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IN SEARCH OF MEMORY

The Emergence of a New Science of Mind

ERIC R. KANDEL

Copyright © 2006

ISBN 0-393-05863-8

POUR DENISE

CONTENTS

Preface xi

ONE

1.Personal Memory and the Biology of Memory Storage 3

2.A Childhood in Vienna 12

3.An American Education 33

TWO

4.One Cell at a Time 53

5.The Nerve Cell Speaks 74

6.Conversation Between Nerve Cells 90

7.Simple and Complex Neuronal Systems 103

8.Different Memories, Different Brain Regions 116

9.Searching for an Ideal System to Study Memory 135 10. Neural Analogs of Learning 150

THREE

11.Strengthening Synaptic Connections 165

12.A Center for Neurobiology and Behavior 180

13.Even a Simple Behavior Can Be Modified by Learning 187

14.Synapses Change with Experience 198

15.The Biological Basis of Individuality 208

16.Molecules and Short-Term Memory 221

17.Long-Term Memory 240

18.Memory Genes 247

19.A Dialogue Between Genes and Synapses 201

FOUR

20.A Return to Complex Memory 279

21.Synapses Also Hold Our Fondest Memories 286

22.The Brain's Picture of the External World 295

23.Attention Must Be Paid! 307

FIVE

24.A Little Red Pill 319

25.Mice, Men, and Mental Illness 335

26.A New Way to Treat Mental Illness 352

27.Biology and the Renaissance of Psychoanalytic Thought 363

28.Consciousness 376

SIX

29.Rediscovering Vienna via Stockholm 393

30.Learning from Memory: Prospects 416

Glossary 431

Notes and Sources 453

Acknowledgments 485

Index 489

PREFACE

Understanding the human mind in biological terms has emerged as the central challenge for science in the twenty-first century. We want to understand the biological nature of perception, learning, memory, thought, consciousness, and the limits of free will. That biologists would be in a position to explore these mental processes was unthinkable even a few decades ago. Until the middle of the twentieth century, the idea that mind, the most complex set of processes in the universe, might yield its deepest secrets to biological analysis, and perhaps do this on the molecular level, could not be entertained seriously.

The dramatic achievements of biology during the last fifty years have now made this possible. The discovery of the structure of DNA by James Watson and Francis Crick in 1953 revolutionized biology, giving it an intellectual framework for understanding how information from the genes controls the functioning of the cell. That discovery led to a basic understanding of how genes are regulated, how they give rise to the proteins that determine the functioning of cells, and how development turns genes and proteins on and off to determine the body plan of an organism. With these extraordinary accomplishments behind it, biology assumed a cen-

tral position in the constellation of sciences, one in parallel with physics and chemistry.

Imbued with new knowledge and confidence, biology turned its attention to its loftiest goal, understanding the biological nature of the human mind. This effort, long considered to be prescientific, is already in full swing. Indeed, when intellectual historians look back on the last two decades of the twentieth century, they are likely to comment on the surprising fact that the most valuable insights into the human mind to emerge during this period did not come from the disciplines traditionally concerned with mind—from philosophy, psychology, or psychoanalysis. Instead, they came from a merger of these disciplines with the biology of the brain, a new synthesis energized recently by the dramatic achievements in molecular biology. The result has been a new science of mind, a science that uses the power of molecular biology to examine the great remaining mysteries of life.

This new science is based on five principles. First, mind and brain are inseparable. The brain is a complex biological organ of great computational capability that constructs our sensory experiences, regulates our thoughts and emotions, and controls our actions. The brain is responsible not only for relatively simple motor behaviors, such as running and eating, but also for the complex acts that we consider quintessentially human, such as thinking, speaking, and creating works of art. Looked at from this perspective, mind is a set of operations carried out by the brain, much as walking is a set of operations carried out by the legs, except dramatically more complex.

Second, each mental function in the brain—from the simplest reflex to the most creative acts in language, music, and art—is carried out by specialized neural circuits in different regions of the brain. This is why it is preferable to use the term "biology of mind" to refer to the set of mental operations carried out by these specialized neural circuits rather than "biology of the mind," which connotes a place and implies a single brain location that carries out all mental operations.

Third, all of these circuits are made up of the same elementary signaling units, the nerve cells. Fourth, the neural circuits use specific molecules to generate signals within and between nerve cells. Finally, these specific signaling molecules have been conserved—retained as it

were—through millions of years of evolution. Some of them were present in the cells of our most ancient ancestors and can be found today in our most distant and primitive evolutionary relatives: single-celled organisms such as bacteria and yeast and simple multicellular organisms such as worms, flies, and snails. These creatures use the same molecules to organize their maneuvering through their environment that we use to govern our daily lives and adjust to our environment.

Thus, we gain from the new science of mind not only insights into ourselves—how we perceive, learn, remember, feel, and act—but also a new perspective of ourselves in the context of biological evolution. It makes us appreciate that the human mind evolved from molecules used by our lowly ancestors and that the extraordinary conservation of the molecular mechanisms that regulate life's various processes also applies to our mental life.

Because of its broad implications for individual and social well-being, there is now a consensus in the scientific community that the biology of mind will be to the twenty-first century what the biology of the gene was to the twentieth century.

In addition to addressing the central issues that have occupied Western thought since Socrates and Plato first speculated about the nature of mental processes more than two thousand years ago, the new science of mind gives us the practical insights to understand and cope with important issues about mind that affect our everyday lives. Science is no longer the exclusive domain of scientists. It has become an integral part of modern life and contemporary culture. Almost daily, the media report technical information that the general public cannot be expected to understand. People read about the memory loss caused by Alzheimer's disease and about age-related memory loss and try, often unsuccessfully, to understand the difference between these two disorders of memory—one progressive and devastating, the other comparatively benign. They hear about cognitive enhancers but do not quite know what to expect from them. They are told that genes affect behavior and that disorders of those genes cause mental illness and neurological disease, but they are not told how this occurs. And finally, people read that gender differences in aptitude influence the academic and career paths that men and women follow. Does this

mean there are differences between the brains of women and of men? Do men and women learn differently?

In the course of our lives, most of us will have to make important private and public decisions that involve a biological understanding of mind. Some of these decisions will arise in the attempt to understand variations in normal human behavior, while others will concern more serious mental and neurological disorders. It is essential, therefore, that everyone have access to the best available scientific information presented in clear, understandable form. I share the view now current in the scientific community that we have a responsibility to provide the public with such information.

Early in my career as a neuroscientist I realized that people without a background in science are as eager to learn about the new science of mind as we scientists are to explain it. In this spirit, one of my colleagues at Columbia University, James H. Schwartz, and I wrote Principles of Neural Science, an introductory college and medical school textbook that is now entering its fifth edition. The publication of that textbook led to invitations to give talks about brain science to general audiences. That experience convinced me that nonscientists are willing to work to understand the key issues of brain science if scientists are willing to work at explaining them. I have therefore written this book as an introduction to the new science of mind for the general reader who has no background in science. My purpose is to explain in simple terms how the new science of mind emerged from the theories and observations of earlier scientists into the experimental science that biology is today.

A further impetus for writing this book came in the fall of 2000, when I was privileged to receive the Nobel Prize in Physiology or Medicine for my contributions to the study of memory storage in the brain. All Nobel laureates are invited to write an autobiographical essay. In the course of writing mine, I saw more clearly than before how my interest in the nature of memory was rooted in my childhood experiences in Vienna. I also saw more vividly, and with great wonder and gratitude, that my research has allowed me to participate in a historic period of science and to be part of an extraordinary international community of biological scientists. In the course of my work

I have come to know several outstanding scientists in the front ranks of the recent revolution in biology and neuroscience, and my own research has been greatly influenced by my interactions with them.

Thus, I interweave two stories in this book. The first is an intellectual history of the extraordinary scientific accomplishments in the study of mind that have taken place in the last fifty years. The second is the story of my life and scientific career over those five decades. It traces how my early experiences in Vienna gave rise to a fascination with memory, a fascination that focused first on history and psychoanalysis, then on the biology of the brain, and finally on the cellular and molecular processes of memory. In Search of Memory is thus an account of how my personal quest to understand memory has intersected with one of the greatest scientific endeavors—the attempt to understand mind in cellular and molecular biological terms.

ONE

It is not the literal past that rules us, save, possibly, in a biological sense. It is images of the past. These are often as highly structured and selective as myths. Images and symbolic constructs of the past are imprinted, almost in the manner of genetic information, on our sensibility. Each new historical era mirrors itself in the picture and active mythology of its past.

—George Steiner, In Bluebeard's Castle (1971)

1

PERSONAL MEMORY

AND THE BIOLOGY

OF MEMORY STORAGE

Memory has always fascinated me. Think of it. You can recall at will your first day in high school, your first date, your first love. In doing so you are not only recalling the event, you are also experiencing the atmosphere in which it occurred—the sights, sounds, and smells, the social setting, the time of day, the conversations, the emotional tone. Remembering the past is a form of mental time travel; it frees us from the constraints of time and space and allows us to move freely along completely different dimensions.

Mental time travel allows me to leave the writing of this sentence in my study at home overlooking the Hudson River and project myself backward sixty-seven years and eastward across the Atlantic Ocean to Vienna, Austria, where I was born and where my parents owned a small toy store.

It is November 7, 1938, my ninth birthday. My parents have just given me a birthday gift that I have craved endlessly: a battery-operated, remote-controlled model car. This is a beautiful, shiny blue car. It has a long cable that connects its motor to a steering wheel with which I can control the car's movement, its destiny. For the next two days, I drive that little car everywhere in our small apartment—through the living room, into the dining area, under the legs of the dining room

table where my parents, my older brother, and I sit down for dinner each evening, into the bedroom and out again—steering with great pleasure and growing confidence.

But my pleasure is short-lived. Two days later, in the early evening, we are startled by heavy banging on our apartment door. I remember that banging even today. My father has not yet returned from

working at the store. My mother opens the door. Two men enter. They identify themselves as Nazi policemen and order us to pack something and leave our apartment. They give us an address and tell us that we are to be lodged there until further notice. My mother and I pack only a change of clothes and toiletries, but my brother, Ludwig, has the good sense to bring with him his two most valued possessions—his stamp and coin collections.

Carrying these few things, we walk several blocks to the home of an elderly, more affluent Jewish couple whom we have never seen before. Their large, well-furnished apartment seems very elegant to me, and I am impressed with the man of the house. He wears an elaborately ornamented nightgown when he goes to bed, unlike the pajamas my father wears, and he sleeps with a nightcap to protect his hair and a guard over his upper lip to maintain the shape of his moustache. Even though we have invaded their privacy, our appointed hosts are thoughtful and decent. With all their affluence, they also are frightened and uneasy about the events that brought us to them. My mother is embarrassed to be imposing on our hosts, conscious that they are probably as uncomfortable to have three strangers suddenly thrust upon them as we are to be there. I am bewildered and frightened during the days we live in this couple's carefully arranged apartment. But the greatest source of anxiety for the three of us is not being in a stranger's apartment; it is my father—he disappeared abruptly and we have no idea where he is.

After several days we are finally allowed to return home. But the apartment we now find is not the one we left. It has been ransacked and everything of value taken—my mother's fur coat, her jewelry, our silver tableware, the lace tablecloths, some of my father's suits, and all of my birthday gifts, including my beautiful, shiny, remote-controlled blue car. To our very great relief, however, on November 19, a few days after we

have returned to our apartment, my father comes back to us. He tells us that he had been rounded up, together with hundreds of other Jewish men, and incarcerated in an army barracks. He won his release because he was able to prove that he had been a soldier in the Austro-Hungarian army, fighting on the side of Germany during World War I.

The memories of those days—steering my car around the apartment with increasing assurance, hearing the bangs on the door, being ordered by the Nazi policemen to go to a stranger's apartment, finding ourselves robbed of our belongings, the disappearance and reappearance of my father—are the most powerful memories of my early life. Later, I would come to understand that these events coincided with Kristallnacht, the calamitous night that shattered not just the windows of our synagogues and my parents' store in Vienna, but also the lives of countless Jews all over the German-speaking world.

In retrospect, my family was fortunate. Our suffering was trivial compared with that of millions of other Jews who had no choice but to remain in Europe under the Nazis. After one humiliating and frightening year, Ludwig, then age fourteen, and I were able to leave Vienna for the United States to live with our grandparents in New York. Our parents joined us six months later. Although my family and I lived under the Nazi regime for only a year, the bewilderment, poverty, humiliation, and fear I experienced that last year in Vienna made it a defining period of my life.

IT IS DIFFICULT TO TRACE THE COMPLEX INTERESTS AND

actions of one's adult life to specific experiences in childhood and youth. Yet I cannot help but link my later interest in mind—in how people behave, the unpredictability of motivation, and the persistence of memory—to my last year in Vienna. One theme of post-Holocaust Jewry has been "Never forget," an exhortation to future generations to be vigilant against anti-Semitism, racism, and hatred, the mindsets that allowed the Nazi atrocities to occur. My scientific work investigates the biological basis of that motto: the processes in the brain that enable us to remember.

My remembrances of that year in Vienna first found expression even before I became interested in science, when I was a college stu-

dent in the United States. I had an insatiable interest in contemporary Austrian and German history and planned to become an intellectual historian. I struggled to understand the political and cultural context in which those calamitous events had occurred, how a people who loved art and music at one moment could in the very next moment commit the most barbaric and cruel acts. I wrote several term papers on Austrian and German history, including an honors thesis on the response of German writers to the rise of Nazism.

Then, in my last year in college, 1951-52, I developed a fascination with psychoanalysis, a discipline focused on peeling back the layers of personal memory and experience to understand the often irrational roots of human motivation, thoughts, and behavior. In the early 1950s most practicing psychoanalysts were also physicians. I therefore decided to go to medical school. There, I was exposed to the revolution occurring in biology, to the likelihood that fundamental mysteries of the nature of living things were about to be revealed.

Less than a year after I entered medical school in 1952, the structure of DNA was being elucidated. As a result, the genetic and molecular workings of the cell were beginning to open up under scientific scrutiny. With time, that investigation would extend to the cells that make up the human brain, the most complex organ in the universe. It was then that I began to think about exploring the mystery of learning and memory in biological terms. How did the Viennese past leave its lasting traces in the nerve cells of my brain? How was the complex three-dimensional space of the apartment where I steered my toy car woven into my brain's internal representation of the spatial world around me? How did terror sear the banging on the door of our apartment into the molecular and cellular fabric of my brain with such permanence that I can relive the experience in vivid visual and emotional detail more than a half century later? These questions, unanswerable a generation ago, are yielding to the new biology of mind.

The revolution that captured my imagination as a medical student transformed biology from a largely descriptive field into a coherent science firmly grounded in genetics and biochemistry. Prior to the advent of molecular biology, three disparate ideas held sway: Darwinian evolution, the idea that human beings and other animals evolved gradually

from simpler animal ancestors quite unlike themselves; the genetic basis of the inheritance of bodily form and mental traits; and the theory that the cell is the basic unit of all living things. Molecular biology united those three ideas by focusing on the actions of genes and proteins in individual cells. It recognized the gene as the unit of heredity, the driving force for evolutionary change, and it recognized the products of the gene, the proteins, as the elements of cellular function. By examining the fundamental elements of life processes, molecular biology revealed what all life-forms have in common. Even more than quantum mechanics or cosmology, the other fields of science that saw great revolutions in the twentieth century, molecular biology commands our attention because it directly affects our everyday lives. It goes to the core of our identity, of who we are.

The new biology of mind has emerged gradually over the five decades of my career. The first steps were taken in the 1960s, when the philosophy of mind, behaviorist psychology (the study of simple behavior in experimental animals), and cognitive psychology (the study of complex mental phenomena in people) merged, giving rise to modern cognitive psychology. This new disipline attempted to find common elements in the complex mental processes of animals ranging from mice to monkeys to people. The approach was later extended to simpler invertebrate animals, such as snails,

honeybees, and flies. Modern cognitive psychology was at once experimentally rigorous and broadly based. It focused on a range of behavior, from simple reflexes in invertebrate animals to the highest mental processes in people, such as the nature of attention, of consciousness, and of free will, traditionally the concern of psychoanalysis.

In the 1970s cognitive psychology, the science of mind, merged with neuroscience, the science of the brain. The result was cognitive neuroscience, a discipline that introduced biological methods of exploring mental processes into modern cognitive psychology. In the 1980s cognitive neuroscience received an enormous boost from brain imaging, a technology that enabled brain scientists to realize their dream of peering inside the human brain and watching the activity in various regions as people engage in higher mental functions—perceiving a visual image, thinking about a spatial route, or initiating a volun-

tary action. Brain imaging works by measuring indices of neural activity: positron-emission tomography (PET) measures the brain's consumption of energy, and functional magnetic resonance imaging (fMRI) measures its use of oxygen. In the early 1980s cognitive neuroscience incorporated molecular biology, resulting in a new science of mind—a molecular biology of cognition—that has allowed us to explore on the molecular level such mental processes as how we think, feel, learn, and remember.

EVERY REVOLUTION HAS ITS ORIGINS IN THE PAST, AND THE

revolution that culminated in the new science of mind is no exception. Although the central role of biology in the study of mental processes was new, the ability of biology to influence the way we see ourselves was not. In the mid-nineteenth century, Charles Darwin argued that we are not uniquely created, but rather evolved gradually from lower animal ancestors; moreover, he held, all life can be traced back to a common ancestor—all the way back to the creation of life itself. He proposed the even more daring idea that evolution's driving force is not a conscious, intelligent, or divine purpose, but a "blind" process of natural selection, a completely mechanistic sorting process of random trial and error based on hereditary variations.

Darwin's ideas directly challenged the teaching of most religions. Since biology's original purpose had been to explain the divine design of nature, his ideas rent the historic bond between religion and biology. Eventually, modern biology would ask us to believe that living beings, in all their beauty and infinite variety, are merely the products of ever new combinations of nucleotide bases, the building blocks of DNA's genetic code. These combinations have been selected for over millions of years by organisms' struggle for survival and reproductive success.

The new biology of mind is potentially more disturbing because it suggests that not only the body, but also mind and the specific molecules that underlie our highest mental processes—consciousness of self and of others, consciousness of the past and the future—have evolved from our animal ancestors. Furthermore, the new biology

posits that consciousness is a biological process that will eventually be explained in terms of molecular signaling pathways used by interacting populations of nerve cells.

Most of us freely accept the fruits of experimental scientific research as they apply to other parts of the body: for instance, we are comfortable with the knowledge that the heart is not the seat of emotions, that it is a muscular organ that pumps blood through the circulatory system. Yet the idea that the human mind and spirituality originate in a physical organ, the brain, is new and startling for some people. They find it hard to believe that the brain is an information-processing computational organ made marvelously powerful not by its mystery, but by its complexity—by the enormous number, variety, and interactions of its nerve cells.

For biologists working on the brain, mind loses none of its power or beauty when experimental methods are applied to human behavior. Likewise, biologists do not fear that mind will be trivialized by a reductionist

analysis, which delineates the component parts and activities of the brain. On the contrary, most scientists believe that biological analysis is likely to increase our respect for the power and complexity of mind.

Indeed, by unifying behaviorist and cognitive psychology, neural science and molecular biology, the new science of mind can address philosophical questions that serious thinkers have struggled with for millennia: How does mind acquire knowledge of the world? How much of mind is inherited? Do innate mental functions impose on us a fixed way of experiencing the world? What physical changes occur in the brain as we learn and remember? How is an experience lasting minutes converted to a lifelong memory? Such questions are no longer the province of speculative metaphysics; they are now fertile areas of experimental research.

THE INSIGHTS PROVIDED BY THE NEW SCIENCE OF MIND ARE

most evident in our understanding of the molecular mechanisms the brain uses to store memories. Memory—the ability to acquire and store information as simple as the routine details of daily life and as

complex as abstract knowledge of geography or algebra—is one of the most remarkable aspects of human behavior. Memory enables us to solve the problems we confront in everyday life by marshaling several facts at once, an ability that is vital to problem solving. In a larger sense, memory provides our lives with continuity. It gives us a coherent picture of the past that puts current experience in perspective. The picture may not be rational or accurate, but it persists. Without the binding force of memory, experience would be splintered into as many fragments as there are moments in life. Without the mental time travel provided by memory, we would have no awareness of our personal history, no way of remembering the joys that serve as the luminous milestones of our life. We are who we are because of what we learn and what we remember.

Our memory processes serve us best when we can easily recall the joyful events of our lives and dilute the emotional impact of traumatic events and disappointments. But sometimes, horrific memories persist and damage people's lives, as happens in post-traumatic stress disorder, a condition suffered by some people who have experienced at first hand the terrible events of the Holocaust, of war, rape, or natural disaster.

Memory is essential not only for the continuity of individual identity, but also for the transmission of culture and for the evolution and continuity of societies over centuries. Although the size and structure of the human brain have not changed since Homo sapiens first appeared in East Africa some 150,000 years ago, the learning capability of individual human beings and their historical memory have grown over the centuries through shared learning—that is, through the transmission of culture. Cultural evolution, a nonbiological mode of adaptation, acts in parallel with biological evolution as the means of transmitting knowledge of the past and adaptive behavior across generations. All human accomplishments, from antiquity to modern times, are products of a shared memory accumulated over centuries, whether through written records or through a carefully protected oral tradition.

Much as shared memory enriches our lives as individuals, loss of

memory destroys our sense of self. It severs the connection with the past and with other people, and it can afflict the developing infant as well as the mature adult. Down's syndrome, Alzheimer's disease, and age-related memory loss are familiar examples of the many diseases that affect memory. We now know that defects in memory contribute to psychiatric disorders as well: schizophrenia, depression, and anxiety states carry with them the added burden of defective memory function.

The new science of mind holds out the hope that greater understanding of the biology of memory will lead to better treatments for both memory loss and persistent painful memories. Indeed, the new

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