful insight of molecular
biology, applied it effectively to its own agenda, and moved on. So be it
with psychoanalysis.
Biology and the Future of Psychoanalysis 95
Are We Seeing the Beginnings of a Dialogue?
As we have seen, biology could help psychoanalysis in two ways: conceptually
and experimentally. We are in fact already beginning to see signs of conceptual
progress. A number of psychoanalytic institutes, or at least a number
of people within psychoanalysis, have struggled to make psychoanalysis
more rigorous and to align it more closely with biology. Freud argued for this
position at the beginning of his career. More recently, Mortimer Ostow of the
Neuroscience Project of the New York Psychoanalytic Institute and David
Olds and Arnold Cooper at the Columbia Institute (Olds and Cooper 1997),
as well as others across the country, have earlier expressed ideas similar to
those I outline here.
For many years both the Association for Psychoanalytic Medicine at Columbia
and the New York Psychoanalytic Institute, to use but two examples,
have instituted (with the help of my colleague James H. Schwartz) neuropsychoanalytic
centers that address interests common to psychoanalysis and
neuroscience, including consciousness, unconscious processing, autobiographical
memory, dreaming, affect, motivation, infantile mental development,
psychopharmacology, and the etiology and treatment of mental
illness. The prospectus of the New York Psychoanalytic Institute now reads
as follows:
The explosion of new insights into numerous problems of vital interest to
psychoanalysis needs to be integrated in meaningful ways with the older
concepts and methods as do the burgeoning research technologies and pharmacological
treatments. Similarly neuroscientists exploring the complex
problems of human subjectivity for the first time have much to learn from a
century of analytic inquiry. (New York Psychoanalytic Institute 1999)
Thus, psychoanalysts are beginning to learn about neural science and
psychopharmacology, an exciting step forward, a step that should lead in the
long run to a new curriculum for the analytic clinician.
As a result of these efforts, there has been a bit of progress in the second
function of biology, the experimental function. Several investigators have
seen the exciting possibility of merging psychoanalysis and biology experimentally.
Most commendable are the important attempts by Karen Kaplan-
Solms and Mark Solms to delineate anatomical systems in the brain that are
relevant to psychoanalysis by studying alterations in the mental functioning
of patients with brain lesions (Kaplan-Solms and Solms 2000). Kaplan-
Solms and Solms believe that the power of psychoanalysis derives from its
ability to investigate mental processes from a subjective perspective. However,
as they point out, this very strength is also its greatest weakness. Subjective
phenomena do not readily lend themselves to objective empirical
96 Psychiatry, Psychoanalysis, and the New Biology of Mind
analysis. We need to develop creative ways of studying subjective phenomena.
As a result, these investigators argue that only by connecting psychoanalytic
thought to objective neurobiological phenomena, as in personality
changes following focal lesions of the brain, can one derive empirical correlates
of the subjectively derived constructs of psychoanalysis. Similarly,
there is also the important and long-standing tradition of work by Howard
Shevrin, correlating the perception of subliminal and supraliminal stimuli
with event-related potentials in the brain in an attempt to analyze aspects of
unconscious mental processes (Shevrin 1998; Shevrin et al. 1996).
These beginnings are extremely encouraging. But for psychoanalysis to
be reinvigorated, it will need to match its intellectual restructuring with
institutional changes. For biology to help, two aspects of psychoanalysis require
particular attention: therapeutic outcome and the role of psychoanalytic
The Evaluation of Psychoanalytic Outcome
As a mode of therapy, psychoanalysis is no longer as widely practiced as it
was 50 years ago. Jeffrey (1998) claims that the number of patients seeking
psychoanalysis steadily decreased by 10% a year over the last 20 years, as has
the number of gifted psychiatrists seeking training in psychoanalytic institutes.
This decline is disappointing, because psychoanalytic therapy seems
to have become more realistically focused and therefore is more likely to be
efficacious. During the last several decades, psychoanalysis has largely abandoned
the unrealistic goals of the 1950s, when it attempted to treat by itself
autism, schizophrenia, and severe bipolar illness, illnesses for which it had
little, if anything, to offer. Nowadays, psychoanalysis is thought to be most
successful for people with the nonpsychotic character disorders, people who
have major deficits in working effectively or maintaining satisfactory relationships
and who want to acquire better ways of managing their lives. A
substantial number of these patients suffer from borderline personality disorder
with concomitant disturbances of affect. In these cases, psychoanalysis
and psychoanalytically oriented psychotherapy are thought to be an important
adjunct to pharmacotherapy (see Friedman et al. 1998 for the distribution
of patients seen in psychoanalysis). As a result of this narrower focus on
patients who are not psychotic, psychoanalysis and psychoanalytically oriented
psychotherapy may in the best of hands be more effective today than
ever before.
I am here reminded of Kay Jamison’s (1996) haunting discussion of her
own manic-depressive illness and her effective response to combined lithium
medication and psychotherapy:
Biology and the Future of Psychoanalysis 97
At this point in my existence, I cannot imagine leading a normal life without
both taking lithium and having had the benefits of psychotherapy. Lithium
prevents my seductive but disastrous highs, diminishes my depressions,
clears out the wool and webbing from my disordered thinking, slows me
down, gentles me out, keeps me from ruining my career and relationships,
keeps me out of a hospital, alive, and makes psychotherapy possible. But, ineffably,
psychotherapy heals. It makes some sense of the confusion, reins in
the terrifying thoughts and feelings, returns some control and hope and possibility
of learning from it all. Pills cannot, do not, ease one back into reality;
they only bring one back headlong, careening, and faster than can be endured
at times. Psychotherapy is a sanctuary; it is a battleground; it is a place
I have been psychotic, neurotic, elated, confused, and despairing beyond belief.
But, always, it is where I have believed or have learned to believe—that
I might someday be able to contend with all of this.
No pill can help me deal with the problem of not wanting to take pills;
likewise, no amount of psychotherapy alone can prevent my manias and depressions.
I need both. It is an odd thing, owing life to pills, one’s own quirks
and tenacities, and this unique, strange, and ultimately profound relationship
called psychotherapy.
Given these advances, why is the practice of psychoanalysis no longer
thriving? This decline in the use of psychoanalytic therapy is mostly attributable
to causes outside psychoanalysis: the proliferation of different forms
of short-term psychotherapy (almost all of which are, to varying degrees, derived
from psychoanalysis), the emergence of pharmacotherapy, and the economic
impact of managed care. But one important cause derives from
psychoanalysis itself. One full century after its founding, psychoanalysis still
has not made the required effort to obtain objective evidence to convince an
increasingly skeptical medical profession that it is a more effective mode of
therapy than placebo. Thus, unlike various forms of cognitive therapy and
other psychotherapies, for which compelling objective evidence now
exists—both as therapies in their own right and as key adjuncts to pharmacotherapy—
there is as yet no compelling evidence, outside subjective impressions,
that psychoanalysis works better than nonanalytically oriented
therapy or placebo (Bachrach et al. 1991; Cooper 1995; Doidge 1997; Fonagy
1999; Kantrowitz 1993; Roth and Fonagy 1996; Seligman 1995; Weissman
and Markowitz 1994; Weissman et al. 1979).
The failure of psychoanalysis to provide objective evidence that it is effective
as a therapy can no longer be accepted. Psychoanalysts must be persuaded
by Arnold Cooper’s (1995) realistic and critical view:
To the extent that psychoanalysis lays claim to being a method of treatment,
we are, for better or worse, drawn into the orbit of science, and we cannot
then escape the obligations of empirical research. As long as we develop
practitioners who are members of a profession and charge for their services,
it is incumbent upon us to study what we do and how we affect our patients.
98 Psychiatry, Psychoanalysis, and the New Biology of Mind
As Cooper points out, a number of the major studies initially designed
to evaluate the outcome of therapy—Wallerstein’s (1995) study and the
studies reviewed by Kantrowitz (1993) and by Bachrach (1995)—have
abandoned their long-term goal for a more accessible short-term aim unrelated
to outcome. Despite their cost and complexity, rigorous outcome studies,
with comparison to short-term nonanalytically oriented psychotherapy
and placebo, need to be at the top of any list of priorities if psychoanalysis is
to continue to be a well-recognized therapeutic option.
A Flexner Report for the Psychoanalytic Institutes?
But the much more difficult step is to go beyond an appreciation of biology
and of having a tiny cadre of full-time researchers to the development within
psychoanalysis of an intellectual climate that will make a significant fraction
of psychoanalysts technically competent in cognitive neuroscience and eager
to test their own ideas with new methods. The challenge for psychoanalysts
is to become active participants in the difficult joint attempt of biology
and psychology, including psychoanalysis, to understand the mind. If this
transformation in the intellectual climate of psychoanalysis is to occur, as
I believe it must, the psychoanalytic institutes themselves must change from
being vocational schools—guilds, as it were—to being centers of research
and scholarship.
At the cusp of the twenty-first century, the psychoanalytic institutes in
the United States resemble the proprietary medical schools that populated
this country in the early 1900s. At the turn of the last century, the United
States experienced a great proliferation of medical schools—155 all told—
most of which had no laboratories for teaching the basic sciences. At these
schools, medical students were taught by private practitioners who often
were busy with their own practices.
To examine this problem, the Carnegie Foundation commissioned Abraham
Flexner to study medical education in the United States. The Flexner
Report, which was completed in 1910, emphasized that medicine is a science-
based profession and requires a structured education in both basic science
and its application to clinical medicine (Flexner 1910). To promote a
quality education, the Flexner Report recommended limiting the medical
schools in this country to those that were integral to a university. As a consequence
of this report, many inadequate schools were closed, and credentialed
standards for the training and practice of medicine were established.
To return to its former vigor and contribute importantly to our future understanding
of mind, psychoanalysis needs to examine and restructure the intellectual
context in which its scholarly work is done and to develop a more
critical way of training the psychoanalysts of the future. Thus, what psychoBiology
and the Future of Psychoanalysis 99
analysis may need, if it is to survive as an intellectual force into the twentyfirst
century, is something akin to a Flexner Report for the psychoanalytic
What drew so many of us to psychoanalysis in the late 1950s and early
1960s was its bold curiosity—its investigative zeal. I myself was drawn to
the neurobiological study of memory because I saw memory as central to a
deeper understanding of the mind, an interest first sparked by psychoanalysis.
One would hope that the excitement and success of current biology
would rekindle the investigative curiosities of the psychoanalytic community
and that a unified discipline of neurobiology, cognitive psychology, and
psychoanalysis would forge a new and deeper understanding of mind.
In the course of working on this article, I have benefited greatly from insightful
discussions with Marianne Goldberger, who also gave critical comments
on earlier drafts of this manuscript. In addition, I have received helpful suggestions
from Nancy Andreasen, Mark Barad, Robert Glick, Jack Gorman,
Myron Hofer, Anton O. Kris, Charles Nemeroff, Russell Nichols, David Olds,
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Donald F. Klein, M.D.
Like Eric Kandel, I went to medical school hoping to become a psychoanalyst.
I have had substantial exposure to the psychoanalytic process, since I
was a candidate at the New York Psychoanalytic Institute for 4 years (1957–
1961) and spent 17 years evaluating the effects of pharmacotherapy and psychotherapy
in the context of the long-term, psychoanalytic Hillside Hospital.
These years were spent under the indulgent guidance of the director, Lew
Robbins, an open-minded training analyst from the Topeka School.
Kandel describes how his brilliant cohort of classmates split: some pursued
becoming better therapists, while others, hoping to develop a basic science
for psychiatry, became immersed in biology. In contrast, my career was
molded by the advent of clinical psychopharmacology. In the 1950s, long before
we had a clue to the biology of antipsychotics, tricyclic antidepressants,
monoamine oxidase inhibitors, and benzodiazepines, the problem of an objective
estimate of specific therapeutic benefit had to be addressed. This was
largely because the idea that pills could do anything but stun patients into
unthinking compliance was the conventional wisdom of the dominant psychoanalytically
minded. This need for objective evaluation of specific effects
led to the development of comparative, placebo-controlled, double-blind–
108 Psychiatry, Psychoanalysis, and the New Biology of Mind
rated, randomized clinical trials. During placebo treatment, remarkable
gains often occurred. These gains were not directly due to the placebo but
rather to a factor we had radically underestimated; that is, many illnesses,
after having hit bottom (which led to entering treatment), tend to get better
under therapeutic, optimistic, and caring circumstances.
The fact of clinical reconstitution during placebo treatment highlighted
the ubiquitous post hoc, ergo propter hoc fallacy. Psychotherapy was respected
as a powerful tool because it was reported that patients often showed marked
improvements during therapy. The placebo findings showed that this causal
attribution was, at least, premature.
When the Kefauver-Harrison Drug Amendments of 1962 demanded that
medications be proven effective as well as safe, there was a sudden recognition
of clinical psychopharmacology as a respectable field. The remarkable
discoveries of Julius Axelrod (1972) and Arvid Carlsson (2003) regarding
the action of psychotropic drugs on chemical synaptic transmission caused
a wave of optimism. Not only were patients having remarkably better treatments
but we were coming close to understanding what made them better
and, by inference, what had gone wrong. Unfortunately, this optimism was
premature. We learned that all novel advances in psychopharmacology have
been due to chance and the prepared mind rather than deduced from a basic
grasp of pathophysiology and pharmacological structure, function, or relationships.
It became clear that neuroscience was the sensible route to an
eventual understanding of the mechanisms of psychiatric illnesses and deducing
novel therapeutic benefits, but the road is longer than we had hoped.
The important 1983 article “From Metapsychology to Molecular Biology:
Explorations Into the Nature of Anxiety” by Eric Kandel served as an
icebreaker for more dedicated neuroscientific psychiatric study by addressing
how animal models can yield insights, extending from behavioral to
molecular levels, relevant to both experimental animals and humans. Experimental
neurosis has a distinguished ancestry, starting with Pavlov, but such
studies were almost exclusively behavioral. Kandel’s extraordinary, fruitful
ambition was to lay bare the functioning neurocircuits.
However, Kandel’s article must be put into historical context. As he discusses,
American psychiatry from the 1950s through the 1980s was largely
dominated by psychoanalytic theory, which emphasized dynamic understanding
while denigrating descriptive psychiatry as superficial. The discovery
that the marked unreliability of descriptive diagnosis was due to criteria
variability led directly to the work of the DSM-III Task Force. Its guiding
principles were syndromal definition by specific inclusion and exclusion criteria.
These consensual definitions were almost entirely derived from clinical
experience, amplified somewhat by clinical psychopharmacological
trials. Brain physiology and pathophysiology were too undeveloped to play
From Metapsychology to Molecular Biology 109
any role in these discussions, which abjured questionable etiologic theory as
a basis for diagnosis.
The most pointed conflict with the psychoanalytic establishment came
with the realization that the “neuroses” had a common exclusion criterion
(loss of contact with reality), but there was no common inclusion criterion,
except for dubious psychogenic theory. This led to formulating several syndromally
distinct “anxiety disorders.”
That imipramine blocked apparently spontaneous clinical panics while
concurrently having little effect upon either anticipatory anxiety or phobic
avoidance indicated that the single label “anxiety” was simplistic. Furthermore,
imipramine did not benefit simple phobia. Having a treatment for
panic disorder and a delineation of this syndrome, the question arose regarding
what to do about patients who did not have panic attacks but were
chronically anxious. Chronic anxiety occurred in several different contexts—
for example, social phobia, obsessive-compulsive disorder, generalized
anxiety disorder, the inter-panic periods of panic disorder (which often
initiated agoraphobia), and posttraumatic stress disorder. Clinical nosology
with regard to anxiety is still a work very much in progress.
There seem to be, clinically at least, several types of chronic anxieties.
Patients with recurrent, apparently spontaneous panic attacks often develop
chronic anxiety between panics, claiming their chronic anxiety is due to fear
of the recurrence of a panic attack. Their chronic symptomatology is occasionally
associated with tachycardia, a mildly elevated blood cortisol level,
sighing, and compensated respiratory alkalosis. In contrast, generalized anxiety
disorder, another syndrome with “chronic anxiety,” usually has neither
cortisol elevation nor autonomic symptomatology nor sighing respiration.
In his 1895 paper “On the Grounds for Detaching a Particular Syndrome
From Neurasthenia, Under the Description Anxiety Neurosis,” Freud lucidly
described the spontaneous panic attack, the existence of limited symptom
attacks, and the salience of dyspnea during the attack. Freud initially
viewed the attack as a nonpsychological process, whereby ungratified libido
was transformed into anxiety. However, the psychoanalytic understanding of
anxiety went through many modifications that progressively focused upon
the possible eruption of chronically repressed drives that would elicit anxiety,
which would then reinforce repression. The chronic conflict brought
forth chronic symptomatology, so that the panic attack came to be viewed as
the occasional exacerbation of chronic anxiety. The specific phenomenology
of the attack, and even references to anxiety attacks, progressively dropped
from view. This may be an unfortunate case of how theory can narrow one’s
field of vision.
The major thrust of Kandel’s seminal 1983 paper was to demonstrate animal
models of human anxiety that allow explorations at cellular and molec110
Psychiatry, Psychoanalysis, and the New Biology of Mind
ular levels. Chronic and anticipatory anxiety in humans were held to
respectively parallel sensitization and aversive classical conditioning, as
demonstrated in the sea snail Aplysia californica. In Aplysia, both of these
forms of learned fear rely on presynaptic facilitation; augmentation of presynaptic
facilitation accounts for associative conditioning. These findings
suggest that a surprisingly simple set of mechanisms, arranged in various
combinations, may underlie a wide range of both adaptive and maladaptive
behavioral modifications. This simplified paraphrase demonstrates the innovative,
rigorous approach Kandel took to illuminate neural functioning,
with implications for learning and affect. Using advanced technology, adroit
experimental design, and a wonderfully appropriate animal for study, Kandel
penetrated Skinner’s “black box” by causal experimentation. Perhaps
Kandel, like Pavlov, has a sign on his laboratory wall that reads, “From the
simple to the complex.”
However, Kandel also stated that anxiety “can be adaptive: it prepares us
for potential danger.…Anxiety can become dysfunctional, by either being
inappropriately intense or being displaced by association with neutral events
that neither are dangerous themselves nor indicate danger. Thus, anxiety is
pathological when it becomes inappropriately severe and persistent or no
longer serves only to signal danger” (p. 127). For Kandel to consider anticipatory
anxiety as a “learned abnormality” was inconsistent, reflecting the
definitional problems of that era. Anticipatory anxiety is brief, triggered by
an identifiable signal, and distinguished from fear in that fear requires a
present danger. However, is it necessarily learned?
Kandel analogized anticipatory (signaled) anxiety to aversive conditioning,
where the lack of a conditioned stimulus predicts the non-occurrence of
the unconditioned stimulus. Therefore, the lack of a conditioned stimulus
serves as a safety signal, which relieves anxiety. In contrast, if shock is repeated
without warning, no safety signal is possible. A state of chronic anxiety
or sensitization ensues.
The fact that chronic anxiety is severe and does not serve to signal danger
supports a case for abnormality, but the case for necessary learning also requires
further evidence. Moreover, recurrent unsignaled shock is often used
to model depression, associated with learned helplessness, rather than anxiety.
Epidemiological studies indicate that recent-onset generalized anxiety
disorder (GAD) is usually transient, whereas GAD lasting for six months often
transforms into a depression, indicating clinical complexities.
In Aplysia, trauma incites serotonin release, which acts on the presynaptic
receptors of the sensory neuron so that, after a complex cascade, the
amount of neurotransmitter released by the afferent neuron is chronically
increased. This finding was a potent springboard for further work leading to
refined synaptic analyses. A further groundbreaking idea, initiated by KanFrom
Metapsychology to Molecular Biology 111
del and James H. Schwartz, was the suggestion that structural change may
depend upon patterns of gene activation and inactivation (Kandel et al.
2000): that experience, and therefore learning, may also cause such patterns.
Kandel emphasized the utility of Freudian insights concerning internal
representations for neuroscience. What I would emphasize is the admirable
acuteness of the psychopathological observations made by Freud—for
example, the importance of anxiety for psychopathology; the continuity
between childhood pathological states and adult illnesses; the astute delineation
of panic attacks and their antecedent relationship to agoraphobia; the
emphasis on dyspnea as a cardinal feature of anxiety attacks; and the importance
of separation anxiety both as a normal stage of development and as a
manifestation of psychopathology.
However, Freud’s explanatory insights about anxiety were frequently
misleading. For instance: that behind every phobic fear lay a repressed wish;
that attachment to the mother was “anaclitic,” derived from need satisfaction;
that the infant’s stranger anxiety and separation anxiety were both due
to anticipation of a rising flood of ungratified libidinal drives; that school
phobia was due to the child’s unconscious hostility to the mother (A. Freud
1972); that dyspnea is due to the lasting effects of birth trauma; that the
panic attack is due to undischarged libido caused by coitus interruptus; that
castration anxiety is central to masculine development and superego formation;
that social anxiety is due to repressed exhibitionistic desires, and so on.
Such claims were based on the flawed but fundamental analytic procedure
of “interpretation.”
Specific psychoanalytic explanatory insights, as those above, are less and
less referred to and have undergone disuse atrophy (rather than invalidation
and retraction). As Kandel well knows, contemporary psychoanalytic thinking
about anxiety derives more from John Bowlby, whose views were considered
heretical (Bowlby 1960), and Harold F. Harlow, who experimentally
showed the independence of attachment from oral gratification (Harlow
1964). Current psychological treatment of separation anxiety was initiated
by Leon Eisenberg (1958). Contemporary neuroscientific investigations into
unconscious processes have little to do with a Freudian, defense-generated,
dynamic unconscious responsible for psychopathology. Neuroscientific illumination
of the complexities of the descriptive unconscious should not be
considered as a psychoanalytic validation.
One of the views expressed in this 1983 paper calls for modification.
Kandel emphasized the heritability of major psychotic illnesses, which presumably
represent mutations, as opposed to certain neurotic illnesses, “such
as chronic anxiety (that are acquired by learning and can respond to psychotherapy)”
(p. 145). Recent anxiety disorder studies have shown genetic
loadings comparable to the major psychoses. Therefore, this hypothesis re112
Psychiatry, Psychoanalysis, and the New Biology of Mind
flected the psychoanalytic ideology of the day and appears invalidated. That
is irrelevant to the bold, fruitful hypothesis that experiential learning depends
on alterations of gene expression. Perhaps most surprising is that
panic attacks are not necessarily associated with terror, which leads to the
apparent oxymoron of nonfearful panic attacks. Indeed, Freud, in 1895, reported
“larval” attacks associated only with physical distress. Patients in
general medical practices, rather than psychiatric offices, often have acute
episodic distress, chest discomfort and dyspnea, but not fear. It is estimated
that half of those whose cardiac catheterization shows no evidence of coronary
disease actually have panic disorder.
Furthermore, the spontaneous panic attack is not associated with a sudden
sympathetic autonomic crisis, or evidence of hypothalamic-pituitaryadrenal
stimulation, as one might expect in terror. Recently, the emphasis on
sympathetic discharge has been modified by recent findings on vagal withdrawal,
as indicated by heart rate variability studies. Freud’s emphasis on
dyspnea, which led him to entertain birth trauma as the prototype of anxiety,
resurfaced in the recognition that the attack in panic disorder is frequently
associated with acute air hunger, which is not a salient feature of other anxiety
disorders or realistic fear.
What can be learned (if anything) from this historical survey? My notto-
original take is that 1) brilliant, persuasive insights should not be the end
of inquiry but rather provide the promising initiative that fosters the hard labor
of meticulous, experimental testing; 2) scientific advances often depend
on technical advances, chance observations, and the recognition of fruitful
investigative areas that can be put to good use by gifted people; and 3) we
should “seek simplicity and distrust it” (Whitehead 1926).
Axelrod J: Noradrenaline: fate and control of its biosynthesis, in Nobel Lectures,
Physiology or Medicine, 1963–1970. Amsterdam, Elsevier, 1972
Bowlby J: Separation anxiety. Int J Psychoanal 41:89–113, 1960
Carlsson A: A half century of neurotransmitter research: impact on neurology and
psychiatry, in Nobel Lectures, Physiology or Medicine, 1996–2000. Edited by
Jornvall H. Singapore, World Scientific Publishing Company, 2003
Eisenberg L: School phobia: a study in the communication of anxiety. Am J Psychiatry
114:712–718, 1958
Freud S: On the grounds for detaching a particular syndrome from neurasthenia under
the description “anxiety neurosis,” in The Standard Edition of the Complete
Psychological Works of Sigmund Freud, Vol 3. Edited and translated by Strachey
J. London, The Hogarth Press, 1962, pp 90–115
From Metapsychology to Molecular Biology 113
Harlow HF, Rowland GL, Griffin GA: The effect of total social deprivation on the development
of monkey behavior. Psychiatr Res Rep Am Psychiatr Assoc 19:116–
135, 1964
Kandel ER, Schwartz JH, Jessel TM (eds): Principles of Neural Science, 4th Edition.
New York, McGraw-Hill, 2000
Whitehead AN: The Concept of Nature. Cambridge, England, Cambridge University
Press, 1926, p 163
114 Psychiatry, Psychoanalysis, and the New Biology of Mind
Joseph LeDoux, Ph.D.
Anxiety disorders take a huge toll on society. More people visit mental health
professionals each year for problems related to anxiety than for any other
reason. Although we still know little about the neurobiological basis of anxiety,
a new wave of research has emerged attempting to understand anxiety
from the point of view of brain mechanisms. This research starts from the
assumption that anxiety and the related state of fear are normal functions of
the brain in response to threatening stimuli. Fear and anxiety disorders are
said to exist when the brain systems that normally process threats are activated
inappropriately (when no threat exists) or respond more intensely
than the situation warrants. While some environmental stimuli and situations
are preordained with threat value by evolution, fear and anxiety in humans
are largely products of learning, and they leave their marks on the
brain in the form of memory. If we are to understand how fear and anxiety
disorders come about and how they might be most effectively treated, we
need to know how the brain processes emotions, like fear and anxiety, and
especially how the brain learns and stores information about threats. This is
an active area of research today, but it was not always so.
In the early 1980s, the study of fear and other emotions was a research
backwater; neuroscience was much more enthralled with the idea of studying
higher cognition than emotion. Nevertheless, this topic did not escape
Eric Kandel, who, as his introduction to this volume tell us, began his medical
career as a psychiatrist with special interest in Freudian psychoanalysis.
Kandel’s research soon turned toward a rigorous scientific analysis of the
neurobiology of learning and memory—and not in humans but in the lowly
sea snail Aplysia californica. Nevertheless, through it all, he remained fascinated
with the deep questions of psychiatry, such as the how and why of anxiety.
In fact, in 1983 he wrote the following paper in the American Journal of
Psychiatry that sought a rapprochement between psychoanalysis and modern
neuroscience in the understanding of anxiety. I’m honored to make a few
comments about this paper.
From Metapsychology to Molecular Biology 115
Building on Freud, Pavlov, and Darwin, as well as his own research, Kandel
noted that the ability to anticipate threats is biologically adaptive.
Through learning and memory we can acquire information that allows us to
begin to respond to a threatening stimulus prior to the arrival of the actual
harm. If such learning capacities are conserved across species, it might be
possible to extrapolate findings in simple organisms, like snails, in the effort
to understand and treat anxiety.
To some, Kandel’s idea that research on snails could have any relevance
to one of the most profound and troubling human conditions, one that has
preoccupied poets and philosophers for centuries, if not millennia, might
seem absurd. After all, anxiety is a problem of subjective experience. A snail
does not have a brain, and whatever mind it has, if any, is not likely to have
much in common with human consciousness. The key to understanding
why Kandel was correct in principle rests not on any similarity between the
mental life of a snail and the subjective or conscious manifestation of anxiety
in humans. Instead, the key is that the mechanism underlying learning and
information storage, including about threats, is likely to be conserved at the
level of molecules and possibly genes. In 1983, this was still somewhat of a
long shot. Today, it is essentially taken for granted by neuroscientists.
For example, certain gene products (proteins) that have been implicated
in learning and memory storage in the snail have also been shown to be involved
in learning and information storage in flies, worms, and bees. If that’s
where it stopped, no one would have been surprised. But through the work
of Kandel and others, similar molecules have also been shown to play a role
in memory formation in mammals, especially mice and rats.
Let’s look a little more closely at the specific proposals in Kandel’s 1983
paper. He divides Freud’s notion of acquired or signal anxiety into several
categories and focuses on two of these: anticipatory anxiety and chronic
anxiety. He then argues that anticipatory anxiety can be modeled in the laboratory
using Pavlovian fear conditioning, a procedure in which a neutral
stimulus comes to elicit fear reactions after pairing with an aversive event
(such as electric shock), while chronic anxiety can be modeled by the procedure
called sensitization, in which an aversive stimulus primes or sensitizes
the organism to respond to any neutral stimulus that later appears. The
difference is that in conditioned fear the neutral stimulus is specifically
paired with the aversive event and only it is conditioned, whereas in sensitization
the response to any neutral stimulus is facilitated. A very important
point is that fear and anxiety, in these models, do not refer to subjective manifestations
but only to the role of the nervous system in controlling protective
or defensive responses, what we would call the fight-flight response in
Over the years, Kandel’s work has elucidated in exquisite detail how
116 Psychiatry, Psychoanalysis, and the New Biology of Mind
these two forms of learning work in the snail at the levels of behavior, neural
circuits, cells and synapses, and molecules. More recently, building on Kandel’s
work, and especially following the cellular-connectionist strategy he pioneered
in the Aplysia, I and some others have made progress at exploring
the neural basis of fear conditioning at the level of the system, cells, synapses,
and molecules in mammals (Kandel himself has also done important
research on this topic). Although the neural system of fear conditioning is
different in mammals and invertebrates, there are fundamental similarities
in the rules that govern learning at the level of behavior and, as already
noted, in the molecules that allow the cells and synapses to change with experience
and to store the results in memory.
In the end, Kandel’s 1983 paper is important not because it solved the
problems of pathological fear and anxiety, but because it suggested a strategy
about how we might go about using what we know about the neural basis of
learning and memory to gain insights into acquired fear and anxiety. Kandel’s
groundbreaking research on learning and memory in the Aplysia continues
today—so does his effort to bring modern neuroscience into
psychiatry, as the various other articles in this volume illustrate. Sigmund
Freud started his career studying the nervous system before he turned his efforts
to the human mind. Were he alive today, he would likely be a very big
fan of Eric Kandel’s research and writings.
C H A P T E R 4
Explorations Into the Nature of Anxiety
Eric R. Kandel, M.D.
Despite important progress during the last decade, the cell-biological mechanisms
of mentation have until very recently eluded analysis. However,
growth in the conceptual and technical power of cognitive psychology on
the one hand and neurobiology on the other now makes it possible to confront
one of the last frontiers of science. Within a theoretical framework
This article was originally published by the American Journal of Psychiatry, Volume
40, Number 10, 1983, pp. 1277–1293.
Expanded version of the first John Flynn Memorial Lecture, presented to the Department
of Psychiatry, Yale University Medical School, New Haven, Connecticut,
April 1982. Received November 4, 1982; revised April 7, 1983; accepted May
13, 1983. From the Center for Neurobiology and Behavior, College of Physicians and
Surgeons, Columbia University; and the New York State Psychiatric Institute, New
York, New York.
The original work described in this paper was supported by Career Scientist
Award MH-18558 from NIMH, grant MH-26212 from NIMH, and a grant from the
McKnight Foundation.
The author thanks Morton Rieser, Ethel Person, E. Terrell Walters, Tom Carew,
Sally Muir, and James H. Schwartz for comments on an earlier draft of this paper.
118 Psychiatry, Psychoanalysis, and the New Biology of Mind
based largely on insights from experimental psychology and psychiatry, biologists
are beginning to study successfully elementary aspects of mentation
and to address a number of central questions: What functional changes must
take place in nerve cells for learning and memory to occur? Are there unifying
cellular and molecular principles that relate one form of learning to another?
That relate short-term to long-term memory? Can experience lead to
enduring structural changes in the nervous system? Do these structural
changes involve alteration of gene expression, and, if so, is psychotherapy
successful only when it induces such changes? These questions, although
originating from different behavioral and neurobiological perspectives, are
increasingly converging on a common ground. In this essay, I shall try to illustrate
how the independent contributions of psychiatry, psychology, and
neurobiology can be combined in animal models to yield insights into mentation
that extend from the behavioral to the molecular level and that promise
to apply to experimental animals and humans alike.
To emphasize the relevance of these new developments for psychiatry,
I shall concentrate on two learned abnormalities of behavior: anticipatory
anxiety and chronic anxiety. I hope to document how cognitive psychology,
which has shown that the brain stores an internal representation of experiential
events, converges with neurobiology, which has shown that this representation
can be understood in terms of individual nerve cells, so as to
yield a new perspective in the study of learned anxiety. In a larger sense,
I shall try to illustrate that mentation loses none of its power or its beauty
when the approach is moved from the domain of metapsychology into the
range of molecular biology. On the contrary, the combined developments in
cognitive psychology and in neurobiology promise to renew interest in aspects
of mentation that until now have been out of experimental reach. Although
behaviorist psychology has been content to explore observable
aspects of behavior, advances in cognitive psychology indicate that investigations
which fail to consider internal representations of mental events are
inadequate to account for behavior, not only in humans but—perhaps more
surprisingly—also in simple experimental animals. This recognition of the
importance of internal representations, a conclusion intrinsic to psychoanalytic
thought, might have been scientifically disappointing as recently as
10 years ago, when internal mental processes were essentially inaccessible to
experimental analysis. However, subsequent developments in cell and molecular
biology have made it feasible to explore elementary aspects of internal
mental processes. Thus, contrary to some expectations, biological
analysis is unlikely to diminish the interest in mentation or to make mentation
trivial by reduction. Rather, cell and molecular biology have merely
expanded our vision, allowing us to perceive previously unanticipated interrelationships
between biological and psychological phenomena.
From Metapsychology to Molecular Biology 119
The boundary between behavior and biology is arbitrary and changing.
It has been imposed not by the natural contours of the disciplines but by lack
of knowledge. As knowledge expands, the biological and behavioral disciplines
will begin to merge at certain points, and it is at these points that the
ground on which modern psychiatry is based will become particularly secure.
The Clinical Syndromes of Anxiety
Anxiety is a normal inborn response either to threat—to one’s person, attitudes,
or self-esteem—or to the absence of people or objects that assure and
signify safety (Bowlby 1969; Freud 1925–1926/1959; Nemiah 1975). Anxiety
has subjective as well as objective manifestations. Subjective manifestations
range from a heightened sense of awareness to deep fear of impending
disaster. The objective manifestations of anxiety consist of increased responsiveness,
restlessness, and autonomic changes (for example, changes in
heart rate and blood pressure). Anxiety can be adaptive: it prepares us for
potential danger and can contribute to the mastery of difficult circumstances
and thus to personal growth. On the other hand, anxiety can become dysfunctional,
by either being inappropriately intense or being displaced by association
with neutral events that neither are dangerous themselves nor
indicate danger. Thus, anxiety is pathological when it becomes inappropriately
severe and persistent or no longer serves only to signal danger.
The biological mechanisms that give rise to feelings of anxiety represent
a central problem in the neurobiology of normal affective behavior. Anxiety
is also an important component of neurotic and psychotic illnesses. Yet despite
the importance of anxiety, little is known of its underlying cellular and
molecular mechanisms.
As in other areas of behavior, most of the initial insights into anxiety
have come from clinical observation. One key insight was the appreciation,
first by Freud and then by others, that anxiety is not unitary but is manifested
in a variety of forms. Thus, in his later writings, Freud distinguished
actual (automatic) anxiety, an automatic, inborn response to external or internal
danger, from signal anxiety, an acquired fear response in anticipation
of danger, either internal (unconscious) or external (Freud 1925–1926/
1959). (Actual anxiety is referred to as fear by some investigators [Kimmel
and Burns 1977; Mowrer 1939]. For a clear discussion of the evolution of
Freud’s writings on anxiety, see Strachey’s editorial introduction to Freud’s
essay in the Standard Edition [Freud 1925–1926/1959] and Brenner 1973.)
Subsequent work (for reviews, see Goodwin and Guze 1979; Klein 1981;
Sheehan 1982) has shown that acquired anxiety can further be subdivided
into three forms on the basis of clinical characteristics and response to psy120
Psychiatry, Psychoanalysis, and the New Biology of Mind
chopharmacological agents. These forms are panic attacks, anticipatory anxiety,
and chronic anxiety.
Panic attacks are brief, spontaneous episodes of terror without manifest
or clearly identifiable precipitating cause. The attacks are characterized by a
sense of impending disaster accompanied by a sympathetic crisis: the heart
races; breath is short and unsteady. This form of anxiety often responds to
tricyclic antidepressants and to MAOIs (Klein 1962, 1964; Sheehan 1982).
Anticipatory (or signaled) anxiety also is typically brief. Unlike panic attacks,
anticipatory anxiety is triggered by an identifiable signal, real or imagined,
that has come to be associated with danger. This form of anxiety tends to respond
to benzodiazepines and β-receptor–blocking agents such as propranolol
(Goodwin and Guze 1979; Klein 1981; Sheehan 1982). Chronic anxiety
is a persistent feeling of tension that cannot be related to obvious external
threats; it may or may not be reduced by benzodiazepines (Mayer-Gross
Panic attacks, occurring suddenly and without an apparent trigger, are
not under obvious stimulus control. In contrast, anticipatory and chronic
anxiety are to some degree under stimulus control. This feature suggests that
both forms are at least partly learned. That is, each form involves learning a
relationship (or the absence of a relationship) between a neutral and a
threatening stimulus.
The idea that anxiety is inborn and that a neutral stimulus can be associated
with it through learning has come from two sources. First, work in
comparative and evolutionary biology beginning with Darwin (1873) and
Romanes (1883, 1888) has shown that most animals, like humans, have a
repertoire of inborn defensive behaviors. Aware of the contributions of Darwin
and Romanes, William James proposed in 1893 that in animals and in
humans these built-in defensive behaviors are triggered by anxiety, an inborn
tendency to react with fear to dangerous situations. Experimental support
for the notion that anxiety can be learned came from Pavlov’s discovery
at the turn of the century that defensive reflexes can be modified by experience
and can be elicited by a previously neutral stimulus. Thus, in 1927 Pavlov
noted the utility of such associative learning for an animal’s survival:
It is pretty evident that under natural conditions the normal animal must respond
not only to stimuli which themselves bring immediate benefit or
harm, but also to other physical or chemical agencies. ...which in themselves
only signal the approach of these stimuli; though it is not the sight or the
sound of the beast of prey which is itself harmful to smaller animals, but its
teeth and claws. (Pavlov 1927, p. 14)
A similar proposal was made independently by Freud. Because painful
stimuli are often associated with neutral stimuli, symbolic or real, Freud
From Metapsychology to Molecular Biology 121
postulated that repeated pairing of a neutral and a noxious stimulus can
cause the neutral stimulus to be perceived as dangerous and to elicit by itself
the anxiety response. Placing this argument in a biological context, Freud
wrote in 1926:
The individual will have made an important advance in his capacity for selfpreservation
if he can foresee and expect a traumatic situation of this kind
which entails helplessness, instead of simply waiting for it to happen. Let us
call a situation which contains the determinant for such expectation a danger
situation. It is in this situation that the signal of anxiety is given [italics
added]. (Freud 1925–1926/1959, p. 166)
Pavlov and Freud not only appreciated that anxiety can be learned, but
each also had the important insight that the ability to manifest anticipatory
defensive responses to danger signals is biologically adaptive. Anxiety as a
signal prepares the individual for fight or flight if the danger is external. For
internal danger, Freud suggested that defensive mental mechanisms substitute
for actual flight or withdrawal. I would only make a cautionary comment
here: simply because aspects of anxiety may be learned and thus
acquired does not exclude the possible contribution of a genetic predisposition
to anxiety. In fact, what might be inherited is the predisposition to learn
certain stimulus relationships (Cohen et al. 1951; Crowe et al. 1980; Goodwin
and Guze 1979; Pauls et al. 1980; Sargant and Slater 1963; Sheehan
1982; Slater and Shields 1969).
Anxiety Can Be Studied in Animal Models
In people suffering from anticipatory anxiety, a cue stimulus is thought to
predict the occurrence of an aversive stimulus (Estes and Skinner 1941;
Miller 1948; Mowrer 1939; Pavlov 1927). By contrast, chronic or unsignaled
anxiety is thought to occur when people learn either that danger is associated
with a wide range of ever-present environmental cues or that danger is
always present and not signaled by any cues (Kandel 1976; Seligman 1975).
As a result, chronic anxiety is triggered in a less discriminating way.
With the recognition of distinct types of acquired anxiety, experimental
interest turned to the development of animal models for studying each type.
From work with experimental models it soon became clear that animals can
learn to manifest aspects of anticipatory and chronic anxiety. This evidence
has strengthened the initial clinical distinction between anticipatory and
chronic anxiety and supports the belief that aspects of these forms of anxiety
are also learned in humans. (For earlier discussions of animal models, see
Dollard and Miller 1950; Estes and Skinner 1941; Hammond 1970; Miller
1948; Mowrer 1939.)
122 Psychiatry, Psychoanalysis, and the New Biology of Mind
Since we think of anxiety as characteristically human, it is important to
review the evidence that simple animals can learn anxiety and that conditioned
fear in these animals approximates certain forms of anxiety in
humans. I shall argue that classically conditioned fear and long-term sensitization
provide models of anticipatory and chronic anxiety, respectively (see
Figure 4–1).
In classical (Pavlovian) conditioning, an animal learns to associate two
stimuli, a conditioned (or cue) stimulus (CS) and an unconditioned (or reinforcing)
stimulus (US). The US, by definition, elicits from the animal an effective
reflex, or instinctive response, that is called the unconditioned
response because it is present before conditioning. In contrast, the CS need
not elicit a reflex response before conditioning takes place. After repeated
pairing, the animal learns to associate the CS with the US and as a consequence
will show reliable conditioned responses to the CS that often resemble
the inborn unconditioned response to the US. In Pavlov’s classic
experiment, food (meat powder) served as a US, eliciting an inborn response,
reflex salivation. After several trials in which the food was paired
with a neutral stimulus, a tone, the tone reliably elicited salivation. For pairing
to be effective, Pavlov found that he had to present the tone and the food
in a precise sequence: the tone had to precede the food on each training trial.
This, as we shall see later, is because what the animal actually learned during
classical conditioning is that tone predicts food. The animal salivates after
the tone to prepare for food. Thus, if the pairing sequence is reversed (backward
conditioning), the animal does not respond to the tone by salivating.
FIGURE 4–1. Two forms of learning that give rise to two forms
of anxiety.
Comparison of anticipatory anxiety and its animal model, aversive conditioning, to
chronic anxiety and its animal model, long-term sensitization.
From Metapsychology to Molecular Biology 123
Pavlov further found that by varying the nature of the US he could produce
different types of learning. Unconditioned stimuli that satisfied the animal’s
needs or that enhanced survival gave rise to appetitive learning, leading
to satisfaction and ultimately satiation. Unconditioned stimuli that threatened
survival, such as a painful shock, produced aversive learning, leading
to conditioned fear (Estes and Skinner 1941; Mowrer 1939; Watson and
Rayner 1920).
Is there a relationship between aversive conditioning in animals and specific
anxiety in humans? One of the first experiments to apply aversive conditioning
to humans illustrated how classical conditioning could give rise to
anticipatory anxiety. In 1920, Watson and Rayner found that an infant they
were studying cried readily (Watson and Rayner 1920). Loud and sudden
noise proved a particularly effective US for eliciting the unconditioned response,
crying. They then added a neutral CS, a white rat that initially did
not elicit crying. After several pairings of CS and US, the infant started to cry
the instant the white rat was presented: the previously neutral CS produced
the conditioned response.
Aversive conditioning can lead to one of two forms of anxiety, depending
on whether the aversive stimulus is presented in a signaled or an unsignaled
manner (Figure 4–1). As emphasized by Mowrer (1939) and Miller (1948),
the presence of a CS, as a cue that predicts the occurrence of the aversive
stimulus (US), allows the animal to learn to focus its anxiety on a particular
event in time (see also Estes and Skinner 1941; Pavlov 1927). By contrast,
repeated exposure to the aversive stimulus without a cue stimulus produces
chronic anxiety (long-term sensitization), as pointed out by Seligman (1975)
and by Pinsker, Hening, Carew, and me (Pinsker et al. 1973) (for a review,
see Kandel 1975).
Seligman (1975) has used the following analogy to illustrate the distinctions
between the two forms of anxiety in terms of biological adaptation.
Imagine a world in which each aversive stimulus capable of causing pain,
and therefore fear, is predicted accurately and invariably by a brief neutral
stimulus so that the presence of this neutral stimulus comes to produce a
brief episode of anxiety. As long as the cue stimulus is not present the animal
can relax and do what it wants. A consequence of traumatic events being
predictable is that the absence of traumatic events is also predictable. When,
however, aversive events are unpredictable, safety also is unpredictable: no
reliable event exists to indicate that the trauma will not occur. Lacking a
safety signal, organisms remain in a state of chronic anxiety. According to
this view, people and animals seek safety signals (Seligman 1975). They look
for predictors of danger because these also provide information about safety
(Badia and Culbertson 1970; Badia et al. 1967; Weiss 1970).
Thus, both in people and in experimental animals, what distinguishes
124 Psychiatry, Psychoanalysis, and the New Biology of Mind
signaled (anticipatory) from unsignaled (chronic) anxiety is that signaled
anxiety is predictive with respect to its cause, whereas unsignaled anxiety is
completely unpredictive. The two variants of aversive training that we have
already considered therefore model the essential difference between anticipatory
and chronic anxiety.
Mechanisms Underlying Anxiety Are Likely to
Be General Throughout Phylogeny
An implication of these observations is that the development of anticipatory
and chronic anxiety in animals depends on mechanisms by which animals
process information about the predictive interrelationships among various
environmental events. A useful perspective on these problems has been provided
by cognitive psychologists, who have shown that learning involves
considerable mental processing and elaboration of sensory information,
with the result that humans and animals develop internal representations
(“cognitive structures”) of environmental events that allow flexible behavioral
decisions (for reviews, see Bindra 1978; Bolles and Fanselow 1980;
Dickinson 1980; Rescorla 1978).
If learning in humans and other higher animals involves the establishment
of certain cognitive structures, why are aspects of such cognitive mechanisms
likely to be similar in humans and in simple animals like the snail
Aplysia? One good reason for believing that this would be the case lies in the
consequences of adaptation to evolutionary pressure. Animals that differ
greatly in habitat and heritage nonetheless face common problems of adaptation
and survival, problems for which learning and flexible decision making
are useful. When different species face a common environmental
constraint, they often manifest homologous patterns of adaptation because
a successful solution to an environmental challenge, first evolved in a common
primitive ancestor, will continue to be inherited as long as it remains
useful and the selective pressure is present. As the physicist Weisskopf
(1981) put it, “nature likes to use the same old tricks again.” In addition,
common environmental pressures often lead to the independent evolution
of functionally analogous processes in distantly related species.
What constraint might have shaped or maintained a common cognitive
learning mechanism in a wide variety of species? Testa (1974) and Dickinson
(1977) have argued that to function effectively, animals need to recognize
certain key relationships between events in their environment. They
must be able to recognize and mate with their own species and to avoid even
closely related species; they must distinguish animals that are prey and learn
to avoid those that are predators; they must search out food that is nutritious
and avoid food that is poisonous. There are two ways in which an animal arFrom
Metapsychology to Molecular Biology 125
rives at such knowledge: the correct information for every choice can be preprogrammed
in the animal’s nervous system, or the ability to choose
correctly among alternatives can be acquired through learning. Genetic and
developmental programming may suffice for all of the behavior of simple
parasites and certain free-living forms such as the nematode worm C. elegans,
which exists in a limited and relatively invariant environment in the
soil. But for more complex animals, extensive learning is probably required
to cope efficiently with varied or novel situations. Complex animals need to
maximize their ability to order the world. An effective way to do this is to be
able to learn about predictive relationships between related events.
Given that humans and experimental animals should be capable of learning
predictive relationships, do such relationships have properties in common
that could constitute a universally selective evolutionary pressure?
They do. First, predictors always precede the signaled event, and second,
they are highly correlated with it; they provide optimal information about
the probability of its occurrence. As Dickinson (1980, 1981) and Testa
(1974) have argued, these distinctive properties of predictive relationships
are of such importance that they probably form the basis of widespread adaptational
and evolutionary pressures that have acted on all animals and enhanced
the survival of those species capable of taking them into account (for
a related discussion, see also Staddon and Simelhag 1971). Some psychologists
therefore believe that common associative mechanisms of learning exist
in all species capable of learning and that these common mechanisms are
designed to recognize and store information about predictive relationships
in the environment (Dickinson 1980; Rescorla 1968, 1973, 1978, 1979). As
we have already seen, this issue is not new but was first raised by William
James in 1892, when, following Darwin, he argued with his usual prescience
that mental processes evolved to serve adaptive functions for animals
in their struggle with a complex environment: “Mental facts cannot be properly
studied apart from the physical environment of which they take
cognizance.…Our inner faculties are adapted in advance to the features of the
world in which we dwell, adapted, I mean, so as to secure our safety and prosperity
in its midst.…Mind and world in short have evolved together, and in
consequence are something of a mutual fit” (James 1892, p. 4).
What is the evidence that animals are particularly adept at learning predictive
relationships? Actually, until quite recently, animal psychologists
thought that classical conditioning depended only on temporal contiguity:
A conditioned stimulus had only to precede the reinforcing unconditioned
stimulus by a certain critical period to be effectively conditioned (Gormezano
and Kehoe 1975; Guthrie 1935). However, this simple idea appears to
be inadequate. If animals learned to derive predictive information simply
from the occurrence of two events in close temporal contiguity, they might
126 Psychiatry, Psychoanalysis, and the New Biology of Mind
acquire a variety of erroneous notions about signals in the environment and
begin to act maladaptively. The world is full of chance, and events sometimes
occur together without being highly correlated or causally related.
Analyses of learning by Prokasy (1965), Rescorla (1968), Kamin (1969),
Mackintosh (1974), Wagner (1976), and their colleagues have shown that
classical conditioning develops best when in addition to contiguity there is
also a contingency—a truly predictive relationship—between the conditioned
(or cue) stimulus and the unconditioned stimulus (Dickinson 1980,
1981; Rescorla 1973, 1978; Rescorla and Wagner 1972). Classical conditioning
works not simply because the CS and US are temporally paired but
also because there are time intervals between successive pairings within
which the US does not occur. Thus, in addition to being paired in time, the signal
and reinforcer need to be positively correlated; the signal must indicate
an increased probability that the reinforcer will occur. It therefore appears
likely that animals learn classical conditioning, and perhaps all forms of associative
learning, so readily because the brain has evolved to enable animals
to distinguish events that reliably and predictively occur together from those
which are unrelated.
Behaviorism, Cognitive Psychology, and
Renascence of Psychoanalytic Perspective
These several arguments indicate that explanations of learning based solely
on temporal contiguity are limited. The behaviorist position, which has emphasized
temporal contiguity (Gormezano and Kehoe 1975; Guthrie 1959;
Skinner 1957), has also run into difficulty in addressing questions central to
other areas of behavior and learning (for critiques of the behaviorist position,
see Chomsky 1959; Kandel 1976; Neisser 1967; Rescorla 1978; Tolman
1932). Objective measurements of behavior through analysis of stimuli and
responses are clearly important for the study of behavior. They are the only
indices of behavior that can be manipulated experimentally and the only
ones that can be measured objectively. Indeed, the most useful definition of
behavior—observable movement—derives from traditional behaviorism.
Nonetheless, despite the great technical and conceptual debt that psychology
owes to behaviorism, there is a substantial difference between the view
of mental life held by behaviorists such as Watson and Skinner and that
found useful by most current students of behavior (Klatzky 1980; Neisser
1967; Posner 1973; Seligman and Meyer 1970). The extreme behaviorist
view (Watson 1913, 1925) is that observable behavior is synonymous with
mental life. This view narrowly defines a larger reality, psychic life, in terms
of the scientific techniques available for studying it. By so doing, this approach
denies the existence both of consciousness and of unconscious menFrom
Metapsychology to Molecular Biology 127
tation, feelings, and motivation merely because they cannot be studied
objectively. Broader perspectives such as those used by cognitive psychology
are necessary to account for the behavioral capabilities both of people and of
animals (Dickinson 1980; Dickinson and Macintosh 1978; Griffin 1982;
Kandel 1976). Cognitive psychologists have emphasized the richness of the
internal representations that intervene between stimuli and response. Even
the acquisition of simple associative tasks by invertebrates involves the
learning of surprisingly complex predictive relationships, which suggests
that many animals may form “cognitive” representations of relationships
among events in their environment (Sahley et al. 1981).
In the past, ascribing a particular behavioral feature to an unobservable
mental process essentially excluded the problem from direct biological study
because the complexity of the brain posed a barrier to any complementary
biological analysis. But the nervous systems of invertebrates are quite accessible
to a cellular analysis of behavior, including certain internal representations
of environmental experiences that can now be explored in detail. This
encourages the belief that elements of cognitive mentation relevant to humans
and related to psychoanalytic theory can be explored directly and need
no longer be merely inferred.
The psychoanalytic perspective has been devalued recently and, in the
United States, is in decline. Its propositions have relied heavily on intervening
constructs: on a mental apparatus for unconscious and conscious mental
activity and on postulated libidinal and aggressive drives. Some of these
ideas are vague; all are difficult to quantify. As a result, the exploration of
psychoanalytic theories has been hampered by a lack of opportunities for experimental
verification. Nevertheless, psychoanalytic thought has been particularly
valuable for its recognition of the diversity and complexity of
human mental experience, for discerning the importance both of genetic
and learned (social) factors in determining the mental representation of the
world, and for its view of behavior as being based on that representation. By
emphasizing mental structure and internal representation, psychoanalysis
served as a source of modern cognitive psychology, a psychology that has
stressed the importance of the logic of mental operations and of internal representations.
Just as I believe that the vigor now evident in cognitive psychology
will be strengthened by its contact with the cellular neurobiology of
behavior through work on simple systems such as invertebrates, I also think
that the emergence of an empirical neuropsychology of cognition based on
cellular neurobiology can produce a renascence of scientific psychoanalysis.
This form of psychoanalysis may be founded on theoretical hypotheses that
are more modest than those applied previously but that are more testable because
they will be closer to experimental inquiry.
In the remainder of this paper I shall try to document these ideas by de128
Psychiatry, Psychoanalysis, and the New Biology of Mind
scribing studies directed at developing an animal model for both anticipatory
anxiety and chronic anxiety in Aplysia that makes it possible to explore
their cellular and molecular mechanisms.
Aplysia Shows Aspects of Anticipatory
and Chronic Anxiety
Because of language, we know that in humans anxiety is to an important extent
subjective. In assessing anxiety in animals, we must rely exclusively on
inferences derived from objective manifestations. Although the correspondence
of the two types of anxiety to the two objectively defined laboratory
forms of aversive learning is imperfect, the analogy is useful because it allows
aspects of acquired anxiety to be explored experimentally. Being able to
study aspects of anxiety in animals like rats and monkeys is not surprising.
But it is surprising—at least it surprised my colleagues Terrell Walters and
Thomas Carew and me—to find that even simpler animals, such as the marine
snail Aplysia, manifest behavioral changes that by inference resemble
anxiety and that can be used as a model of anxiety in higher forms. The advantage
of invertebrate animals over monkeys and rats is that their nervous
systems are much simpler, which offers a chance to explore the cellular and
molecular mechanisms that contribute to anxiety.
I emphasize at the outset that I do not, even in my most optimistic moments,
believe that the mechanisms for anxiety in simple animals are likely
to be identical to those in humans. However, I would argue that, at this early
stage in our understanding of the biological mechanisms of anxiety, the precision
of the fit is not critically important. What is important initially is that
we learn something meaningful about the mechanisms by which any form
of anxiety arises in any animal, no matter how simple the animal (or the anxiety).
In view of the biological adaptiveness of anxiety and its apparent conservation
across diverse species, it seems likely that a rigorous analysis of the
mechanisms of anxiety in any animal will prove instructive for understanding
human anxiety. An analogy from recent developments in molecular biology
underscores this point. The regulation of gene expression in eukaryotes
(animal cells) has recently been shown to be more complex than in prokaryotes
(bacteria) (for reviews, see Crick 1979; Darnell 1979; Gilbert 1978;
Lewin 1980; Stryer 1981). Nevertheless, almost everything that has been
learned from bacteria applies to animal cells, and without the foundation
provided by the earlier work with bacteria, our understanding of gene regulation
in animals would still be fairly primitive.
As with humans, Aplysia manifests behavioral states resembling anticipatory
anxiety (or fear) in response to a classical aversive conditioning paradigm
and chronic anxiety in response to a long-term sensitization paradigm
From Metapsychology to Molecular Biology 129
(Walters et al. 1979, 1981) (Figures 4–2 and 4–3). This is most clearly demonstrated
by using the same aversive, unconditioned stimulus (strong shock
to the head) during training and the same test pathway (escape locomotion
in response to a weak tail shock) to assess learning in both paradigms. The
degree of learned anxiety is assayed by measuring the amount of escape locomotion
an animal displays following training. The only difference between
sensitization training and classical conditioning is the presence in the
latter of a cue, the conditioned or cue stimulus, specifically paired with the
head shock (Figure 4–3). A particularly effective cue is a neutral chemical
stimulus, extract of shrimp. Aplysia is a herbivore; it eats only seaweed. Although
it normally ignores shrimp, its chemosensitivity can readily detect
the presence of shrimp. Thus, shrimp can be an effective signal.
The two training procedures produce two forms of conditioned anxiety
that differ primarily in their specificity to the neutral signal. To demonstrate
this difference, Walters and associates (1979) tested the conditioned and
sensitized groups twice (Figure 4–4), first in the absence and then in the
presence of the CS. The animals trained with a paired stimulus showed no
increase in escape locomotion when tested in the absence of the CS; when
the signal was present, however, this group exhibited significantly more escape
locomotion than it had either to the same test stimulus in the absence
of the signal stimulus or before training. For animals trained with a cue signal,
the neutral signal is required for anxiety to be expressed; they thus show
a form of anticipatory anxiety. In the absence of the cue, the animals show
no apprehension. In contrast, the chronically sensitized animals, trained
FIGURE 4–2. Experimental arrangements for studying aversive
conditioning and long-term sensitization in Aplysia.
In both cases a strong noxious stimulus to the head serves as the unconditioned stimulus
(US), and a weak test probe to the tail elicits escape locomotion and other defensive
130 Psychiatry, Psychoanalysis, and the New Biology of Mind
without a signal stimulus, show a generally heightened responsiveness that
is unaffected by the presence or absence of the cue and thus show a form of
chronic anxiety.
Human anticipatory anxiety and anxiety in Aplysia are also comparable
in the pattern of effects produced by the anxiety. Some behaviorists, including
Pavlov (1927), assumed that anticipatory anxiety results from stimulus
substitution: the learned response to the previously neutral stimulus comes
to produce the same overt response as does the painful stimulus. In contrast,
Freud, in some ways the founder of modern cognitive psychology, assumed
that actual danger produces an internal state, which, as we have seen, he
called “actual anxiety.” A neutral signal, he argued, that comes to be associated
with danger may elicit any of a variety of responses, which may differ
dramatically from the response to the actual trauma that the signal predicts.
Indeed, the immediate reaction to the danger signal is not an overt response
but an internal state of tension, an augmented preparedness for action,
which Freud called “signal anxiety.” By signaling fear, anxiety motivates behavioral
response systems designed to reduce danger. In Freud’s view, anxi-
FIGURE 4–3. Experimental protocols used on Aplysia for conditioning
and sensitization.
The test stimulus was a train of electrical pulses to the tail. The US was a shock to the
head. The CS was 1.5 mL of crude shrimp extract. These procedures were identical
for paired and sensitized groups except that the latter was not exposed to the CS during
From Metapsychology to Molecular Biology 131
ety is a motivational state, a defensive arousal, similar to other motivational
states stemming from hunger, thirst, or the need for sex (Figure 4–5).
In humans and other mammals, Freud’s view appears accurate. Both
chronic and anticipatory anxiety represent a motivational (defensive) state
in preparation for expected danger, a preparation that is not necessarily expressed
in motor activity. As such, these forms of anxiety have two characteristics.
They act not just on a single response but are likely to engage a
repertory of responses, some components of which are enhanced while others
are suppressed, and the effects are motivationally consistent: defensive
responses are enhanced and appetitive responses suppressed (Figure 4–5).
To test the possibility that simple invertebrates can also learn to associate
a neutral stimulus with a motivational state analogous to anxiety during aversive
conditioning, Walters and associates (1981) examined the effect of the
CS, after aversive conditioning (pairing of shrimp extract and head shock), on
FIGURE 4–4. Comparison of responses of conditioned (paired)
and sensitized animals after training.
Differences between test and pretest scores are shown for two administrations of the
test stimulus: one in the absence and the other (3 hours later) in the presence of the
CS. Zero on the scale represents the mean number of steps of escape locomotion taken
in the pretest. Paired animals showed significantly more escape locomotion after
training than before when tested in the presence of the CS but not when tested in the
absence of the CS. Sensitized animals took significantly more steps to escape than
they did before training in both the presence and absence of the CS.
Source. Adapted from Walters et al. 1979.
132 Psychiatry, Psychoanalysis, and the New Biology of Mind
three defensive responses in addition to locomotion: two graded reflex acts
(head and siphon withdrawal) and an all-or-none fixed act (inking). They also
examined the suppressive effects of the CS on an appetite behavior, feeding.
They found that conditioning modulates these responses in a manner that is
motivationally consistent with anxiety in mammals: defensive responses are
enhanced and appetitive responses are inhibited (Figure 4–6).
A Simple Form of Chronic Anxiety Can
Now Be Understood in Terms of Its
Cell-Biological Mechanisms
Knowing that Aplysia shows elementary forms of both anticipatory and
chronic anxiety, we are in a position to explore the cellular mechanisms of
each and to examine the relationships between them. I shall begin by considering
sensitization, the animal model of chronic anxiety, because this
form of anxiety has been analyzed in detail at both the cellular and molecu-
FIGURE 4–5. Comparison of behaviorists’ and Freud’s views of
anticipatory anxiety.
The behaviorists view anxiety as a form of stimulus substitution. Initially, defensive
responses are produced only in response to the US. After pairing of the CS and US,
the CS produces the same defensive responses elicited by the US (a conditioned response,
or CR). According to Freud’s view (and that of modern cognitive psychology),
the learning of anticipatory anxiety involves the endowment of a neutral
stimulus with the ability to trigger an internal state—anxiety or defensive arousal—
which then modulates in a motivationally consistent way not just a single response
but an entire family of responses or a behavioral repertoire.
From Metapsychology to Molecular Biology 133
lar levels. I shall focus on a very simple defensive system modulated by anxiety—
siphon and gill withdrawal—because it is understood most fully
(Figure 4–7).
As is the case with other snails, Aplysia has a respiratory chamber called
the mantle cavity that houses the gill. This cavity is covered by a protective
sheet, the mantle shelf, which terminates in a fleshy spout, the siphon. When
the siphon or mantle shelf is touched, the siphon and gill contract vigorously,
withdrawing into the mantle cavity. The gill-withdrawal reflex to stimulation
of the siphon is analogous to simple defensive responses in humans
such as withdrawing a hand from a hot object.
Most of the nerve cells making up the neural circuit (or wiring diagram)
of the gill-withdrawal reflex have now been identified (Figure 4–7). The siphon
skin is innervated by 24 sensory neurons, and there are six motor neurons.
There are also several interneurons, one of which produces inhibition
and five others which produce excitation. The sensory neurons that carry
tactile input from the siphon skin connect to the interneurons and to the
motor neurons; the motor neurons connect directly to the muscles of the gill
that effect the behavior. By examining this neural circuit during sensitization,
Castellucci and associates (Castellucci and Kandel 1976; Castellucci et
al. 1970) found that a stimulus which produces chronic anxiety in Aplysia
FIGURE 4–6. Conditioning of anticipatory anxiety in Aplysia.
The conditioning is consistent with a cognitive interpretation whereby the US elicits
a motivational state (defensive arousal), which then becomes associated with the CS
after repeated pairing. This motivational state suppresses appetitive behavior and
augments defensive responses.
Source. Reprinted from Walters ET, Carew TJ, Kandel ER: “Associative Learning in
Aplysia: Evidence for Conditioned Fear in an Invertebrate.” Science 211:504–506,
1981. Used with permission from the American Association for the Advancement of
134 Psychiatry, Psychoanalysis, and the New Biology of Mind
leads to an enhancement of the connections made by the sensory neurons
on their target cells: the interneurons and the motor neurons. This enhancement,
called presynaptic facilitation, works as follows: a noxious stimulus to
the head activates a group of cells—the L29 cells—that are thought to use a
transmitter closely related to serotonin as their chemical transmitter (Bailey
et al. 1981; Hawkins et al. 1981a, 1981b). This group of facilitating cells acts
as a defensive arousal system. The cells impinge on the synaptic terminals of
the sensory neurons of the reflex system for gill withdrawal, and they amplify
the strength of the connections that these sensory synapses make onto
the motor neurons and interneurons (Hawkins 1981; Hawkins et al. 1981a,
1981b). Serotonin simulates all the actions of this defensive arousal and produces
its amplifying action by increasing the intracellular messenger cyclic
AMP in the sensory neurons (Bernier et al. 1982). The increase in intracellular
cyclic AMP in turn strengthens the connections of the sensory neurons
by facilitating transmitter release from their terminals (Brunelli et al. 1976;
Castellucci and Kandel 1976) (Figure 4–8).
A Molecular Explanation for Chronic Anxiety
On the basis of pharmacological and biochemical studies, we have been able
to piece together a coherent sequence of biochemical steps that take place in
the sensory neurons when the behavior is altered by anxiety (Kandel and
Schwartz 1982; M. Klein and Kandel 1980). As an action potential propa-
FIGURE 4–7. Neural circuit mediating sensitization of the gillwithdrawal
reflex in Aplysia.
The interneurons and the motor cells are all unique, identified cells.
From Metapsychology to Molecular Biology 135
gates toward the synaptic terminals of the sensory neurons, it begins to depolarize
the terminals and open up the sodium channels, thereby producing
more depolarization and generating an action potential in the terminal. The
depolarizing component of the action potential in the terminal then opens
up calcium channels and allows a certain amount of calcium to come into
the cell. The depolarizing component of the action potential also opens up
potassium channels; the resulting influx of potassium repolarizes the action
FIGURE 4–8. Experimental application of serotonin and cyclic
AMP to simulate presynaptic facilitation in Aplysia.
In part A, serotonin, a sensory neuron was stimulated 15 times, at the rate of once
every 10 seconds, and produced a monosynaptic excitatory postsynaptic potential in
a gill or siphon motor neuron, as seen in the set of electrical recordings on the left.
Between the fifteenth and sixteenth action potentials, the ganglion was bathed with
104 M serotonin, which produced presynaptic facilitation (right). In part B, cyclic
AMP, as in part A, a sensory neuron was stimulated once every 10 seconds for
15 stimuli (left). Between the fifteenth and sixteenth action potentials, cyclic AMP
was injected into the cell body of the sensory neuron and produced presynaptic facilitation
Source. Adapted from Brunelli et al. 1976.
136 Psychiatry, Psychoanalysis, and the New Biology of Mind
potential and turns the calcium channels off. Thus the activation of the sodium
and potassium channels not only generates the action potential and
determines its duration but also activates the calcium channels and determines
how long they remain open. Entry of calcium into the terminals is
critical for transmitter release. Calcium is thought to allow the vesicles that
contain the transmitter to bind to discharge sites—a necessary step for transmitter
release. Serotonin and cyclic AMP work to prolong the action potential
and thus enhance calcium influx into the sensory neuron terminals.
When the action potential is prolonged, the calcium channels stay open
longer, and more calcium is available to allow more transmitter-containing
vesicles to bind to release sites.
Klein and I have outlined a molecular model for sensitization based on a
series of biophysical and biochemical experiments (Klein and Kandel 1980)
(Figure 4–9). According to this model, serotonin released by the facilitating
neurons acts on a serotonin receptor in the membrane of the presynaptic
terminals of the sensory neuron; the receptor then activates a serotoninsensitive
adenylate cyclase. The adenylate cyclase increases cyclic AMP
within the terminals, which activates a protein kinase—the enzyme thought
to be the common site of action for cyclic AMP in all eukaryotic cells. Protein
kinases are enzymes that phosphorylate proteins; that is, they add phosphoryl
groups to certain amino acid residues in the protein. The addition of
a phosphoryl group changes the charge of the protein, making it more negative.
This in turn changes the three-dimensional shape and therefore the
functional state of the protein. We have found that the activated protein kinase
phosphorylates a certain species of potassium-channel protein or a protein
that is associated with the potassium channel. Phosphorylation in effect
closes this species of potassium channel and thereby reduces the potassium
currents that normally repolarize the action potential. Reduction of these
currents prolongs the action potential, allowing more calcium to flow into
the terminals. Consequently, more vesicles bind to release sites, more transmitter
is released, the functional output of the cell increases, and the animal
shows the enhanced responsiveness that characterizes chronic anxiety in
My colleagues Schwartz, Castellucci, Hawkins, and Klein and I have
tested this model in a variety of ways, and we have found that we can either
trigger or block the enhancement of transmitter release by perturbing any
one of the several steps in the biochemical cascade (Castellucci et al. 1980,
1982). Thus, there now is compelling evidence that serotonin increases the
level of cyclic AMP in individual sensory cells, that cyclic AMP activates a
protein kinase, and that kinase activation leads to closing of a certain species
of potassium channel (Figure 4–9). Indeed, recently Siegelbaum, Camardo,
and I have been able to record the activity of a single potassium channel and
From Metapsychology to Molecular Biology 137
FIGURE 4–9. Molecular model of presynaptic facilitation underlying
sensitization in Aplysia.
Serotonin or related amine released from the facilitating interneurons reaches a serotonin
receptor in the presynaptic terminal of the sensory neuron, where it activates
an adenylate cyclase. The receptor does not activate the cyclase directly but, as indicated
in the diagram, through another membrane protein called the G protein. Once
activated, the adenylate cyclase causes an increase in cyclic AMP, which in turn activates
a protein kinase (an enzyme that is composed of separate regulatory and catalytic
subunits). This kinase phosphorylates a protein associated with the potassium
channel so that the channel closes. With the potassium channel closed, the inflow of
potassium ions that would normally repolarize the action potential is reduced. Consequently,
the action potential is prolonged and calcium remains free to continue entering
the cell, where it binds vesicles of transmitter (large circles at bottom) to their
release sites. Thus, in presynaptic facilitation the amount of time available for transmitter
release from the sensory neuron terminal is extended. Eventually, the enzyme
phosphatase dephosphorylates the potassium channel, which causes it to reopen,
thereby terminating the action of the cascade activated by serotonin.
Source. Adapted from M. Klein and Kandel 1980.
138 Psychiatry, Psychoanalysis, and the New Biology of Mind
the conformational changes in a single protein molecule, and we have shown
that phosphorylation of this species of potassium channel either directly or
indirectly (by means of a regulatory protein that affects the channel) decreases
the probability that the channel will open (Siegelbaum et al. 1982).
Thus, we have been able to take the analysis of a form of anxiety from
the behavior of the intact animal to the neural circuit of the behavior and to
some of the critical cells involved. Within these critical cells (the sensory
neurons of the reflex), we localized the change to a particular component of
the neuron, the presynaptic terminals, and demonstrated that the expression
of anxiety involves enhancement of transmitter release. We found that the
molecular mechanism of this enhancement is protein phosphorylation,
which leads to a broadening of the action potential and a greater influx of
calcium. We are now able to focus on the individual protein molecules modulated
by learning and explore them in a behavioral as well as a biochemical
The Maintenance of Chronic Anxiety
Involves Structural Changes
Sensitization is a form of chronic anxiety whereby a defensive arousal system
is activated and increases the release of transmitter from particular
identified synapses. We can therefore ask: Does the maintenance of this
learned anxiety involve a morphological change? To answer this question,
Bailey and Chen (1983) have visualized the synaptic terminals of the sensory
neuron electron-microscopically using the electron-dense marker
horseradish peroxidase. Their evidence suggests that, as in other neurons,
synaptic vesicles, the likely storage sites for transmitter, are released at varicose
expansions of the presynaptic terminal of the axon. The varicosities
contain specialized regions called active zones, where the vesicles are
loaded into release sites from which they subsequently discharge their contents.
Comparing sensory neurons from chronically sensitized and control
animals, these researchers have analyzed the changes in the number and
distribution of the synaptic vesicles and in the size and extent of the active
zones. They found that in normal animals not all varicosities contain active
zones. Rather, the incidence of active zones and the average size of
each active zone can be modified by anxiety. In sensory neurons from naive
animals, only 41% of varicosities have active zones; the rest do not. In contrast,
in animals that have been sensitized, the incidence of active zones is
increased to 65%. In addition, the average size of each zone is larger in sensitized
than in naive animals (Figure 4–10).
Thus, simple forms of anxiety produce profound morphological as well
From Metapsychology to Molecular Biology 139
as functional changes (Figure 4–11). The normal set of varicosities serves as
a mere scaffolding for behavior. Learning experiences, such as the acquisition
of chronic anxiety, can build upon this scaffolding by altering the functional
expression of neural connections.
Chronic Anxiety Might Involve
Alterations in Gene Expression
How is this structural change achieved? We do not yet know the answer to
this question. But recent progress in the molecular genetics of animal cells
suggests a possible mechanism. Each somatic cell in the body contains all
the genes present in every other cell. What makes a liver cell a liver cell and
a brain cell a brain cell is that during development from a single fertilized
egg cell, the various cells of the body differentiate by shutting off the activity
of certain genes while allowing others to be expressed. This developmentally
determined repression and activation of organ- and tissue-specific genes
occurs during certain critical periods in development and is then selfmaintained
throughout the life of the differentiated cell (for review, see
Davidson 1976; Gurdon 1974; Lewin 1980; Stryer 1981; J.D. Watson 1976).
As a result, in any given cell most genes are closed; only some are open and
available for transcription.
In addition to these relatively permanent changes in gene expression
FIGURE 4–10. Morphological correlates of long-term sensitization
in Aplysia.
Long-term sensitization produces an increase in both the number (A) and size (B) of
sensory neuron active zones. These complementary changes are even more apparent
when viewed together, as illustrated in part C. The value for the average number of
varicosities per sensory neuron has been taken from total reconstructions of simple
horseradish peroxidase-injected sensory neurons in untrained animals (N=2, mean±SE).
Source. Based on data reported in Bailey and Chen 1983.
140 Psychiatry, Psychoanalysis, and the New Biology of Mind
produced by differentiation, the genes that are available for expression
within a given cell type can be regulated. For example, a gene’s rate of activity
(its rate of transcribing mRNA) can be transiently enhanced or depressed
(Brown 1981; Darnell 1982) by a variety of molecules, such as hormones
that act directly on the genes or on proteins that regulate the genes. In contrast
to differentiation, these forms of gene modulation can be either rapid
and readily reversible or self-maintained and enduring. Because learning
produces enduring changes in the structure and function of synapses,
Schwartz and I have proposed that learning is likely to involve enduring,
self-maintained alterations in gene expression (Kandel and Schwartz 1982).
This idea is consistent with the suggestion that new protein synthesis is required
for long-term memory (Agranoff et al. 1978; Barondes 1970). If this
speculation proves correct, it would provide a new perspective on the nature
of normal learning and thereby on the nature of certain learned neurotic illnesses
such as chronic anxiety. Specifically, the possibility of gene regulation
by experience suggests a class of molecular regulatory defects that might be
caused by learning.
To put this view into perspective, let me illustrate one way of looking at
FIGURE 4–11. Ionic and morphological mechanisms of long-term
sensitization in Aplysia.
The ionic mechanism leads to the closing of a species of potassium channel, which
results in an increase in calcium influx due to a broadening of the action potential.
This contrasts with the situation in control, in which potassium flowing in through
open channels leads more quickly to a closure of the calcium channels (filled
squares). In addition, a morphological stabilization of the varicosities occurs during
long-term sensitization, whereby there are increases in both the number of varicosities
containing active zones (filled triangles) and the number of active zones per active
varicosity. Consequently, more synaptic vesicles can be released.
From Metapsychology to Molecular Biology 141
the relationship between psychotic and neurotic illness. There is substantial
evidence that the major psychotic illnesses, such as schizophrenia and depression,
are heritable. The illnesses presumably represent mutations—alterations
in the nucleotide sequence of the DNA—leading to abnormal
messenger RNA and abnormal protein. The hereditary information of a cell
is carried in its nucleic acid, DNA. The strands of DNA contain one of four
characteristic bases: adenine, guanine, thymine, and cytosine. The information
carried by a gene is defined by the sequence of bases along the strand.
Consecutive triplets of bases serve as code words called codons; with some
exceptions, each codon specifies an amino acid, and a string of 100 or more
codons provides the genetic code for the assembly of a protein chain. The
sequence of amino acids in a protein chain determines how the chain folds
and therefore how it assumes the three-dimensional structure necessary for
its biological activity. Alteration by mutation in only one nucleotide subunit—
one base—of one codon will be sufficient to alter the amino acid sequence
of the protein and thereby alter the protein properties, possibly even
making it inactive.
The information of DNA is not translated directly into a protein. Rather,
the sequence of bases that codes for a protein is transcribed into a complementary
strand of RNA called messenger RNA (mRNA) because it carries
the information for the sequence of amino acids necessary to construct the
protein. The mRNA in turn is translated into protein. Thus, altered genes
give rise to altered mRNAs, which produce altered proteins.
How the genetic abnormalities of schizophrenia and depression are manifest
in the brain is still not known, but it is thought that they lead to changes
in synaptic function either by altering the release process of the biogenic
amine that serves as a transmitter in the presynaptic neuron or by affecting
the expression or onset of receptors on the postsynaptic cell (for a review,
see Kety 1979; Sachar 1981a, 1981b). I would now suggest that whereas the
major psychotic illnesses (that do not respond to psychotherapy because the
disease is not fundamentally acquired or altered by learning) may involve alteration
in the structure of specific genes, certain neurotic illnesses such as
chronic anxiety (that are acquired by learning and that can respond to psychotherapy)
might involve alterations in the regulation of gene expression. According
to this speculative view, schizophrenia and depression would be due
primarily to heritable genetic changes in synaptic function in a substrain or
mutant population; neurotic illnesses would not be. Rather, neurotic illnesses
might represent alterations in synaptic function produced by environmentally
induced modulation of gene expression (Figure 4–12). Even
though the learning mechanisms are inherited, neurotic individuals would
be neurotic only if experience taught their genes to be pathologically expressed.
A corollary to this argument is that insofar as psychotherapy works
142 Psychiatry, Psychoanalysis, and the New Biology of Mind
From Metapsychology to Molecular Biology 143
FIGURE 4–12. Comparison of mutation of the DNA sequence by disease, leading to the expression of an altered
gene, and modulation of gene expression by environmental stimuli, leading to the transcription of a previously inactive
gene (opposite page).
For simplicity, a specific example is illustrated. The gene is illustrated as having two segments, a structural gene (that is transcribed by a mRNA and
in turn is then translated into a specific protein) and a regulatory or promoter segment. The promoter is located upstream from the structural gene
and regulates the initiation of the transcription of the structural gene. In this example, the promoter segment can be activated (and made accessible
to transcription) only when a regulatory protein binds to the promoter. To bind, the regulatory protein must first be phosphorylated. Thus, in part
A, the phosphorylated regulatory protein binds to the promoter, thereby activating the transcription of the structural gene leading to the production
of a gene product: protein 1. In part A(2), a mutant form of the structural gene is illustrated in which a single base change has occurred; a thymidine
(T) has been substituted for cytosine (C). As a result, an altered mRNA is transcribed and an abnormal protein (protein 2) is produced, giving rise
to the disease state. This alteration in gene structure is present in the germ line and is inherited. Part B illustrates a specific example of alteration in
expression of a normal structural gene that is not heritable. The regulatory protein is indicated in its dephosphorylated state; it therefore cannot
bind to the promoter site and gene translation cannot be initiated. An (epigenetic) learning experience, such as learned anxiety, acting through serotonin
and cyclic AMP, activates a protein kinase enzyme. This enzyme has both a regulatory unit component (R) and a catalytic unit component
(C). The increase in cyclic AMP removes the regulatory unit, thereby activating the catalytic unit. The catalytic unit phosphorylates the regulatory
protein, which can now bind to the promoter and consequently initiate gene transcription.
144 Psychiatry, Psychoanalysis, and the New Biology of Mind
From Metapsychology to Molecular Biology 145
FIGURE 4–13. A model for the biochemical basis of long-term memory (opposite page).
In short-term sensitization (part A1), the cyclic AMP–dependent protein kinase is proposed to have a normal regulatory subunit (RN) and no particular
orientation with respect to a substrate membrane protein associated with the K+ channel. In naive terminals, relatively high concentrations
of cyclic AMP are needed to activate the catalytic subunit (C) (part A2) to phosphorylate the membrane protein (part A3). This phosphorylation
brings about enhanced release of transmitter, the neurophysiological event underlying sensitization. The memory is brief because the concentration
of cyclic AMP diminishes soon after stimulation with serotonin. In trained neurons (part B1), a new class of regulatory subunit (RL) has been induced.
As a result, the protein kinase differs from the naive enzyme in being site specific and thus being advantageously oriented both to the channel
and to the mechanism that governs the organization of dense projections at the active zone (filled triangles), where synaptic vesicles line up to release
transmitter. In addition, this new kinase has higher affinity for cyclic AMP. Consequently, lower concentrations of cyclic AMP are required to
phosphorylate these target proteins (part B2). In part B3, functionally, as in part A3, the K+ channel is inhibited as long as the channel protein remains
phosphorylated. Morphologically, protein phosphorylation leads to the stable enlargement of the synapse. In this form of sensitization, the
memory persists for longer periods of time because it is embodied in RL, a protein molecule.
Source. Reprinted from Kandel ER, Schwartz JH: “Molecular Biology of an Elementary Form of Learning: Modulation of Transmitter Release by
Cyclic AMP.” Science 218:433–443, 1982. Used with permission from the American Association for the Advancement of Science.
146 Psychiatry, Psychoanalysis, and the New Biology of Mind
and produces long-term learned changes in behavior, it may do so by producing
alterations in gene expression. Needless to say, psychotic illness, in
addition to partaking obligatorily of alterations in gene structure, may also
involve a secondary disturbance in gene expression.
A Molecular Genetic Model for the
Maintenance of Anxiety
How might one envision the alteration of gene expression in learning? The
model in Figure 4–9 accounts only for the immediate (short-term) effects of
sensitization, that is, for the acquisition of anxiety. It is attractive to think,
however, that this model might be more general and might account for the
long-term maintenance of anxiety, including the structural changes. Indeed,
Schwartz and I recently extended this model to account for the long-term
maintenance of anxiety by positing a specific kind of alteration in gene
expression (Kandel and Schwartz 1982). According to this theory, a gene is
induced to produce a new protein kinase that ensures prolonged phosphorylation
of the potassium channel (Figure 4–13).
The cyclic AMP–dependent kinase is a protein consisting of two classes
of subunits, a catalytic subunit and a regulatory subunit. The free catalytic
subunit carries out the phosphorylation. The regulatory subunit binds to the
catalytic subunit and prevents it from acting. The function of cyclic AMP is
to cause the regulatory unit to dissociate from the catalytic unit and free it
for action.
Serotonin, acting repeatedly on the terminals of the sensory neuron (as
a result of repeated aversive stimulation), might activate a gene able to produce
a novel class of regulatory subunit for the protein kinase. The specific
inducer that activates the gene for the regulatory subunit might be cyclic
AMP. The prolonged elevation of cyclic AMP that occurs in short-term sensitization
may allow cyclic AMP to enter the nucleus of the cell and there to
cause the gene for a new regulatory subunit to be expressed by cyclic AMP–
dependent phosphorylation (of perhaps one or more proteins). Activation of
a gene for a new class of subunit could be permanent or it could slowly decay
if not reinforced by subsequent aversive training. Schwartz and I posited that
this regulatory subunit would have two novel features: it would have greater
sensitivity to cyclic AMP, thereby allowing the catalytic subunit to dissociate
more readily; and it would be site specific, allowing the kinase to be bound
to the presynaptic membrane near the potassium channels that are to be
modulated (Kandel and Schwartz 1982) (Figure 4–13B). The synthesis of a
regulatory subunit with greater affinity for cyclic AMP would allow the
cyclic AMP–dependent protein kinase to work at relatively normal concentrations
of the cyclic nucleotide. Slight elevations above the normal concenFrom
Metapsychology to Molecular Biology 147
trations of cyclic AMP of the sort that accompany the arousing stimuli of
everyday life are inadequate to evoke sensitization in the untrained terminal.
However, with the new regulatory subunit facilitating the work of the protein
kinase, such slight elevations in cyclic AMP would now be sufficient to
provide, by modification of ion channels, the enhanced influx of calcium required
to increase transmitter release and thus sustain the learned anxiety
reaction (Figure 4–13B, 2 and 3).
A subunit that would position the protein kinase optimally could allow
it to trigger a family of parallel cyclic AMP–dependent changes in the sensory
neuron. For example, it could 1) produce the functional change in the
potassium-channel protein and 2) alter the assembly of the protein components
that constitute the active zone (Figure 4–13B) and thereby initiate the
striking change in morphology of sensory terminals observed by Bailey and
Chen (1983). These two molecular changes, both caused by the same cyclic
AMP–dependent kinase, could operate together to bring about enhanced
transmitter release from the long-term sensitized neuron.
Although obviously premature because of lack of experimental support,
this speculative explanation for the maintenance of anxiety can be tested. The
large nerve cells of Aplysia offer special experimental advantages for molecular
genetic studies of the nervous system, since nuclei of individual cells can be
isolated by hand dissection (Lasek and Dower 1971; Schwartz et al. 1971). In
addition, recombinant DNA techniques have recently been successfully applied
to Aplysia, allowing genes of known function to be isolated (Scheller et
al. 1982). But the primary reason I have engaged in this speculative digression
is to illustrate that the molecular regulatory processes are likely to prove important
for understanding long-term modification in behavior produced by
natural experience and by psychotherapeutic intervention.
Anticipatory Anxiety Shares Molecular
Components With Chronic Anxiety
We do not yet know in cellular detail the mechanisms underlying the aversive
conditioning that is used as a model for anticipatory anxiety in Aplysia,
but there is already good evidence that the cellular mechanisms of aversive
conditioning are related to those of long-term sensitization (Duerr and
Quinn 1982; Hawkins et al. 1983; Walters and Byrne 1983). Analyses of
classical conditioning of simple reflexes in Aplysia suggest that the learning
of signaled anxiety involves a modified form of the same cellular and molecular
mechanisms—those of presynaptic facilitation—that underlie chronic
anxiety. The mechanism for associative specificity is an augmented form of
presynaptic facilitation called activity-dependent enhancement of presynaptic
facilitation. The invasion of the sensory neuron terminals by action po148
Psychiatry, Psychoanalysis, and the New Biology of Mind
tentials resulting from activation of the CS pathway makes these terminals
more responsive to the effects of serotonin released by the facilitating neurons
in the US pathway. Thus, classical conditioning uses an amplification
of the molecular machinery used by sensitization, suggesting that there may
be a molecular alphabet to learning, whereby complex forms of learning use
components found in simple forms. In signaled anxiety, these presynaptic facilitating
mechanisms appear to be used for two components of the learning
at two points in the neural circuit: an associative component to provide for
the temporal specificity of the modulation and a modulatory component to
enhance defensive reflexes.
The first component, enhancement, is a modulatory component identical
to the presynaptic facilitation that accounts for sensitization. As is the
case with sensitization, the modulatory component enhances defensive reflex
responses (such as gill withdrawal) through the serotonergic defensive
arousal cells (Figure 4–14).
The second component, called the associative component, consists of a
modified and augmented form of the same mechanism and gives classical conditioning
its temporal specificity. Using a simple reflex pathway that can be associatively
conditioned, Hawkins and associates (1983) and Walters and
Byrne (1983) found that after a series of pairing trials in which action potentials
in the sensory neuron of a CS pathway immediately precede activity in the
US pathway the sensory neuron releases more transmitter than when action
potentials in the sensory neuron are not paired with the US. This evidence suggests
that classical conditioning is essentially an amplified form of the mechanism
of presynaptic facilitation. It produces a more profound depression of
the potassium channels and a larger increase in the duration of the action potential
than does conventional presynaptic facilitation.
According to this model for anticipatory anxiety, when head shock is
paired with shrimp, serotonergic cells in the head ganglia produce a highly
robust presynaptic facilitation of the sensory neurons that respond to
shrimp. In this augmented form of facilitation, the ability of the serotonergic
neurons to produce presynaptic facilitation is substantially enhanced because
an action potential in the neurons of the CS pathway that responds to
shrimp immediately precedes the action of the serotonergic cell (which is activated
by the aversive US). Activity dependence of classical conditioning
explains why the CS must precede the US during pairing for anticipatory
anxiety to be acquired.
A Molecular Model for Anticipatory Anxiety
How does the action potential in the neurons of the CS pathway lead to the
enhanced presynaptic facilitation that underlies the association of the anxiety
From Metapsychology to Molecular Biology 149
state with a specific environmental signal? Clearly, one or more aspects of the
action potential produce the amplification. Four events occur during the action
potential: depolarization, sodium influx, calcium influx, and potassium
efflux. One attractive possibility is that calcium influx is the signal, since calcium
affects the activity of cyclic AMP in a number of ways (Cheung 1980).
The activity-dependent enhancement produced by calcium could be achieved
by modulating one or more steps in the cyclic AMP cascade. For example, calcium
might modulate the activation of the adenylate cyclase in the sensory
cells by serotonin. According to this idea, the action of the serotonergic facilitating
neuron would be more effective in classical conditioning than in sensitization
because activation of the cyclase by serotonin is preceded by an influx
FIGURE 4–14. Relationship of classical conditioning to sensitization
in Aplysia.
According to the model this form of learning involves two components: an associative
component that accounts for the timing or temporal specificity of the modulation and
a modulatory component that enhances or reduces a number of behavioral responses.
It is attractive to think that presynaptic facilitation, the mechanism underlying sensitization,
could be used in each component, although in different ways, conventional
and amplified, to modulate the strength of a particular connection. The key point of
the model is that the two components represent distinct neuronal processes: 1) Activity-
dependent presynaptic facilitation could yield the temporal discrimination necessary
to achieve associative specificity, and 2) conventional presynaptic facilitation
could provide the modulatory component responsible for enhancing the strength of
the response.
150 Psychiatry, Psychoanalysis, and the New Biology of Mind
of calcium within the sensory neuron. Calcium, perhaps in association with
calmodulin, could bind to a site on the adenylate cyclase, producing a conformational
change that leads to its greater activation by serotonin.
Thus, a basic presynaptic regulatory mechanism involving enhancement
of transmitter release by cyclic AMP–dependent phosphorylation could be
used in different ways (conventional and amplified) to achieve chronic (unsignaled)
anxiety or anticipatory (signaled) anxiety. This model of classical
conditioning further suggests that we are on the threshold of understanding
our ability to learn predictive relationships. I would argue that the ability to
learn predictive relationships—an ability critical to our mental life—lies in
the precise temporal requirement of a signal produced by spike activity (perhaps
calcium) for the adenylate cyclase system of certain neurons.
An Overall View
The models that I have considered emphasize the cellular interrelationship
of chronic and anticipatory anxiety in Aplysia. Both forms of anxiety involve
the strengthening of connections by modulating synaptic transmission. Both
lead to enhancement of transmitter release by depressing a potassium channel
and thereby increasing influx of calcium. Thus, these studies suggest that
there is a basic molecular grammar underlying the various forms of anxiety,
a set of mechanistic building blocks that can be used in different combinations
and permutations. They further suggest that a variety of mental processes
that appear phenotypically unrelated may share a fundamental unity
on the cellular and molecular levels.
I have in this discussion purposely gone beyond the facts in pointing arguments
based on animal studies toward human behavior because I have
wanted to emphasize two conceptual points that I believe will be fundamental
for the future study of the cellular mechanisms of anxiety. The first is the
power of experience in modifying brain function through altering synaptic
strength and regulating gene expression. The second is the utility and promise
of animal models for the study of anxiety. Unlike schizophrenia, which
does not exaggerate a normal adaptive process and is therefore a characteristically
human mental illness, fear or anxiety is a general adaptive mechanism
found in simple as well as complex animals. There is good reason to
believe that some of the cellular mechanisms of anxiety may also be general.
Moreover, I have suggested that normal learning, the learning of anxiety
and unlearning it through psychotherapeutic intervention, might involve
long-term functional and structural changes in the brain that result from alterations
in gene expression. Thus, we can look forward, in the next decade
of research into learning, to a merger between aspects of molecular genetics
and cellular neurobiology. This merger, in turn, will have important conseFrom
Metapsychology to Molecular Biology 151
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on the other.
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Eric J. Nestler, M.D., Ph.D.
Reading this incisive and penetrating essay by Eric Kandel for the first time
in 20 years offered a fascinating glimpse into the world of neuroscience of
the early 1980s and underscored for me the tremendous advances that have
been made in the neurosciences over the last two decades. When I first read
the article in 1983, I had just completed my Ph.D. research in Paul Greengard’s
laboratory at Yale University and was headed off for residency training
in psychiatry. I thought a lot about setting up my own laboratory and about
which experimental methods were most ripe for new approaches to psychiatric
In his essay “Neurobiology and Molecular Biology: The Second Encounter,”
Kandel weighed in on a key debate at the time: the role of molecular
biology in the neurosciences. Many leading investigators in the neurosciences,
whose research focused on the detailed anatomical connections in
the central nervous system, on the ionic basis of nerve conductance or on
nervous system development, did not envision the value of molecular approaches
to the nervous system. Kandel had first described a wave of molecular
approaches to neuroscience in the 1960s, which largely involved
prominent molecular biologists from other disciplines moving to investiga158
Psychiatry, Psychoanalysis, and the New Biology of Mind
tions of the nervous system. He astutely noted that this early period was
overly optimistic, in that those involved predicted rapid, transforming advances
akin to advances provided by molecular biology in other disciplines.
Although such transforming advances did not materialize, this period was
important in providing fundamentally new models for neuroscience, such as
the use of non-mammalian organisms (C. elegans, Drosophila) to study nervous
system development and function.
The second encounter with molecular biology, the subject of Kandel’s
1983 essay, represented a much more systematic application of molecular
methods to neuroscience. At the time of the essay, such studies were largely
dominated by molecular cloning techniques and the production of monoclonal
antibodies. For the first time, proteins that had been discovered and
characterized based solely on some functional activity (e.g., ion channel
conductance, neurotransmitter receptor binding) were being cloned. This
age also witnessed the first identification of families of novel regulatory proteins
that drive the formation and differentiation of neural cells during development.
Kandel predicted the degree to which this wave of molecular
biology would transform neuroscience and that it would not primarily be by
conceptual leaps forward but by providing uniquely powerful tools that
would enable neuroscientists to probe their systems at an increasingly penetrating
molecular level.
Kandel’s essay is impressively prescient in its predictions, and I have to
admit that unlike Kandel, I did not fully appreciate the magnitude of these
contributions back in 1983, while I was in the thick of experiments at the
bench. Kandel foretold, for example, the widespread use of mutational analysis
of simple organisms and homology screening of molecular libraries to
identify new families of genes involved in nervous system function and development.
As another example, he emphasized the importance of using
molecular tools to characterize changes in gene expression during development
and in the adult animal to understand how the nervous system adapts
and changes over time.
Indeed, in rereading Kandel’s essay, it is very impressive to see just how
far the field has come in 20 years. In the early 1980s, only one ion channel
(the nicotinic acetylcholine receptor from skeletal muscle) was cloned and
its subunit structure delineated. Today, hundreds of ion channels have been
cloned, some have even been crystallized, and detailed information is available
concerning the molecular mechanisms governing channel gating. Mutations
in many of these channels have been found to be the cause of a range
of neurological disorders. In the early 1980s, neurotransmitter release was
understood at a descriptive level: Ca2+ influx during the nerve impulse triggers
the translocation of transmitter-filled vesicles to the presynaptic membrane
where the transmitter is released via exocytosis. Today, this process
Neurobiology and Molecular Biology 159
has been elucidated with an impressive degree of molecular detail, where
Ca2+ binding to target proteins triggers cascades of protein-protein interactions
that control vesicle trafficking and fusion. In the early 1980s, the
notion that the phosphorylation of neural proteins regulates nerve conductance
and synaptic transmission was still controversial. Today, protein phosphorylation
is known as the dominant molecular mechanism by which all
types of neural proteins are regulated. These are just some of the advances
in neuroscience achieved over the past two decades that would not have
been possible without the extraordinary tools of molecular biology.
Equally striking in Kandel’s review is one major area of knowledge where
our progress has been less dramatic: understanding precisely how neural circuits
produce complex behavior. This goal is of particular importance to
Kandel, myself, and our many colleagues in psychiatry as we strive to explain
the neural basis of mental disorders. Clearly, some critical progress has
been made; for example, through the explosive use of conventional and,
more recently, inducible cell-targeted mouse mutants, viral vectors, antisense
oligonucleotides, RNAi, and related tools, we have seen extraordinary
advances in the ability to relate individual proteins within particular brain
structures to complex behavior. Yet the precise circuit mechanisms by which
these proteins, through altered functioning of individual nerve cells, give
rise to most types of complex behavior remain almost as elusive as they were
20 years ago.
This cuts to the heart of a central theme in Kandel’s elegant overview to
this current volume. Are we simply waiting for still additional methodological
advances to enable us to gain a neural understanding of complex behavior,
or is such a reductionist approach inherently limited? I strongly agree
with Kandel’s notion that neuroscience will one day provide a mechanistic
understanding of complex behavior under normal and pathological conditions.
In taking stock of where we’ve come as a field since 1983, I remain as
optimistic as ever that we will achieve this goal, and I look forward to reading
about our field’s progress in this and other remaining challenges two decades
from now!
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C H A P T E R 5
The Second Encounter
Eric R. Kandel, M.D.
As this symposium illustrates, the recent application of molecular genetics
to cellular neurobiology is generating a great deal of excitement. Although
this excitement is in many ways unique, for many of us who have been
working in neurobiology it is accompanied by a sense of déjà vu. The sense
that we have been here before is accurate, since this present contact between
neurobiology and molecular biology is in fact the second, not the first, encounter
between the two disciplines. To put into perspective the recent impact
of molecular genetics on neurobiology, I will divide this summary into
two parts. I will begin with some comments about the first encounter—the
historical origins of the relationship between molecular biology and neural
science viewed from a personal and obviously limited perspective. These origins
set the tradition that has culminated in this symposium. Second, I will
This article was originally published in the Cold Spring Harbor Symposia on Quantitative
Biology, Volume 48, 1983, pp. 891–908.
162 Psychiatry, Psychoanalysis, and the New Biology of Mind
use the issues raised by this symposium to highlight the major themes
emerging in contemporary molecular neurobiology. Although in this summary
I restrict citations mostly to the papers of this volume, I use these papers
as a starting point for considering other issues, which for brevity I will
describe without further citation.
The Return of Molecular Biology
The first encounter between neurobiology and molecular biology dates to
the late 1960s. At that time, several distinguished molecular biologists believed
that many of the interesting problems in their field were close to being
solved; they turned to the brain as their next problem, as their descendants
are now doing. During the preceding two decades, molecular biology had
enjoyed an enormous increase in technical capabilities and explanatory
power. This molecular approach to biological problems had several roots:
the classical genetics of T.H. Morgan and his disciples in America; the examination
of the structure of ordered biological polymers by X-ray crystallography
that was introduced by Astbury and Bragg in England; and finally, the
application of the thinking used in modern physics to problems of biology,
especially characterized by the speculations of Schrödinger (What Is Life?)
and the work of Max Delbrück and his associates. All of these intellectual
precursors shared an experimental approach that depended on model building
and therefore on a willingness to study preparations that best exemplified
the phenomena of interest. This led to a search for conveniently simple
systems that provided abundant material. Thus, geneticists interested in inheritance
in higher organisms first studied Drosophila and Escherichia coli;
crystallographers first analyzed keratin and hemoglobin; and molecular biologists
interested in replication of DNA examined bacterial viruses. Although
the impetus was to understand complex phenomena, study was
governed by optimization of simple experimental systems and by the presumed
universality of the phenomena chosen for study.
With this approach, the flow of genetic information from the nucleus to
the protein-synthetic machinery of the cell was elegantly outlined between
1950 and 1965. Implicit in Watson and Crick’s discovery of the double helical
structure of DNA is the insight it provided into the nature of replication.
This soon led to the discovery of mRNA, the deciphering of the genetic code,
and an understanding of the mechanism of protein synthesis.
By 1965, we were well on the way to understanding the informational
biochemistry of gene expression because of the development of the Jacob-
Monod model of the operon. In this model, a structural gene that codes for
a specific protein is regulated by a promoter element that contains a DNA
sequence called the operator. The structural gene is normally blocked from
Neurobiology and Molecular Biology 163
being transcribed by a repressor protein that is bound to the operator sequence
of the promoter element. But the gene can be switched on rapidly by
a small signal molecule produced by cellular metabolism that binds to and
removes the repressor protein. These small molecules ultimately determine
the rate of transcription of the structural gene. The insight that gene function
is not fixed but can be regulated by the environment through small molecules
(such as inducers) provided a coherent intellectual framework for
understanding much of bacterial physiology. In addition, this model suggested
the first molecular explanation of cellular differentiation during eukaryotic
embryogenesis. According to this view (now known to be slightly
oversimplified), every cell in the body contains all the genes of the genome.
Development, thus, would result from the appropriate switching on and off
of particular patterns of genes in different cells.
To many workers, it then seemed that most of biology, including development,
could be inferred, in principle if not in detail, from rules already at
hand. The rules, the argument went, had been derived from viruses and bacterial
cells, but the code was universal, and evolution conservative. Many
could not help agreeing with Monod that an elephant is an E. coli writ large.
As a result, these biologists felt that only one major frontier remained—the
brain, and within it, development and the biology of mentation: cognition,
perception, thought, and learning.
Although time has shown this view to be overly optimistic, neurobiology
benefited from this optimism, for within a few years a number of talented molecular
biologists migrated into neurobiology: Francis Crick, J.P. Changeux,
Sidney Brenner, Seymour Benzer, Cyrus Levinthal, Gunther Stent, and Marshall
Nirenberg, for example. Their enthusiasm immediately brought many
younger people into the field (some of whom were at this symposium—Regius
Kelly, Louis Reichardt, and Douglas Fambrough) who infused neurobiology
with new perspectives and methods.
This first encounter was characterized by the same experimental approaches
that had served molecular biology so well: model building, the selection
of convenient experimental preparations endowed with abundant
material for study, and, most novel for neurobiology, the use of mutational
genetics. An outstanding example of a preparation rich in substances of neurobiological
interest is the electric organ of Torpedo and eel used originally
by David Nachmansohn (1959) to study the biochemical components of
cholinergic transmission. This starting material has yielded detailed structural
information about the nicotinic acetylcholine receptor (AChR), the enzymes
responsible for the synthesis and degradation of acetylcholine (ACh),
and the cholinergic vesicle. Various other preparations were introduced into
neurobiology explicitly because they were useful for mutational analysis, including
tumor cell lines, neuroblastoma and PC12 cells, and simple organ164
Psychiatry, Psychoanalysis, and the New Biology of Mind
isms such as C. elegans and Drosophila, whose short life cycles make them
suitable for genetic analysis. Interest also focused on isogenic lines of fish
and mice that promised to shed light on how genes determine the specificity
of connections in the vertebrate brain.
After the initial excitement, however, these first émigrés encountered
difficult footing in the new terrain. In 1965, good systems for carrying out
mutational analyses of the nervous system did not exist. As a result, the early
pioneers spent much effort and ingenuity developing systems that were new
to neurobiology. A full decade and longer passed before the potential and
promise of the first encounter were fulfilled—before the emphasis moved
from developing systems to answering important questions about the systems.
Although the methods of mutational analysis ultimately made an impact
on neurobiology, these methods did not prove immediately applicable.
As a result, the influence of the first migration was gradual rather than dramatic,
leading to an evolution rather than a revolution in neurobiology. At
times during those years, many workers may have felt that molecular neurobiology
would never reach a lively generative phase—that rapid pace of
progress that had made the rest of molecular biology so exciting. There was
continued movement; the problems were becoming progressively better defined,
more interesting, and more accessible; the standard of work within all
of neurobiology was rising; but progress was slow.
As this symposium has illustrated, in the last 3 years we have benefited
from a second encounter—a return of molecular biology. This renewal of interest
has come with the development of a variety of powerful molecular
techniques: recombinant DNA, DNA- and protein-sequencing methods, and
monoclonal antibodies. Complementing these developments in molecular
biology, patch-clamp techniques have allowed electrophysiologists to measure
currents through single ion channels.
The second encounter, however, differs from the first in several important
respects. Neurobiology now has a stronger tradition in molecular biology.
The work of the first generation of émigrés took hold and a variety of
well-defined and well-studied systems are available for mutational analysis.
The neurobiology of Drosophila and C. elegans has come of age. Most important,
the questions currently answerable on the molecular level have been
greatly clarified. In addition, the techniques of recombinant DNA are applicable
to a much broader range of preparations than are those of mutational
analysis. Moreover, the fact that at least some neurobiologically interesting
genes are conserved in evolution raises the possibility that one might be able
to benefit routinely from the mutational advantages of Drosophila by cloning
genes in Drosophila, and then by using those clones to screen the genomic
libraries of higher animals.
Furthermore, cloning offers the possibility of transforming an E. coli into
Neurobiology and Molecular Biology 165
a family of electric organs, for example. Because of this capability, the gene
products from even the smallest neurons might be harvested in abundance.
If one is interested in a particular molecular component of a cell, cloning
techniques could be used to produce the material of interest in amounts sufficient
for biochemical analysis. For instance, this approach could be used to
characterize the Na+ channel protein, which has been difficult to study because
it represents much less than 0.1% of the nerve cell’s total protein.
The new technology can also elucidate the changes in gene expression
that certainly take place as the nervous system develops and that are likely
to underlie long-term forms of synaptic plasticity. Libraries of cDNA can be
probed with nucleotide sequences from nerve cells, both at different stages
of development and from the mature animal under different protocols of
training to assess changes in mRNA synthesis.
It is now also possible to delineate the organization of particular genes.
If one assumes that neurobiological processes are mediated by universal molecular
mechanisms, the preparations at hand can be used to determine
whether there are brain-specific varieties of molecules within a class and,
within this class, whether different neurons use different molecular entities.
Which components are shared or common, and which are diverse?
Given the fact that the terrain looks inviting for the return of molecular
biology, how has neurobiology been affected in the 3 years since the second
encounter? This symposium attests that the progress has been encouraging
and that we not only have learned much, but have learned it more rapidly
than one might have expected. With the development of new techniques and
the recruitment of excellent scientists trained in a new set of disciplines, the
landscape of certain segments of neurobiology is beginning to change. In addition,
and perhaps more important in the long term, a critical shift in attitude
has taken place within neurobiology. Neurobiology is beginning to
overcome an intellectual barrier that has separated it from the rest of biological
science, a barrier that has existed because the language of neurobiology
has been based heavily on neuroanatomy and electrophysiology and only
modestly on the more universal biological language of biochemistry and molecular
biology. Until 3 years ago, most molecular biologists felt that merely
being interested in the central question posed by neurobiology—how does
the brain operate?—was insufficient for starting work in the field and that
even to begin work required an extensive knowledge of neuroanatomy or
electrophysiology. This meeting has shown that this need not be so—at least
at the outset. I am not here describing, much less advocating, lack of adequate
preparation. A thorough understanding of the issues confronting the
study of the brain is clearly needed. To work in a particular area of the nervous
system, one has to come to grips with its structure and physiology. But
one now can begin to work on molecular aspects of a problem without being
166 Psychiatry, Psychoanalysis, and the New Biology of Mind
intimidated by the formidable facts of electrophysiology or overwhelmed by
the wealth of fine detail in brain anatomy. Since in principle the methodologies
of recombinant DNA and monoclonal antibodies can be applied to any
system of interest, some gifted newcomers have already made interesting
contributions to neurobiology by selecting systems in which the anatomical
and physiological detail is limited or straightforward.
Moreover, this is only the tip of the iceberg. As progress accelerates, the
barriers that have traditionally separated neurobiology from cell biology will
be reduced even more. Two further consequences are likely to result from
this change in the landscape of neurobiology. First, talented scientists from
other areas of biology will increasingly be attracted to neurobiology because
its intrinsically fascinating problems will be posed in ways that lend themselves
to molecular approaches. Second, we in neurobiology will begin to appreciate
that some of the problems we find fascinating are not unique to the
nervous system and might be more profitably studied elsewhere.
On the other hand, this symposium has also illustrated that recombinant
DNA and hybridoma methodologies are techniques, not conceptual schemes.
There will be life in neurobiology after cloning. The basic questions that confront
the study of the brain continue to be: How do nerve cells work? How do
their interactions produce thought, feeling, perception, movement, and memory?
New techniques are interesting for neurobiology only insofar as they help
answer these questions. It is clear that the techniques of molecular genetics
will prove to be of great value, but it is also clear that these techniques cannot
go it alone; additional approaches will be needed.
Let me now turn to consider some specific issues addressed in the symposium
and to use them as a springboard for reviewing some of the major
themes in current molecular neurobiology.
Molecular Neurobiology:
From Molecules to Behavior
Channel Proteins
Membrane proteins endow nerve cells with signaling capabilities
The distinctive electrical signaling capabilities of nerve cells derive from two
families of specialized membrane proteins called channels and pumps that
allow ions to cross the membrane. Pumps actively transport ions against an
electrochemical gradient and therefore require metabolic energy. Channels
allow ions to move rapidly down their electrochemical gradient and do not
require metabolic energy.
Channel proteins, in turn, are grouped into two classes: 1) nongated
channels that are always open and 2) gated channels that can open and close.
Neurobiology and Molecular Biology 167
Voltage-gated channels sense the electrical field and are opened by changes
in membrane potential. Chemically gated channels open when ligands such
as transmitter or hormone molecules are bound to them. Neurons vary in
the types of channels they possess. Even different regions of a single neuron
can have different types of channels.
The current understanding of signaling in nerve cells originates from the
ionic hypothesis formulated in mathematical terms by Hodgkin, Huxley,
and Katz in 1952. According to this theory, the resting and action potentials
result from unequal distribution of K+, Na+, and Cl– across the membrane.
The Na+ pump maintains the concentration of Na+ inside the axon approximately
20 times lower than that on the outside. The resting membrane has
nongated channels (called leakage channels) permeable to K+, and the resting
potential of nerve cells is therefore close to the equilibrium potential for
K+ (approximately –80 mV). The small deviation from the equilibrium potential
for K+ results from a slight permeability of the leakage channels to
Na+ and Cl–. An axon membrane is able to generate an action potential because
it contains two independent voltage-gated channels, one for Na+ and
the other for K+. Both are closed at rest and are opened with depolarization.
Depolarization gates the Na+ channel, admitting some Na+ into the cell,
which in turn causes further depolarization; this opens up more Na+ channels
and gives rise to a regenerative process that drives the membrane potential
toward the Na+ equilibrium potential of about +55 mV. Depolarization
also opens K+ channels, but with a delay. K+ channels allow K+ to move out
of the cell, and this event, together with the inactivation of the Na+ channel,
repolarizes the cell and terminates the action potential.
Over the last several years, the ionic hypothesis has been extended by the
finding of additional ion channels in the cell body and in the terminal regions
of the nerve cell that are not present in its axon. For example, nerve
terminals and cell bodies contain voltage-gated Ca++ channels. The opening
of these channels is responsible for the influx of the Ca++ necessary for the
exocytotic release of transmitter by synaptic vesicles. In muscle cells, opening
of the Ca++ channels is a crucial step in initiating contraction. Moreover,
in addition to the K+ channel described by Hodgkin and Huxley (1952),
called the delayed K+ channel, several other types of gated K+ channels have
been found in both the nerve terminals and cell bodies. These include the
early K+ channel and the Ca++-activated K+ channel.
Synaptic transmission in its simplest form represents an extension of this
set of mechanisms. It uses channels that are gated chemically rather than by
voltage. For example, at the nerve-muscle synapse in vertebrates, Fatt and
Katz (1951) and Takeuchi and Takeuchi (1966) showed that synaptic transmission
involves the gating of a channel that passes small cations—primarily
Na+ and K+—when ACh binds to the channel.
168 Psychiatry, Psychoanalysis, and the New Biology of Mind
The best-understood membrane protein is the
ion channel activated by ACh
The initial findings of Fatt and Katz and Takeuchi and Takeuchi opened up
the study of the molecular properties of the channel gated by ACh. Here the
progress has been remarkable. I still remember discussions in the early
1960s of whether the AChR was a protein or a lipid. When this issue was settled,
the question persisted until 1970 as to whether the AChR and acetylcholinesterase
(AChE) are the same molecule. On the basis of studies that
showed the esterase to be a peripheral rather than an integral membrane
protein that does not react with affinity labels or with ligands highly specific
for the receptor, we now know that the receptor and the esterase are different
In addition, studies by Katz and Miledi (1970) and by Anderson and
Stevens (1973) using noise analysis, and subsequent patch-clamp studies by
Neher and Sakmann (1976), have delineated the elementary currents that
flow when a single AChR channel changes from a closed to an open conformation
in response to ACh. Each channel opens briefly (on an average for
1 msec) in the presence of ACh and gives rise to an all-or-nothing square
pulse of inward current that allows about 20,000 Na+ ions to move into the
cell (Anderson and Stevens 1973; Katz and Miledi 1970; Neher and Sakmann
1976). The resulting transport rate of 107 ions/sec is 1,000 times
greater than that of carrier-mediated transport mechanisms such as that by
valinomycin. These measurements have confirmed the basic idea of
Hodgkin, Huxley, and Katz—long thought to be correct—that ions can cross
the membrane through transmembrane pores.
We are now also beginning to learn something about the molecular biology
of the AChR. The work of Karlin, Lindstrom, Raftery, and others has
shown that the receptor protein is an asymmetrical molecule with five subunits
divided into four types (2 α, 1 β, 1 γ, 1 δ). Each α subunit binds one
ACh molecule (Karlin et al.). This is consistent with the earlier pharmacological
finding that two molecules of ACh are necessary to gate the channel.
Each of the four types of subunits is encoded by a different mRNA and therefore
by a different gene (Anderson and Blobel; Numa et al.; Raftery et al.).
Indeed, each of the genes for the four types of subunits has now been cloned
(Numa et al.; Patrick et al.) and there is direct evidence that both copies of
the α subunit are transcribed from a single gene (Numa et al.). The biochemical
difference between the two α subunits results from posttranslational
modifications, although the exact nature of the modifications remains unclear
(Hall et al.; Karlin et al.; Lindstrom et al.; Merlie et al.; Numa et al.; Raftery
et al.).
A comparison of the complete nucleotide sequences of the subunits reNeurobiology
and Molecular Biology 169
veals a substantial homology among them, consistent with the notion that
they all arose from a single ancestral protein (Numa et al.; Raftery et al.). An
obvious possibility is that the ancestral AChR consisted of a homo-oligomer
and that later gene duplication and divergence led to the evolution of the
gene family that now encodes for the various subunits of the contemporary
nicotinic AChR.
Sequence data and related immunological, biochemical, and structural
information on the AChR are also beginning to give us some ideas of how
the subunits are oriented in the membrane (Anderson and Blobel; Changeux
et al.; Fairclough et al.; Karlin et al.; Numa et al.; Patrick et al.). Each of the
four subunits is a transmembrane protein (Anderson and Blobel; Changeux
et al.; Raftery et al.). The aminoterminal region of each subunit is thought to
lie on the extracellular side of the membrane, and this region of the α subunits
is likely to contain the recognition sites for ACh, which are certainly
extracellular. Earlier affinity-labeling studies had shown that the AChbinding
sites contain cysteine residues (Karlin et al.), and on the basis of the
sequence data, it has been possible to pick out the cysteine residues that are
also probably components of these sites (Numa et al.). As we shall see below,
the disposition of the carboxyl terminus is still not clear (Fairclough et al.;
Numa et al.).
Electron microscopic studies indicate that the five chains are arranged
around the central channel (Fairclough et al.; Karlin et al.). Since the sequence
homology extends through most of the primary structure of the subunits,
each subunit is likely to have a similar structural motif. As a result,
each subunit probably makes a similar contribution to the total structure
Fairclough et al.; Numa et al.). For example, Numa’s data suggest that each
subunit has four extended hydrophobic regions. Each of these hydrophobic
regions is believed to traverse the membrane once. If that is so, each subunit
threads through the membrane four times (Changeux et al.; Hershey et al.;
Numa et al.; Patrick et al.). The hydrophobic transmembrane domains are
postulated to link hydrophilic domains that extend beyond the surfaces of
the membrane into the cytoplasm on one side and the extracellular space on
the other. The extracellular domain of each chain is about 25 kD and the cytoplasmic
domains are smaller and of variable size.
One possibility that was entertained a few years ago was that the channel
(ionophore) and the recognition site for ACh (the receptor) might represent
different and separable polypeptide chains. But current structural information
(including negative-stain electron microscopy and image reconstruction)
suggests that all subunits contribute to and are positioned around the
channel like the staves of a barrel. Conductance studies suggest that the
channel narrows to a diameter of 6 Å (Hille 1977). Since the channel is only
weakly selective—it excludes anions but is permeable to monovalent and di170
Psychiatry, Psychoanalysis, and the New Biology of Mind
valent cations as well as nonelectrolytes—it is thought to be a water-filled
neutral pore without fixed charge. Numa has therefore proposed that the
walls of the channel might be made up of the polar side chains of the helices
of the inferred transmembrane segments and that these side chains (primarily
the hydroxyl oxygens of threonine and serine residues) bestow upon the
channel its cation selectivity.
An alternative model has been advanced by Stroud and his colleagues on
the basis of a search, using Fourier analysis, for the periodicities that characterize
the amphipathic secondary structure (Fairclough et al.). According
to Stroud’s model, each subunit has not four but five helical transmembrane
segments. Four are identical to Numa’s, and the fifth helix is believed to be
hydrophobic on one face and hydrophilic on the other. This structure suggested
to Stroud that the fifth α helix forms the walls of the ion channel. The
existence of a fifth transmembrane segment in this model would have an additional
consequence: it would cause the carboxyl terminus of the subunits
to lie on the cytoplasmic side of the membrane. This also is in contradistinction
to Numa’s model of four transmembrane segments, which places the
carboxyl terminus together with the amino terminus on the external surface.
It should be possible to distinguish experimentally between the two models.
Monoclonal antibodies to subunits of the AChR have contributed importantly
to all aspects of the study of the receptor: its synthesis, assembly, conformation,
and the structure of its subunits (Lindstrom et al.). These studies
also have had a key role in elucidating the molecular nature of myasthenia
gravis. This disease of neuromuscular function is characterized by muscular
weakness that is increased by activity and relieved, sometimes dramatically,
by rest. Modern immunological techniques have shown that myasthenia is
an autoimmune disease resulting from self-produced antibodies to AChR.
These antibodies lead to a higher turnover of AChRs by cross-linking them
as well as by facilitating their endocytosis (Lindstrom et al.). As a result, the
affected skeletal muscles of patients with myasthenia gravis contain fewer
AChRs than do those of normal people. In view of the clinical importance of
the AChR, it is fortunate that the receptor is highly conserved through evolution;
its gene has been isolated from humans (Numa et al.) as well as from
Drosophila (Ballivet et al.), where it might be studied effectively.
Although we now know a great deal about the nicotinic AChR, we still
know little on the molecular level about how the structure of the channel is
expressed in its function. In addition to the problem of ion selectivity, which
I will consider below, other key questions must be addressed. First, how is
the binding of ACh transduced into opening of the channel? Does the transduction
process explain why the total mass of the receptor protein is so large
(250 kD) and why the protein is divided into five chains? It is clear from
studies of ionophoric antibiotics (such as gramicidin A) and of bacterioNeurobiology
and Molecular Biology 171
rhodopsin (Dunn et al.) that one can build a perfectly good channel with
only one small polypeptide chain. Second, how is the receptor assembled?
Is it by self-assembly, or are other proteins involved? Third, how is gene expression
for the subunits regulated during development and following denervation?
These questions illustrate a point that I will return to repeatedly. Defining
nucleotide sequence is an important step toward achieving a molecular
understanding of neuronal function, but it is only a beginning. It will be essential
to combine information derived from molecular genetic techniques
with insights gained from cell biological, biophysical, and structural approaches.
In particular, sequence data must be tied to structural biochemistry,
on the one hand, and to function, on the other. Indeed, it will not be easy
to study the molecular mechanisms by which the AChR channels work (how
permeation occurs, for example). This difficulty stems from the fact that, unlike
organic molecules, the substrates—the ions that move through the various
ACh channels—cannot be altered for specificity studies (although in
the case of the Na+ or K+ channels much has been learned by using ions of
different size, shape, and charge). Thus, the tricks that are possible in the
study of enzyme mechanisms—based on the use of substrate analogs—cannot
be applied to ion channels. However, photoactivated affinity labels of the
channel have been used to identify the subunits that contribute to the channel
of the AChR (Changeux et al.; Karlin et al.).
Site-directed mutagenesis, which has been used in the case of bacteriorhodopsin
to alter the gene products at specific molecular loci (Dunn et al.),
can assist in the analysis of channels. With this form of molecular genetic
analysis, each subunit of the ligand-gated channel might be analyzed in
terms of the contribution that a particular peptide sequence makes to the
various aspects of permeation. The most direct approach to these problems
is likely to come from studies in which site-directed mutagenesis is used to
alter, in defined ways, the structure of the genes for the subunits. These altered
genes or their mRNAs can then be introduced into nonneuronal cells
capable of expressing them—such as oocytes or cell lines (Barnard et al.). If
the approach works, it can be used to elucidate the nature of the recognition
sites on the channel for the transmitter and the selectivity sites within the
channel for the ion, as well as other components crucial to permeation. The
availability of cloned individual subunits will also make it possible to use reconstitution
systems to examine the mechanisms by which subunits assemble
and the functions they perform.
The nicotinic AChR at the vertebrate nerve-muscle synapse is the beststudied
AChR. But ACh also interacts with other receptors, which control
other ion channels. The predominant AChRs in the vertebrate central nervous
system show greater sensitivity to muscarine and atropine than to nic172
Psychiatry, Psychoanalysis, and the New Biology of Mind
otine and d-tubocurarine and are therefore called muscarinic receptors.
There are several different muscarinic receptors (Birdsall et al.). One, for example,
produces its excitatory action not by opening a cation channel for
Na+ and K+ but by closing a channel to K+. What are the structures of these
muscarinic receptors? Do they resemble the nicotinic receptor? The availability
of cloned nicotinic receptor genes now might make it possible to
probe the genomic libraries of animals to see whether there are homologous
subunits of the muscarinic receptor.
In addition to the nicotinic and muscarinic receptors of vertebrates, at
least three other AChRs are present in invertebrates such as Aplysia, and
each of these receptors controls different ionic channels (Na+ and K+; Cl–
and K+). It will be fascinating to see whether there is a structural or ontogenic
logic to this large family of AChR channels—the nicotinic, the muscarinic,
and the several invertebrate receptors. Comparative analysis of their
sequence and additional structural information might offer important clues
to one of the central problems of channel function, ion selectivity: How do
some ACh channels select for K+ alone while others select for Na+ and K+,
and still others only for Cl–.
We still know little about the structure
of the Na+, K+, and Ca++ channels
I have so far reviewed what we know of the structure of the AChR channel
and have pointed out some of the gaps remaining in our knowledge that
must be filled before we understand this channel thoroughly. When it comes
to the structure of the Na+ channel, the various K+ channels, and the Ca++
channel, unfortunately even less is known, although some information is
likely to emerge soon for the Na+ channel. However, studies of these channels
illustrate how much voltage- and patch-clamp experiments have contributed
to our understanding of kinetic properties, gating, and channel
modulation. For example, we know that the Na+ channel (unlike the AChR
channel) is highly discriminating in its selectivity for ions. It is 10 times
more selective for Na+ than for K+. The Ca++ channel is 10 times more selective
still, being 100 times more selective for Ca++ than for either Na+ or K+.
In addition to the selectivity of the Na+ channel, we know that it exists in
three functional states: closed, open, and inactivated. Patch-clamp analysis
by Aldrich and Stevens has revealed that the inactivated state is accessible
from both the resting and the active states but that open channels move into
the inactive state about 100 times more rapidly than do closed or resting
Until recently, we thought that the channels contributing to the action
potential were gated only by voltage (as is the case with the Na+ channel),
Neurobiology and Molecular Biology 173
whereas channels that produce synaptic actions were gated only by a transmitter
(as is the case with the ACh channel). We have now learned that this
old rule has several exceptions. Single-channel and other biophysical analyses
have shown that some channels that contribute to the action potential
are also modulated by transmitters. Particularly interesting is the finding
that two of these dual-purpose channels are modulated by their transmitter
through a cAMP-dependent protein phosphorylation—the Ca++ channel in
the heart modulated by adrenergic agonists (Reuter et al.; Tsien et al.) and
the K+ channel in sensory neurons of Aplysia modulated by serotonin (Camardo
et al.). Although these studies provide direct evidence for cAMPdependent
protein phosphorylation in modulating ion channels in excitable
membranes, a key problem still remains: What is the substrate or substrates
that are actually phosphorylated? Does the kinase phosphorylate the channel
protein itself or does it modify a regulatory protein closely associated
with the channel?
Although single-channel analysis has contributed much to our understanding
of the kinetics of the Na+, Ca++, and K+ channels, we still know little
about the molecular details. A good beginning is being made in the case of
the Na+ channel, however. This has been possible because of the finding of
ligands with high affinity and specificity (TTX, saxitoxin, and batrachotoxin),
as well as antibodies for this channel. The Na+ channels isolated
from mammalian synaptosomes, from mammalian muscle, and from eel
electroplax and brain, all contain a large polypeptide of 250–300 kD that is
glycosylated (Agnew et al.; Catterall et al.; Fritz et al.). In the mammalian
brain, this peptide is called the α subunit; it is isolated together with two
smaller subunits, β1 (39 kD) and β2 (37 kD). β
2 is linked to the α subunit
by disulfide bonds. The Na+ channel in sarcolemma from mammalian muscle
has three small components (39 kD, 38 kD, and 47 kD), in addition to a
large peptide.
To what degree are the Na+ channels from these various sources related?
Does the existence of the large peptide in each of them indicate that all of
these Na+ channels share a major subunit? To answer this question it will be
necessary to determine parts of the amino acid sequence of the large peptide.
Just as Raftery’s data on the partial amino acid sequence of the AChR opened
the way for the cloning of this molecule, so now some sequence data are
badly needed to move analysis of the Na+ channel to the next level.
The K+ and Ca++ channels pose even greater problems for molecular
analysis because, unlike the Na+ channel, there were until recently no comparable
ligands or antibodies for these channels. The dihydroxypyridines,
however, are a new class of drugs thought to interact specifically with Ca++
channels (Gengo et al.; Gould et al.) and thus may aid in their isolation. But
attention is focused at the moment on one of the K+ channels, the early K+
174 Psychiatry, Psychoanalysis, and the New Biology of Mind
channel, which is altered in the Drosophila mutant called shaker (L.Y. Jan et
al.; Salkoff). Shaker mutants show spontaneous, nonfunctional movements
under certain circumstances that are due to prolonged action potentials in
nerve and muscle cells. These abnormal action potentials are the result of a
single gene mutation that deprives shaker of early K+ channels. Were this
mutation to exist only in mice, the problem might have to rest for a while,
but in Drosophila, specific techniques now make it possible to isolate mutant
genes. A particularly effective technique is transposon tagging, whereby the
gene of interest is both mutated and marked by the insertion of moveable
(transposable) genetic elements (transposons). A transposable genetic element
in Drosophila that is especially useful is the P element because it becomes
highly mobile when males from a strain that carries the P element are
mated with females from a strain that does not. This type of mating leads to
hybrid dysgenesis, a process that greatly increases mutations in the offspring.
Because the P element is inserted into new sites in the genome of the
offspring, these mutations allow one to screen dysgenic flies for the shaker
defect phenotypically (L.Y. Jan et al.). Shaker mutants isolated in this way
indeed contain P elements close to the shaker locus (L.Y. Jan et al.). One
should now be able to isolate the P element and the surrounding nucleotide
sequences, and thereby to isolate segments of the gene for the early K+
Isolation of any K+ channel might lead to the isolation of other K+ channels
if they share sequence homology. A comparative approach here would
be of particular interest because there are at least five identified K+ channels
on the membranes of nerve cells. It will be fascinating to see to what degree
the various kinetically distinct K+ channels are related. Do they share any
subunits? Perhaps the K+ channels, like the AChR channels, are made up of
several subunits and all K+ channels will be found to share all but one of
them, the unique subunit giving each class of K+ channel its particular voltage
and time parameters. Characterization of all the K+ channels can also
suggest functional interrelationships among them, and site-directed mutagenesis
can help to specify the nature and physiological relevance of their
One of the most challenging tasks in channel physiology for the next
5 years is clearly to understand the nicotinic AChR better and to move beyond
it to other channels. Some general molecular rules, about channel selectivity,
kinetic properties, and voltage and transmitter gating, should
underlie the structure and function of membrane channels, and a detailed
comparison of the family of AChR channels and of the various K+ channels
may well lead us to them. Outlines of some of these rules are already emerging
from single-channel analysis. Combining in situ mutagenesis with single-
channel analysis, on the one hand, and with modern structural analysis
Neurobiology and Molecular Biology 175
(X-ray, neutron, and electron diffraction; electron microscopy; and nuclear
magnetic resonance), on the other, should prove immensely instructive.
Synaptic Transmission: It Now Seems as If Neurons Use
Two Major Classes of Synaptic Transmitters
Neurons have available to them two means for intercellular communication:
electrical and chemical. A particular membrane specialization is used for
each. Electrical transmission involves a well-characterized membrane protein
called connexon, which forms channels within specializations called
gap junctions that connect the cytoplasm of the pre- and postsynaptic cells.
At gap junctions, electrical current generated by the action potential in one
cell flows directly across into the connected cell.
Chemical transmission is more specialized; in addition to distinctive
zones of apposition between the two neighboring cells, it involves molecular
machinery in the presynaptic neuron for the storage and release of transmitter
as well as receptor molecules in the postsynaptic cell. An action potential
that invades the presynaptic terminal of a neuron activates voltage-gated
Ca++ channels. The resulting inflow of Ca++ allows synaptic vesicles, each
containing several thousand molecules of transmitter, to bind to specialized
release sites called active zones. Once released, the transmitter diffuses
across the synaptic cleft, where it binds to a receptor and opens (or closes)
chemically gated channels, initiating current flow in the postsynaptic cell.
Depending on the channels gated by the transmitter, the current flow will
produce excitation or inhibition.
Whereas something is now known about the receptors to a variety of
transmitters and the ion channels they control (see, for example, Barker et
al.; Sakmann et al.), we are only beginning to understand the presynaptic
molecular machinery that controls vesicle binding and transmitter release
(Goldin et al.; Kelly et al.). A significant conceptual advance has come from
the appreciation that vesicle release is intimately tied to vesicle mobilization,
the process by which vesicles are loaded onto release sites. In turn, mobilization
of vesicles is related to axonal transport and, at its origin in the Golgi
apparatus of the cell body, transport of vesicles is related to membrane sorting.
Kelly’s data on membrane sorting indicate that there are two pathways
for externalizing products manufactured in the Golgi apparatus: a constitutive
pathway and a regulated pathway. Only the regulated pathway is used
by material stored in synaptic vesicles. Synaptic vesicles move from the
Golgi apparatus into the axon by interacting with specific transport elements.
A given vesicle must select, for example, whether it will be transported
to the terminal regions of the axon for release or to the dendrite for
insertion into the dendritic membrane. For different vesicles to move to dif176
Psychiatry, Psychoanalysis, and the New Biology of Mind
ferent regions of the cell, two conditions must exist: 1) there must be several
transport systems, and 2) secretory vesicles must have a recognition molecule
for selecting the appropriate system. After they are carried by axonal
transport to the nerve terminal, synaptic vesicles can be loaded into active
zones for release. Ca++ entry promotes fusion of the vesicle to the membrane,
presumably by means of calmodulin or a similar Ca++-binding protein.
Small molecule transmitters
A nice example of how an analysis of the underlying molecular logic of a system
can lead to much broader insights comes from studies of the genes encoding
the synthetic enzymes for small molecule transmitters (Joh et al.;
Mallet et al.; O’Malley et al.). Catecholamines are synthesized through a
pathway consisting of four well-characterized and related enzymes. The first
step of the pathway, the amino acid tyrosine, is converted to L-dopa by the
enzyme tyrosine hydroxylase (TH). Second, L-dopa is decarboxylated to
dopamine by aromatic L-amino acid decarboxylase. Third, the enzyme
dopamine β-hydroxylase (DBH) converts dopamine to norepinephrine. Finally,
the last enzyme in the pathway, phenylethanolamine N-methyltransferase
(PNMT), catalyzes the synthesis of epinephrine from norepinephrine.
There are two interesting features about the regulation of these enzymes.
First, not all nerve cells that release catecholamines express all four enzymes,
although the neurons in the adrenal medulla and neurons that release
epinephrine do so. But neurons that synthesize norepinephrine do not
express the enzyme PNMT, and neurons that release dopamine express neither
PNMT nor DBH. The phenotypic expression of catecholamine-synthesizing
enzymes in neurons (and in chromaffin cells) can be independently
regulated so that one cell type can express one of the four enzymes and not
the others. Second, insofar as a neuron expresses one or more of the genes
of this pathway, that expression is coordinately regulated. Conditions that
alter the synthesis of one enzyme also change the synthesis of the others. For
example, neural activity in the noradrenergic neurons of the locus coeruleus
causes an increase in the synthesis of norepinephrine, and this is reflected in
a coordinately regulated increase in the expression of TH, DBH, and PNMT
(Joh et al.; Mallet et al.; O’Malley et al.).
Peptide transmitters
Most of the emphasis in the study of chemical synaptic transmission has
been on small transmitter molecules: norepinephrine, serotonin, ACh, and
various amino acids or closely related substances (Barker et al.; Cull-Candy;
Sakmann et al.). But the number of potential signaling substances is actually
Neurobiology and Molecular Biology 177
much greater, as recently became clear with the discovery that peptides,
ranging in length from 2 to 100 amino acids, also serve as chemical transmitters
within the nervous system. A given peptide can function in three
overlapping ways: 1) as a neurotransmitter by acting over very short distances
(300–500 Å) on neighboring nerve cells, 2) as a local hormone by diffusion
over somewhat larger distances (1–2 mm), and 3) as a neurohormone
by being released into the bloodstream to act on distant targets. These several
functions of peptides (and of certain biogenic amine transmitters) indicate
that the conventional distinction between hormone and transmitter no
longer holds in any rigorous sense. Thus, superimposed upon the anatomical
precision of the pattern of neuronal connections is an equally precise but
spatially more separated pattern of chemically addressed interactions determined
by the peptide transmitters and their receptors on target cells.
The distinction between small molecule transmitters and peptides seems
fundamental, and it is likely to be important for understanding brain function.
As is the case with small molecule transmitters, peptides are released
from the nerve terminals of neurons in a Ca++-dependent manner, and after
they are released they act upon specific receptors in the postsynaptic cell. Although
the actions of these two classes clearly overlap, peptides and small
molecule transmitters tend to differ in their modes of action. Peptides are extremely
active and are effective in concentrations as low as 10–10 M. On the
other hand, conventional small molecule transmitters must be present in
concentrations as much as 105 times greater before they are effective. In addition,
small molecule transmitters are rapidly and effectively removed or
degraded. For example, the enzyme AChE hydrolyzes ACh, and there are
specific high-affinity uptake mechanisms to remove transmitters from the
synaptic cleft. These mechanisms are apparently not available for peptide
transmitters: no uptake mechanisms have yet been discovered and no rapidly
acting degradative enzymes exist (although some peptidases are specific
[see Mason et al., for example]). As a result, peptides tend to have a much
more lasting effect on neurons than the small molecule transmitters that often
can act rapidly (Y.N. Jan et al.). Even more fundamental is the fact that
small molecule transmitters are typically synthesized in the presynaptic terminal
by a series of biosynthetic enzymes (such as choline acetyltransferase
for ACh) and are therefore immediately available for release. In contrast, the
precursors of peptide transmitters are synthesized on ribosomes in the cell
body and the peptides must then be transported to the nerve terminal. Finally,
peptides often coexist with other (small molecule) transmitters (Dodd
et al.; see also Hökfelt et al. 1980).
Particularly interesting is the finding that peptides are characteristically
synthesized from a large precursor molecule (a polyprotein) that often contains
within itself the sequence for other neuroactive peptides (Buck et al.;
178 Psychiatry, Psychoanalysis, and the New Biology of Mind
Herbert et al.; Mahon and Scheller; Roberts et al.). The discovery that
polyproteins are precursors of peptides was made by Herbert, Roberts, and
their colleagues, when they showed that ACTH derives from a much larger
precursor, pro-opiomelanocortin, which also contains α-, β-, and γ-MSH; β-
lipotropin; and the enkephalins. Depending on the nature of its proteolytic
processing, the same polyprotein can yield different sets of peptides in different
cells. For example, pro-opiomelanocortin is expressed in both the intermediate
and the anterior lobes of the pituitary; in the anterior lobe it is
processed to ACTH, but in the intermediate lobe all of the ACTH is further
processed to α-MSH. Pro-opiomelanocortin is also produced in the arcuate
nucleus of the hypothalamus where it is processed to a mixture of ACTH and
α-MSH. In addition to differences in processing the same precursors, cells in
the anterior and intermediate lobes of the pituitary express the same gene for
pro-opiomelanocortin but respond differently to the same stimulus (glucocorticoid)
simply because the cells in the intermediate lobe lack glucocorticoid
receptors (Roberts et al.). It therefore becomes important to localize a
given peptide to its cells of origin. For this purpose, antibodies to the peptide
or labeled probes for its nucleotide sequence can be used in immunocytochemical
or in situ hybridization studies (Buck et al.; Mahon and Scheller;
Roberts et al.).
The study of polyprotein precursors has revealed an underlying unity in
the organization of peptide transmitters (or putative transmitter candidates).
Since the discovery of met- and leu-enkephalins by Hughes, Kosterlitz,
and their colleagues in 1975, 18 additional peptides have been found
that possess opioid-like analgesic activity when injected into the brain. All
of the opioid peptides are extensions of the carboxyl terminus of either metor
leu-enkephalin. Moreover, all 18 peptides derive from only three precursors:
pro-opiomelanocortin, proenkephalin, and prodynorphin (Herbert et
al.; Rossier). The three precursors show remarkable regularities. They are almost
identical in length, and the biologically active peptides are almost exclusively
confined to the carboxyterminal half of the precursor. The active
domain of each precursor is flanked on both sides by pairs of basic amino
acid residues, creating potential cleavage sites for trypsin-like enzymes.
These similarities have two implications. First, the existence of the
flanking basic residues has led to the discovery within polyproteins of several
completely novel and previously unanticipated peptides (Buck et al.;
Evans et al.; Herbert et al.; Mahon and Scheller; Sutcliffe et al.). This finding
in turn suggests one rational strategy in the search for novel peptides: the
precursor molecules of each known peptide can be cloned and then explored
for potentially new peptide sequences outlined by flanking basic cleavage
sites. (For another strategy, see Sutcliffe et al., this volume.) In a beautiful
application of this general approach, a new mammalian peptide was discovNeurobiology
and Molecular Biology 179
ered encoded on the same gene with the calcitonin coding sequence. Immunocytochemistry
was then used to show that this peptide is present in
neurons of the taste pathway (Evans et al.).
The second implication of the similarities among peptide transmitters is
that each family may have evolved from a single ancestral gene. For example,
because the opioid peptides have common opioid activity and share structurally
similar repeated sequences, it seems likely that these peptides arose
from a series of duplications. Herbert et al. have suggested that an enkephalin
gene repeating unit of 48 bases may be the building block for all three
genes of the three opioid precursors. Duplication and rearrangements of this
building block may have led to the various opioid genes that exist today.
The realization that peptides are created from polyproteins raises another
question: Why are polyproteins used as precursors? In principle,
polyproteins provide an opportunity for diversity because they can be processed
or expressed differently in different cells. They also offer a mechanism
for coordinated expression and release and, in the case of gene families,
for the release of different combinations of peptides. The coordinated release
of diverse peptides in various combinations, acting throughout the nervous
system, may be important in orchestrating different aspects of a behavior.
Work by Earl Mayeri and his colleagues (1979; Rothman et al. 1983) on the
component peptides of the precursor for the egg-laying hormone (ELH) in
Aplysia has indicated that these peptides can indeed produce different neuronal
actions. Some peptides from the precursor excite some cells, while
other peptides inhibit other cells. The possibility is intriguing that different
peptides of a polyprotein are involved in mediating complex behavioral sequences.
By means of their several constituent peptides, polyproteins could
ensure that the various neuronal circuits responsible for the different facets
of a stereotyped behavior are activated in a coherent manner. This notion,
consistent with findings in Aplysia (Buck et al.; Mahon and Scheller), is also
supported in mammals, where the complex responses to stress involve the
action not simply of ACTH but also of β-endorphin, γ-MSH, and corticotropin-
releasing factor. It will therefore be important to see exactly how (on
what neurons and on what peripheral targets) these several peptides act in
producing the response to stress.
Thus, it is becoming clear that to make sense of the peptides we will have
to look not only at genes but also at behavior. To correlate peptides with behavior
will in turn require that we look beyond single peptides to the family
of peptides produced by a precursor. It will also be profitable to examine
peptides that have already been linked to certain behaviors—such as cholecystokinin
to satiety, and angiotensin to thirst. Perhaps the precursors to
these peptides contain additional peptides whose function can further enlighten
our understanding of these instinctive (homeostatic) behaviors.
180 Psychiatry, Psychoanalysis, and the New Biology of Mind
Although peptides are providing an additional dimension to our understanding
of neural action, many of the peptides now identified are in an early
stage of analysis. Only in a very few cases has release of a peptide from a neuron
been convincingly demonstrated, or has the action of a peptide been analyzed
on the cellular level. We are still in the age of peptides looking for
functions. Simple behavioral systems in vertebrates and invertebrates should
prove extremely useful here (Buck et al.; Y.N. Jan et al.; Mahon and Scheller).
Moreover, whereas we now know the structures of many peptides, we know
little of the receptors for peptides. Yet understanding these receptors is crucial,
since with peptides, as with small molecules, the ultimate action is determined
by the molecular nature of the receptor. How do these receptors
work? Do they use second messengers? Are they encoded in gene families?
Many peptides seem to have diversified from an ancestral gene. What about
their receptors? Did they evolve independently of the peptides, or coordinately
with them?
I stress the significance of peptides because they constitute an important
bridge between molecular neurobiology and the neurobiology of information
processing and behavior. In the excitement generated by progress in
molecular neurobiology, we should not lose sight of why molecules such as
the Na+ channel and the AChR channel are fascinating. The interest in them
lies not only in their properties as intrinsic membrane proteins but also in
the fact that these proteins must be understood before we can explain the
workings of the brain: how we and simple animals move, behave, and learn.
There is some concern that the dramatic progress in molecular biology,
which one can confidently predict, will lead to a separation of the cellular
aspects of neurobiology from the aspects concerned with information processing.
If this were to happen, it could in fact lead to a fragmentation of
neuroscience that would be regrettable because much of the beauty of the
field consists in its unity and scope. To my mind, the study of peptide precursors
illustrates once again that deep scientific insights are often synthetic,
not divisive. Knowledge of the nucleotide sequence of the gene that encodes
the peptide is likely to illustrate principles of behavior that would be difficult
to extract from study of either the gene products or behavior in isolation.
Development: Cell Lineage, Axon Outgrowth,
Cell Recognition, and Synapse Formation
The nervous systems of all animals develop as a specialization of the ectoderm
of the body surface. In some animals, neurogenesis then proceeds by
proliferation and differentiation in situ. In other animals, proliferation and
differentiation occur at different sites: neurons first proliferate and then migrate
to their definitive location. In nematode worms, the ectodermal cells
Neurobiology and Molecular Biology 181
in the body wall give rise to the neural epithelium. Within this neural epithelium,
primitive neuroblasts lose contact with the inner and outer surfaces
of the ectoderm, round up, and typically proliferate in situ, giving rise to
clones of progeny. Other neurons, common in the nervous system of vertebrates,
develop in the ciliated columnar ectoderm of the neural tube or the
neural crest, then withdraw from the mitotic cycle and migrate over varying
distances to the ultimate destinations of their cell bodies. After they have
reached their destination, neurons start to spin out their axons, which then
travel sometimes over considerable distances and by complex routes to their
appropriate region of the brain. Finally, in that region, the growth cone of
the neuron seeks out the appropriate target cell through what appears to be
chemical trial and error. The outgrowing axon often bypasses thousands of
candidate neurons and, in a selection process that presumably involves
rather precise recognition, selects only the correct target (or one of a small
population of correct targets). The recognition event in turn initiates a new
series of steps involving competition with other outgrowing fibers and eventually
leading to the differentiation and stabilization of the synapse.
The papers at the symposium leave little doubt that we are on the brink
of an important era in the study of neural development.
First, with the increase in experimental detail about the sequence of
events during synapse formation over the last 15 years, we have become
more sophisticated about the questions involved. Before dissociated cell culture
was available, many scientists thought that the critical insights into development
could be achieved by studying what was believed to be one allor-
none step: synapse formation. We now realize that synapse formation is
not one step but a family of steps that probably begins with cell lineage and
extends to the maturation of the functioning synapse. It seems likely, from
what we already know, that each step has its own subroutines, each controlled
by particular molecules acting on a cell at a particular time and priming
it for the next step (Nirenberg et al.; see also Rubin et al. 1980).
Second, we are about to move from descriptive phenomenology to molecular
analysis. Several advances presented at the meeting are particularly
Cell lineage can now be studied with remarkable precision
In the nematode worm C. elegans, it has been possible to trace the entire lineage
of all the cells of the nervous system in the living animal by using
Nomarski differential interference contrast microscopy (Horvitz et al.; Sulston;
J.G. White et al., personal communication). These studies have shown
that the differentiation of most (but not all) nerve cells in the nematode is
largely autonomous and relatively independent of cell-cell interactions. If a
182 Psychiatry, Psychoanalysis, and the New Biology of Mind
given precursor is killed, all cells derived from that precursor will typically
be absent in the adult, and all other nerve cells will be present. But no obvious
rules relate cell lineage to final cell type. Individual members of a class
of neurons (for example, serotonergic or dopaminergic cells) do not come
from a common ancestor but from distant independent lineages. However,
neurons of a given class are generated as homologous descendants of the
separate progenitors, each of which undergoes the same pattern of division
and generates the same complement of cell types. In general, neuronal differentiation
does not require migration. Each neuron is born close to the final
position of its cell body, and the choices for cell-cell interactions are
limited. One of the functions of cell lineage seems to be to put the correct
cell in the correct place at the right time, so that its outgrowing processes
select only the appropriate targets from all available neighborhoods (J.G.
White et al., personal communication). Some nerve cells do migrate and
have a wider range of choices (Sulston).
A promising approach to the molecules that are important in determining
the developmental program of specific cells, including cells of known behavioral
function, is the use of mutants of cell lineage (Horvitz et al.). Work
on C. elegans may also help to clarify aspects of the individuality of neurons,
which I will consider later. C. elegans is ideally suited to this problem because
each of the 273 cells of its nervous system is unique (Sulston; J.G.
White et al., personal communication). It will be interesting to see to what
degree the defining characteristics of these cells are reflected in distinctive
patterns of gene expression.
Pathfinding seems to involve selective adhesion
of growth cones to specific substrates
To establish connections with specific targets, neurons send out axonal
growth cones that navigate from their site of origin at one cell body to the
site of the target. Studies of growth cone navigation in the grasshopper embryo
suggest that these cones use a precise set of pathfinding processes to
seek their target (Bastiani et al.; Bentley et al.; Raper et al.). As an embryonic
limb begins to emerge from the body wall, it is initially devoid of neurons.
The first axons to appear in the limb (the pioneer fibers) are the axons of
sensory neurons that arise within the limb epithelium. As the growth cones
of these pioneer fibers reach the central nervous system, the growth cones
of the first motor axons start to emerge and run in the opposite direction.
These two sets of axons thereby establish the initial scaffolding for subsequent
axon outgrowth. Raper et al. have proposed that the axonal pathways
established by the pioneer axons are distinctly labeled on their cell surface.
Later growth cones are thought to be differentially determined in their abilNeurobiology
and Molecular Biology 183
ity to choose which labeled pathways to follow (Bastiani et al.; Raper et al.).
Some labeled pathways and axon fascicles can be characterized by specific
monoclonal antibodies (Hockfield et al.; Raper et al.).
To analyze the mechanisms that regulate pioneer fiber outgrowth and
that allow later outgrowing axons to follow specific pathways will require a
variety of molecular and mutational approaches. Drosophila mutants have already
been used successfully to manipulate axon morphology and consequently
synapse formation (Wyman and Thomas). The finding that the
Drosophila embryo bears strong resemblances to that of the grasshopper is
therefore encouraging, for it suggests that one might be able to use the
wealth of experimental strategies and mutants available in Drosophila to explore
the possible existence and the functional roles of specific cell-surface
molecules in the initial pioneer fibers as well as in the later outgrowing axons
(Raper et al.).
Nerve cell adhesion molecules have been
characterized at the molecular level
The direction of a field can be dramatically altered when the analysis moves
from description to an examination of the action of specific molecules. A
clear example of this is occurring in the study of cell adhesion, which is important
for various types of cell-to-cell contact. In turn, direct cell-to-cell
contact is thought to be essential for various steps in development, from the
initial separation of neuronal from nonneuronal precursors, to the subsequent
migration of neurons, and to the later stages of differentiation that include
axonal pathfinding and synapse formation. Despite the importance of
cell-to-cell contact throughout development, very little was known about
the molecular events underlying it until recently. A common notion has been
that neurons (and nonneuronal cells) display on their surface or secrete into
the extracellular matrix macromolecules important for cell-cell interactions.
How do these signals work? There is a range of possibilities. At one extreme,
Letourneau (1975) has shown that neurite outgrowth will occur
merely if the growth cone is provided with an effective surface for adhesion.
At the other extreme, highly specific mechanisms involving recognition as
well as adhesion could exist. For example, molecules on the surface of one
cell could be recognized by specific receptors on the surface of the outgrowing
growth cones of other cells. Alternatively, the signal might be secreted by
one cell and internalized by the outgrowing cell, so that it would act from
within the second cell to influence the direction of neurite outgrowth.
Over the last decade, Edelman and his colleagues, in particular Rutishauser,
have used developing chick and mouse nerve cells to isolate and
characterize the first clearly identified nerve cell adhesion molecules (N184
Psychiatry, Psychoanalysis, and the New Biology of Mind
CAMs). N-CAMs are high-molecular-weight glycoproteins (180–250 kD)
that contain large amounts of the charged sugar, sialic acid. Different regions
of the brain are thought to contain different forms of N-CAM, distinguished
by different sialic acid residues. In addition, during development, N-CAM of
high sialic acid content (embryonic N-CAM) is converted to a form much
lower in sialic acid (adult N-CAM). This conversion occurs at different times
in different parts of the developing nervous system. On the basis of these
findings, Edelman has suggested that structurally distinct N-CAMs could
play a role in both early and late development. Early in development, NCAM
might be important for segregating cell types. Once cells are committed
to a given neuronal lineage, N-CAM might function in adhesion as well
as in the recognition required for appropriate cell types to interact in the various
regions of the brain.
There is as yet no direct evidence for the participation of N-CAM in specific
recognition, but its importance for adhesion is supported by two experiments.
First, N-CAM is present in the neural crest when sensory neurons
initially appear, but it is transiently lost during migration while fibronectin
in the pathway undergoes a concomitant increase. After the sensory neurons
reach their target in the dorsal root ganglion, N-CAM reappears. Second,
transformation of nerve cells by Rous sarcoma virus alters both cell-to-cell
adhesion and expression of N-CAM.
We will now need to distinguish between adhesiveness (which may be a
quite general property of stickiness that closely related cells could show) and
cell recognition (which may require a higher degree of specificity). Consequently,
we need to know the degree of specificity introduced into N-CAM
by glycosylation. Alterations in the number of sialic acid residues seem to result
in altered adhesiveness, but it has not been shown that such changes in
adhesiveness will change the nature of the recognition events. Conceivably,
N-CAM could serve to stabilize cell-to-cell contact after recognition has
been achieved by a different set of molecules. Alternatively, N-CAM might
be important for recognition as well.
How many molecular species are likely to be used for cell adhesion and recognition
functions? The discovery of a variety of other factors involved in cellto-
cell adhesion and recognition (Goridis et al.; Lander et al.; Matthew and
Patterson; Schachner et al.; Stallcup et al.) strongly indicates that at least several
molecular species are involved, and there are probably more. However, if the
finding proves general that adhesion molecules can exist in a large number of
different forms (because of posttranslational modifications such as glycosylation),
the informational potential of a few recognition molecules would be
greatly enhanced and the task of analyzing developmental processes simplified.
Neurobiology and Molecular Biology 185
The extracellular matrix contains proteoglycan
important for neurite outgrowth
Molecules that function in cell adhesion and recognition are found not only
in neurons but also in the nonneuronal cells of the extracellular matrix to
which outgrowing neurons attach as they migrate and differentiate. Whereas
it was once thought that the extracellular matrix merely filled the space
between cells, it is now clear that the matrix serves as a substrate for outgrowing
processes, secreting molecules that provide important clues for development.
For example, when cerebellar granule cells or neural crest cells
are cultured, their ability to adhere to and migrate on fibronectin (a protein
secreted by the fibroblasts) correlates well with their migratory pattern in
the animal. Several matrix factors have now been found that stimulate outgrowth
from particular classes of neurons. One of these, a heparan-sulfate
proteoglycan, is secreted by cultured corneal endothelial cells and promotes
rapid outgrowth of neurites from sympathetic or sensory neurons when they
are attached to a substrate. The molecule acts quite specifically: it stimulates
only neurons that send axons to the periphery; nerve cells whose axons are
restricted to the CNS do not respond to it (Lander et al.). A monoclonal antibody
has now been developed that blocks this type of neurite outgrowth,
and this antibody also binds to a heparan-sulfate proteoglycan (Matthew and
Patterson). The appearance of immunoreactivity is correlated with axonal
Another example of the contributions of the extracellular matrix to outgrowth
can be found in the basal lamina present between the pre- and
postsynaptic elements at the nerve-muscle synapse. The basal lamina contains
several polypeptides (the most potent of which is 80 kD) that direct the
reformation of the presynaptic specialization and the final position of outgrowing
axons during regeneration. The polypeptides also direct the infoldings
and aggregation of AChRs in the plasma membrane of regenerating
myofibers (Nitkin et al.; Sanes and Chiu). It will be important to relate these
findings to the initial outgrowth of motor neurons in early development.
The cloning of nerve growth factor may prove important clinically
Although several neuron-specific regulatory signals have now been delineated,
the first to be identified continues to be the best understood. Nerve
growth factor (NGF) was discovered in 1951 by Rita Levi-Montalcini and
Viktor Hamburger. It is essential for the survival of sympathetic neurons and
certain sensory neurons and stimulates the outgrowth of their processes. Antibodies
to NGF produce an immunosympathectomy—a selective destruction
of sympathetic neurons. In a sense, the discovery of NGF and the first
186 Psychiatry, Psychoanalysis, and the New Biology of Mind
isolation of chemical transmitter substances marked the beginning of the
molecular exploration of the nervous system—predating by a decade the
analysis of the AChR. In the ensuing 30 years, research on NGF has provided
a model of the level of understanding that we need to attain about the action
of other factors governing the development and function of the nervous
Recombinant techniques and sensitive immunoassays have focused renewed
attention on NGF (Darling et al.; Thoenen et al.; Ullrich et al.). The
physiological site of origin of NGF, long uncertain, has now been shown to
be in tissues innervated by sympathetic neurons. The density of innervation
is correlated with the levels of NGF. The endogenous NGF is transported retrogradely
and is accumulated in sympathetic ganglia. cDNA probes of nucleotide
sequences coding for NGF should now be useful for exploring the role
of NGF in the CNS and its roles, if any, in familial dystonia and other neurological
diseases of humans.

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