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.