Kandel wrote 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.”
He interweaves two stories, one is an intellectual history of major accomplishments in the study of mind over the last 50 years, and the other is the story of Kandel’s life and scientific career over that time period.
His family lived under Nazi rule for a year in Vienna before being able to escape, separately, to New York. Kandel considered himself very fortunate to be able to escape alive, and this period shaped his life and personality.
He began college at Harvard intending to study contemporary Austrian and German history. But then became interested in practicing psychiatry and decided to go to medical school. He befriended Anna Kris, who’s parents were prominent psychoanalysts, and they influenced him greatly.
“It is difficult to recapture now the extraordinary fascination that psychoanalysis held for young people in 1950. During the first half of the 20th century psychoanalysis provided a remarkable set of insights into the mind - insights about unconscious mental processes, psychic determinism, and perhaps most interesting, the irrationality of human motivation. As a result, in 1950, psychoanalysis outlined by far the most coherent, interesting, and nuanced view of the human mind than did any other school of psychology.”
Began at N.Y.U medical school with the intention of becoming a psychoanalyst, but became very interested in the biology of the mind. Thus, he took an elective period at Columbia University with Harry Grundfest. At that time N.Y.U. had no one on the faculty who was doing basic neural science. While there, he met Denise Bystryn, a very attractive and interesting French Jewish woman, who he decided to marry. Their shared experiences as Jews in Europe during WWII brought them together as well.
In Grundfest’s lab, Kandel fell in love with experimental neurobiology. They were stimulating small areas of cortex and recording resulting neurological activity in experimental models. He came across the work of Stephen Kuffler, a Viennese trained physician turned physiologist, who became a hero of Kandel’s. Kuffler was studying invertebrate neurons in dishes, he was able to see and stimulate individual dendrites in large cells, and was able to study the properties of neurons with unprecedented acuity.
Next, Kandel joined Wade Marshall’s lab at the NIH. Marshall showed that the brain had systematic topographical maps of the sensory surface for each of the three major sensations - touch, vision, and hearing. Around this time, Scoville and Milner had published their work studying HM, and found that while HM had a very selective deficit in forming new memories, thus implicating the hippocampus in this process. In Marshall’s lab, Kandel’s research took a very fortunate turn with the arrival of Alden Spencer. They recorded from hippocampal pyramidal cells, and made a few key discoveries.
“First, we found that action potentials in hippocampal neurons were initiated not only at the axon hillock, as in motor neurons, but also at a second site, which we inferred to be the apical dendrites. These putative dendritic action potentials, which we called fast prepotentials, appeared to trigger the firing at the axon hillock. Second, we found that the hippocampal neurons, unlike motor neurons, were not silent in the absence of synaptic activity, but tended to fire spontaneously, and that this firing often took the form of bursts of spikes that were maintained by summation of depolarizing afterpotentials. Third, we found that the hippocampal neurons engaged a powerful recurrent inhibitory system that gave rise to a prolonged inhibition - several orders of magnitude longer than the inhibition seen in the spinal cord.”
But as they reviewed their work, they realized that the cellular properties of neurons in the hippocampus weren’t super different from those in the spinal cord, so how did they store memory? They realized the ability to store memory probably didn’t reside in the properties of neurons themselves. Kandel searched for the perfect model animal in which to study memory and learning on a cellular level, and settled on aplysia, a type of sea snail.
“I wanted to examine learning in an experimental animal in which a simple behavior was modifiable by learning. Ideally that behavior should be controlled by only a small number of large and accessible nerve cells, so that the animal’s overt behavior could be related to events occurring in the cells that control that behavior.”
In reading contemporary behaviorist papers, Kandel realized that “the paradigms they described - habituation, sensitization, classical conditioning, and operant conditioning - could readily be adapted to experiments with an isolated Aplysia ganglion using artificial electrical rather than natural sensory stimuli. While recording the behavior of a single cell in a ganglion, one nerve axon pathway to the ganglion could be stimulated weakly electrically as a conditioned stimulus, while another pathway was stimulated as an unconditioned stimulus, following the exact protocol used for classical conditioning with natural stimuli in intact animals. One could then see whether synapses changed systematically in response to these patterns of stimulation, and, if so, whether the synaptic changes in any way paralleled changes in the overt behavior of intact animals.”
Kandel set up his own laboratory in Departments of Physiology and Psychiatry at the New York University Medical School. It was a small group, and to do it, he turned down a very prestigious position as chairmanship of the Department of Psychiatry at the Beth Israel Hospital, what would have been his greatest aspiration a few years ago.
“We found that all three simple forms of learning - habituation, sensitization, and classical conditioning - lead to changes in the synaptic strength of specific sensory pathways, and that these changes parallel the time course of the memory process. These findings, which had been fully anticipated by our earlier studies of analogs of learning, gave rise to one of the major themes in our thinking about the molecular mechanisms of memory storage. Even though the anatomical connections between neurons develop according to a definite plan, the strength and effectiveness of those connections is not fully determined developmentally and can be altered by experience.”
“To simulate habituation, I would apply repeated, weak electrical pulses to this neural pathway. To simulate sensitization, I would stimulate a second neural pathway very strongly, one or more times, and see how it affected the target cell’s response to weak stimulation of the first pathway. Finally, to simulate classical conditioning, I would pair the strong stimulus to the second pathway with the weak stimulus to the first pathway in such a way that the strong stimulus would always follow and be associated with the weak stimulus. In this way, I could determine whether the three patterns of stimulation altered the synaptic connections with the target cell and, if so, how. Different changes in synaptic strength in response to the three different patterns of electrical stimulation would represent analogs - biological models - of the synaptic changes in Aplysia’s nervous system brought about by training for the three different forms of learning.”
Kandel also found that if he recorded from one cell, and systematically stimulated other cells in the same cluster, he could map out the synaptic connections over time. These experiments were a lot easier to do technically than the hippocampal recordings he had done with Alden Spencer earlier, and he really enjoyed the pace of life.
“THUS THE REDUCTIONIST APPROACH LED US TO DISCOVER several principles of the cell biology of learning and memory. First, we found that the changes in synaptic strength that underlie the learning of a behavior may be great enough to reconfigure a neural network and its information-processing ability. For example, one particular sensory cell in Aplysia communicates with eight different motor cells - five that produce movement of the gill and three that cause contraction of the ink gland and thus inking. Before training, activation of this sensory cell excited the five gill-innervating motor cells moderately, causing them to fire action potentials and thereby causing the gill to contract. Activation of this same sensory cell also excited the three ink gland-innervating motor neurons but only very weakly, not enough to produce action potentials or to elicit inking. Thus, before learning, gill withdrawal would take place in response to stimulation of the siphon but inking would not. After sensitization, however, synaptic communication between the sensory cell and all eight motor cells is enhanced, causing the three ink gland-innervating motor neurons to fire action potentials as well. Thus, as a result of learning, when the siphon is stimulated, inking will occur along with more powerful gill withdrawal.”
Around the same time, Louis Flexner at the University of Pennsylvania made the remarkable discovery that drugs that inhibit the synthesis of proteins in the brain disrupt long-term memory if given during and shortly after learning, but they do not disrupt short-term memory. This finding suggested that long-term memory storage requires the synthesis of new proteins. Together, the two sets of studies seemed to confirm the idea that memory storage takes place in at least two stages: a short-term memory lasting minutes is converted - by a process of consolidation that requires the synthesis of new protein - into stable, long-term memory lasting days, weeks, or even longer.
Bailey and Chen found that a single sensory neuron has approximately 1300 presynaptic terminals with which it contacts about 25 different target cells. Of these 1300 presynaptic cells, only about 40% have active synapses that have the machinery for releasing a neurotransmitter. The other terminals are dormant. In long-term sensitization, , the number of synaptic terminals more than doubles (from 1300 to 2700), and the proportion of active synapses increases from 40 percent to 60 percent. In time, the number of presynaptic terminals drops down again, but still in excess of the original, which may explain why an animal can learn a task more readily a second time.
Through further investigation using aplysia, they found that cyclic AMP and protein kinase A are both necessary and sufficient for strengthening the connections between sensory and motor neurons. Interestingly, cyclic AMP is not unique to memory storage, or even neurons. It is found in many peripheral organs like the gut and liver and is used to produce persistent metabolic changes. It is the most important, and in some cases the only second-messenger system found in single-celled organisms such as the bacterium E. coli, in which it signals hunger.
“Because human mental processes have long been thought to be unique, some early students of the brain expected to find many new classes of proteins lurking in our gray matter. Instead, science has found surprisingly few proteins that are truly unique to the human brain and no signaling systems that are unique to it.”
Kandel then turned to the study of genes to further understand the changes required to make long term memories specifically, stick around for so long. “We had succeeded in tracing a simple learned response in Aplysia to the neurons and synapses that mediate it and had found that learning gives rise to short-term memory by producing transient changes in the strength of existing synaptic connections between sensory and motor neurons. Those short-term changes are mediated by proteins and other molecules already present at the synapse. We had discovered that cyclic AMP and protein kinase A enhance the release of glutamate from the terminals of the sensory neurons, and that this enhanced release is a key element in short-term memory formation.”
He wondered, how learning and memory processes localized to specific synapses. There must be a way for the new proteins synthesized in the cell to go only to the targeted synapses rather than all synapses in the cell. It’s this independence of synapses that gives the brain such extraordinary computational flexibility. They found that two independent mechanisms are at work. One process initiates long-term synaptic facilitation by sending protein kinase A to the nucleus to activate CREB, which turns on the effector genes that encode the proteins needed for the growth of new synaptic connections. The other process perpetuates memory storage by maintaining the newly grown synaptic terminals, a mechanism that requires local protein synthesis, which was a really surprising finding.
They found, surprisingly, a prion-like protein specific to neurons in aplysia. Prions can fold into two functionally distinct shapes, or conformations; one of these is dominant, the other recessive. The genes that encode prions give rise to the recessive form, but the recessive form can be converted to the dominant form, either by chance or by coming into contact with a protein folded in the dominant form. This self-perpetuating molecule remains at a synapse indefinitely, regulating the local protein synthesis needed to maintain newly grown synaptic terminals. They found that serotonin, which is also required in aplysia to convert short into long-term memory, converts CPEB (the prion-like protein) from its recessive to its dominant form.
Then the workings of the NMDA receptor was elucidated: “The analysis of how the NMDA receptor functions elicited great excitement among neuroscientists, for it showed that the receptor acts as a coincidence detector. It allows calcium ions to flow through its channel if and only if it detects the coincidence of two neural events, one presynaptic and the other postsynaptic. The presynaptic neuron must be active and release glutamate, and the AMPA receptor in the postsynaptic cell must bind glutamate and depolarize the cell. Only then will the NMDA receptors become active and allow calcium to flow into the cell, thereby triggering long-term potentiation.”
Kandel then turned his attention to the role of attention in memory, specifically, the link between attention and spatial memory. Is attention required for the formation of a spatial map? Using mice that learned to navigate a maze, they found”
“Even ambient attention is sufficient to allow a spatial map to form and become stable for a few hours, but such a map becomes unstable after three to six hours. Long-term stability correlates strongly and systematically with the degree to which an animal is required to pay specific attention to its environment… in much the same way that serotonin modulates the amount and state of the CPEB protein in Aplysia, dopamine modulates the amount of the prion-like CPEB protein (CPEB-3) in the mouse hippocampus. This discovery raised the intriguing possibility - so far only that - that spatial maps may become fixed when an animal’s attention triggers the release of dopamine in the hippocampus and that dopamine initiates a self-perpetuating state also mediated by CPEB.”
In 2000, Kandel won the Nobel Prize in Physiology or Medicine. The president of Austria Thomas Klestil called him to say he was happy that there was another Nobel Laureate of Austrian origins. Kandel firmly told him he was an American. Kandel’s feelings towards Austria’s position during WWII are clear:
“For a decade before Austria joined with Germany, a significant fraction of the Austrian population belonged to the Nazi party. Following annexation, Austrians made up about 8 percent of the population of the greater German Reich, yet they accounted for more than 30 percent of the officials working to eliminate the Jews… Yet despite their active participation in the Holocaust, the Austrians claimed to be victims of Hitler’s aggression”
“Austria’s intellectual loss is equally clear and dramatic. Within days of Hitler’s arrival, the intellectual life of Vienna was in shambles. About 50 percent of the university’s medical faculty - one of the largest and most distinguished in Europe - was dismissed for being Jewish. Viennese medicine has never recovered from this “cleansing.” Particularly distressing is how little was done after the collapse of the Third Reich to redress the injustices committed against Jewish academics or to rebuild the academic faculty. Few Jewish academics were invited back to Vienna, and even fewer were given restitution for the property or income they had lost. Of those who did return, some were not reinstated in their university positions, and almost all had great difficulty regaining their homes or even their citizenship, of which they had been stripped.”
At the end of the book, Kandel talks about what scientific problems he would take up if he were to start today.
“I have two requirements of a scientific problem. The first is that it allow me to open a new area that will occupy me for a very long time. I like long-term commitments, not brief romances. Second, I enjoy tackling problems at the border of two or more disciplines. With those predilections in mind, I have found three questions that appeal to me.”
“First, I would like to understand how the unconscious processing of sensory information occurs and how conscious attention guides the mechanisms in the brain that stabilize memory…A second, related issue that fascinates me is the relation of unconscious to conscious mental processing in people. Brain imaging could be used to connect psychoanalysis to brain anatomy and to neural function by determining how these unconscious processes are altered in disease states and how they might be reconfigured by psychotherapy… Finally, I like the idea of applying molecular biology to link my area, the molecular biology of mind, to Denise’s area, sociology, and thus develop a realistic molecular sociobiology.”
Kandel’s advice: “It is better to lose some years trying something new and fundamental than to carry out routine experiments that everyone else is doing and that others could do as well as (if not better than) you.”
Thought questions:
- Kandel says:
“Until the end of the 19th century, the only approaches to the mysteries of the human mind were introspective philosophical inquiries (the reflections of specially trained observers on the nature of their own patterns of thought) or the insights of great novelists, such as Jane Austen, Charles Dickens, Fyodor Dostoevsky, and Leo Tolstoy.”
Do you think novelists still have a role to play in our understanding of the mind?
- Kanel was really enamored with the intellectual life of Vienna, and had complicated feelings about it after the war. What do you think about the connection between culture and morality?
“One conclusion, which is troubling to my sensibilities, is that the quality of a society’s culture is not a reliable indicator of its respect for human life. Culture is simply incapable of enlightening people’s biases and modifying their thinking. The desire to destroy people outside the group to which one belongs may be an innate response and may thus be capable of being aroused in almost any cohesive group.”
- Kandel discusses his conflict between wanting to spend all his time doing science while also spending time with his family. How do you feel he handled the conflict? Does he have more of a responsibility to one over the other?
“It was, and still is, understandably difficult for my children to understand - much less excuse - that I find doing science endlessly fascinating and that my involvement in it can expand almost infinitely. It has required conscious effort on my part and help from Denise and from my psychoanalysis to be more realistic and to structure my time so as to make room for the responsibilities and pleasures of my life with Minouche and Paul and with their children.”
- I found this Tennessee Williams quote really thought provoking: “Has it ever struck you…that life is all memory, except for the one present moment that goes by you so quickly you hardly catch it going? It’s really all memory…except for each passing moment.”
- Kandel says: “From this perspective, to which most neural scientists now subscribe, most of our mental life is unconscious; it becomes conscious only as words and images.”
Do you think that is true? What about being conscious of a feeling you can’t place?
- Kandel describes a weird sexual encounter in his youth, what did you think of the tone with which this was conveyed?
“My encounter with Mitzi, an attractive, sensual young woman of about twenty-five, began one afternoon as I was recovering from a cold at age eight. She sat down at the edge of my bed and touched my face. When I responded with pleasure, she opened her blouse, exposing her ample bosom, and asked me whether I would like to touch her. I barely grasped what she was talking about, but her attempt at seduction had its effect on me, and I suddenly felt different than I ever had before.”