In Search of Memory: The Emergence of a New Science of Mind

by Eric R. Kandel

Repeated trains of electrical stimuli produce a late phase of long-term potentiation that lasts for more than a day. We found the properties of this phase, which previously had not been extensively explored, to be very similar to long-term facilitation of synaptic strength in Aplysia. In both Aplysia and mice, the late phase of long-term potentiation is strongly affected by modulatory interneurons, which in mice are recruited to switch a

short-term, homosynaptic into long-term, heterosynaptic change. In mice those neurons release dopamine, a neurotransmitter commonly recruited in the mammalian brain for attention and reinforcement. Like serotonin in Aplysia, dopamine prompts a receptor in the hippocampus to activate an enzyme that increases the amount of cyclic AMP. However, an important part of the increase in cyclic AMP in the mouse hippocampus occurs in the postsynaptic cell, whereas in Aplysia the increase occurs in the presynaptic sensory neuron. In each case, the cyclic AMP recruits protein kinase A and other protein kinases, which leads to the activation of CREB and the turning on of effector genes. One of the striking things we had found in studying memory in Aplysia was the existence of the memory-suppressor gene that produces the CREB-2 protein. Blocking the expression of that gene in Aplysia enhances both the strengthening...

The thinking of cognitive psychologists was driven by two underlying assumptions. The first was the Kantian notion that the brain is born with a priori knowledge, “knowledge that is…independent of experience.” That idea was later advanced by the European school of Gestalt psychologists, the forerunners, together with psychoanalysis, of modern cognitive psychology. The Gestalt psychologists argued that our coherent perceptions are the end result of the brain’s built-in ability to derive meaning from the properties of the world, only limited features of which can be detected by the peripheral sensory organs. The reason that the brain can derive meaning from, say, a limited analysis of a visual scene is that the visual system does not simply record a scene passively, as a camera does. Rather, perception is creative: the visual system transforms the two-dimensional patterns of light on the retina of the eye into a logically coherent and stable interpretation of a three-dimensional sensory world. Built into neural pathways of the brain are complex rules of guessing; those rules allow the brain to extract information from relatively impoverished patterns of incoming neural signals and turn it into a meaningful image. The brain is thus the ambiguity-resolving machine par excellence!

As a result of the work of Mountcastle, Hubel, and Wiesel, we can begin to discern the principles of cognitive psychology on the cellular level. These scientists confirmed the inferences of the Gestalt psychologists by showing us that the belief that our perceptions are precise and direct is an illusion—a perceptual illusion. The brain does not simply take the raw data that it receives through the senses and reproduce it faithfully. Instead, each sensory system first analyzes and deconstructs, then restructures the raw, incoming information according to its own built-in connections and rules—shades of Immanuel Kant!

The sensory systems are hypothesis generators. We confront the world neither directly nor precisely, but as Mountcastle pointed out: …from a brain linked to what is “out there” by a few million

fragile sensory nerve fibers, our only information channels, our lifelines to reality. They provide also what is essential for life itself: an afferent excitation that maint...

Sensations are set by the encoding functions of sensory nerve endings, and by the integrating neural mechanics of the central nervous system. Afferent nerve fibers are not high-fidelity recorders, for they accentuate certain stimulus features, neglect others. The central neuron is a story-teller with regard to the nerve fibers, and it is never completely trustworthy, allowing dis...

there is no single cortical area to which all other cortical areas report exclusively, either in the visual or in any other system. In sum, the cortex must be using a different strategy for generating the integrated visual image.

Millions of items…are present to my senses which never properly enter into my experience. Why? Because they have no interest for me. My experience is what I agree to attend to…. Everyone knows what attention is. It is the taking possession by the mind, in clear and vivid form, of one out of what seem several simultaneously possible objects or trains of thought. Focalization, concentration of consciousness, are of its essence. It implies withdrawal from some things in order to deal effectively with others.

In addition, it exposed me to how a company works. In a typical academic department, junior faculty members are independent; in the early stage of their career they are encouraged not to collaborate with senior faculty but to develop their own research programs. In business, people must work together for the good of the company using intellectual and financial resources in a way that pushes each potential product in promising directions. Although this cooperative characteristic of industry is generally not found in universities, there are

These results support the notion that the decline in hippocampus-dependent learning in older animals is due, at least

in part, to an age-related deficit in the late phase of long-term potentiation. Perhaps more important, they suggest that benign senescent forgetfulness may be reversible. If it is, the elderly may be treated in the near future with drugs developed from such studies of the mouse. The prospect that benign senescent memory loss is treatable led the leadership of Memory Pharmaceuticals to wonder what other forms of memory impairment might be treated if we knew more about the molecular mechanisms underlying memory formation. With this idea in mind, Memory Pharmaceuticals turned its attention to the early phase of Alzheimer’s disease.

He exposed the mouse hippocampus to the most toxic component of β-amyloid plaques, known as the Aβ peptide, and found that long-term potentiation was impaired before any neurons had died or plaques had formed. In addition, animal models of early Alzheimer’s disease displayed memory deficits before any detectable accumulation of plaque or evidence of cell death. While examining gene expression in hippocampal cells exposed to the Aβ peptide, Shelanski discovered that the peptide

decreases the activity of cyclic AMP and protein kinase A. This finding suggested to him that the peptide may compromise the cyclic AMP-protein kinase A system. Indeed, he found that increasing cyclic AMP via Rolipram prevents Aβ toxicity in mouse neurons. The same drugs that prevent age-related memory loss in mice also prevent memory deficits in mice in the early stages of Alzheimer’s disease. Ottavio Arancio from Columbia University went on to show that Rolipram protects against some of the damage to neurons sustained in Alzheimer’s, thereby suggesting that cyclic AMP not only strengthens the function of pathways whose efficiency has declined, but also helps protect against nerve cell damage and perhaps even leads to regeneration of lost connections in the mouse model of Alzheimer’s disease.

MEMORY PHARMACEUTICALS

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in Nature Reviews Neuroscience as a review article entitled “Neurocognitive Enhancement: What Can We Do and What Should We Do?”

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Furthermore, although most mental illnesses have an important genetic component, they do not have straightforward inheritance patterns, because they are not caused by mutations of a single gene. Thus, there is no single gene for schizophrenia, just as there is no single gene for anxiety disorders, depression, or most other mental illnesses. Instead, the genetic components of these diseases arise from the interaction of several genes with the environment. Each gene exerts a relatively small effect, but together they create a genetic predisposition—a potential—for a disorder. Most psychiatric disorders are caused by a combination of these genetic predispositions and some additional, environmental factors. For example, identical twins have identical genes. If one twin has Huntington’s disease, so will the other. But if one twin has schizophrenia, the other has only a 50 percent chance of developing the disease. To trigger schizophrenia, some other, non-genetic factors in early life—such as intrauterine infection, malnutrition, stress, or the sperm of an elderly father—are required. Because of this complexity in the pattern of inheritance, we have not yet identified most of the genes involved in the major mental illnesses.

The key biological fact that Darwin appreciated, and that has facilitated the development of animal models of anxiety states, is that anxiety—fear itself—is a universal, instinctive response to a threat to one’s body or social status and is therefore critical for

Ansiedad

survival. Anxiety signals a potential threat, which requires an adaptive response. As Freud pointed out, normal anxiety contributes to the mastery of difficult situations and thus to personal growth. Normal anxiety exists in two major forms: instinctive anxiety (instinctive or innate fear), which is built into the organism and is under more rigid genetic control, and learned anxiety (learned fear), to which an organism may be genetically predisposed but which is basically acquired through experience. As we have seen, instinctive anxiety can easily become associated through learning with a neutral stimulus. Since any capability that enhances survival tends to be conserved through evolution, both instinctive and learned fear are conserved throughout the animal kingdom (figure 25–1).

Both forms of fear can be deranged. Instinctive anxiety is pathological when it is excessive and persistent enough to paralyze action. Learned anxiety is pathological when it is provoked by events that present no real threat, as when a neutral stimulus comes to be associated in the brain with instinctive anxiety. Anxiety states were of particular interest to me because they are by far the most common mental illnesses: at some...

Based on this idea, James and the Danish psychologist Carl Lange proposed that the conscious experience of emotion occurs only after the cortex has received signals about changes in one’s physiological state. In other words, conscious feelings are preceded by certain unconscious physiological changes—an increase or decrease in blood pressure, heart rate, and muscular tension. Thus, when you see a fire, you feel afraid because your cortex has just received signals about your racing heart, knocking knees, and sweaty palms. James wrote: “We feel sorry because we cry, angry because we strike, afraid because we tremble, and not that we cry, strike or tremble because we are sorry, angry or fearful, as the case may be.” According to this view, emotions are cognitive responses to information from bodily states mediated in good part by the autonomic nervous system. Our everyday experience confirms that information from the body contributes to emotional experience. Experimental evidence soon supported some aspects of the James-Lange theory. For example, objectively distinguishable emotions are correlated with specific patterns of autonomic, endocrine, and voluntary responses. Furthermore, people whose spinal cord has been accidentally severed, cutting off feedback from the autonomic nervous system in regions of the body below the injury, appear to experience less intense emotions. With time it became clear, however, that the James-Lange theory explains only one aspect of emotional b...

physiological feedback were the only controlling factor, emotions should not outlast physiological changes. Yet feelings—the thoughts and actions in response to emotion—can be sustained long after a threat has subsided. Conversely, some feelings arise much more rapidly than changes in the body. Thus there may be more to emotions than the interpretation of feedback from physiological changes in the body.

They did this by combining the study of animal models with the study of people. As a result, the neural pathways of emotion have been identified with some precision in the last two decades. The unconscious component of emotion, which was identified primarily by means of animal models, involves the operation of the autonomic nervous system and the hypothalamus, which regulates it. The conscious component of emotion, studied in people, involves the evaluative functions of

the cerebral cortex, which are carried out by the cingulate cortex. Central to both components is the amygdala, a group of nuclei clustered together and lying deep in the cerebral hemispheres. The amygdala is thought to coordinate the conscious experience of feeling and the bodily expression of emotion, particularly fear.

The unconscious recall of emotional memory has now been shown to involve implicit memory storage, whereas conscious remembrance of the feeling state has been shown to involve explicit memory storage and therefore to require the hippocampus.

ONE STRIKING FEATURE ABOUT FEAR IS THAT IT CAN READILY become associated with neutral stimuli through learning. Once this happens, the neutral stimuli can be powerful

triggers of long-term emotional memories in people. Such learned fear is a key component of post-traumatic stress disorder, as well as social phobias, agoraphobia (fear of open spaces), and stage fright. In stage fright and other forms of anticipatory anxiety, a future event (being on stage, for example) is associated with the prospect of something going wrong (forgetting one’s lines). Post-traumatic stress disorder occurs following an extremely stressful event, such as life-threatening combat, physical torture, rape, abuse, or natural disasters. It is manifested as recurrent episodes of fear, often triggered by reminders of the initial trauma. One of the striking features of this disorder, and of learned fear in general, is that the memory of the traumatic experience remains powerful for decades and is readily reactivated by a variety of stressful circumstances. Indeed, after a single exposure to a threat, the amygdala can retain the memory of that threat throughout an organism’s entire life. How does this come about?

Consistent with our prediction, we found dramatically enhanced long-term potentiation in the lateral nucleus and a significantly enhanced and persistent memory of fear. The effect proved to be remarkably specific to learned fear: the same mutant mice showed normal innate fear on a variety of other tests. This finding is consistent with the fundamental distinction between learned and innate fear. Thus, a combined cellular and genetic approach allowed us to identify a neural circuit that is important for holding learned fear in check. The discovery could lead to the development of drugs that counteract learned fear associated with such psychiatric syndromes as post-traumatic stress disorders and phobias.

We next asked whether safety training gives rise to a true sense of safety, an actual sense of self-confidence, or whether it simply lowers the baseline of fear that is always present in all of us. To distinguish between the two possibilities, we recorded from the striatum, an area of the brain normally involved in positive reinforcement and in feeling good. (This is the area activated by cocaine and other addictive drugs, which hijack the positive reinforcing neural system and entice a person to use the drug more often.) We found that neural activity in the striatum following a tone is not altered when the animal learns fear—that is, when it learns to associate the tone with a shock. But when an animal learns to associate the tone with safety, the response in the striatum is dramatically enhanced, consistent with the positive sensation of feeling safe.

One important clue to depression has come from the work of Ronald Duman at Yale and Rene Hen at Columbia. They have found that antidepressant drugs also increase the ability of a small region of the hippocampus, the dentate gyrus, to generate new nerve cells. Although the vast majority of nerve cells do not divide, this small nest of stem cells does divide and gives rise to differentiated nerve cells. Over a period of two to three weeks, the time it takes antidepressant drugs to work, a few of the cells are incorporated into the neural networks of the dentate gyrus. The function of these stem cells is unclear. To explore it, Hen used radiation to destroy the dentate gyrus in a mouse model of depression caused by stress. He found that antidepressants could no longer reverse depressionlike behavior in mice lacking the stem cells.

These remarkable new findings raise the possibility that antidepressants exert their effects on behavior in part by stimulating the production of neurons in the hippocampus. This idea is consistent with the finding that depression often compromises memory severely. Perhaps the damage done to the

brain by depression can be overcome by restoring the ability of the hippocampus to produce new nerve cells. A remarkable idea! And one that will be challenging the imagination and skill of a new gener...

By the late 1940s, many psychiatrists, influenced in part by their successful treatment of soldiers who had developed psychiatric problems in battle, had come to believe that psychoanalytic insights might be useful in treating medical illnesses that did not respond readily to drugs. Diseases such as hypertension, asthma, gastric ulcers, and ulcerative colitis were thought to be psychosomatic—that is, induced by unconscious conflicts. Thus by 1960 psychoanalytical theory had become for many psychiatrists, particularly those on the East and West coasts of the United States, the prevailing model for understanding all mental and some physical illnesses.

believe more strongly now, that biology may be able to delineate the physical basis of several mental processes that lie at the heart of psychoanalysis—namely, unconscious mental processes, psychic determinism (the fact that no action or behavior, no slip of the tongue is entirely random or arbitrary), the role of the unconscious in psychopathology (that is, the linking of psychological events, even disparate ones, in the unconscious), and the therapeutic effect of psychoanalysis itself. What particularly fascinated me, because of my interest in the biology of memory, was the possibility that psychotherapy, which presumably works in part by creating an environment in which people learn to change, produces structural changes in the brain and that one might now be in a position to evaluate those changes directly.

Perhaps the most important force driving the first trend has been Aaron Beck, a psychoanalyst at the University of Pennsylvania. Influenced by modern cognitive psychology, Beck found that a patient’s major cognitive style—that is, the person’s

way of perceiving, representing, and thinking about the world—is a key element in a number of disorders, such as depression, anxiety disorders, and obsessive-compulsive states. By emphasizing cognitive style and ego functioning, Beck was continuing a line of thought initiated by Heinz Hartmann, Ernst Kris, and Rudolph Lowenstein.

Beck’s emphasis on the role of conscious thought processes in mental disorders was novel. Traditionally, psychoanalysis had taught that mental problems arise from unconscious conflicts. For example, in the late 1950s, when Beck began his investigations, depressive illness was commonly viewed as “introjected anger.” Freud had argued that depressed patients feel hostile and angry toward someone they love. Because patients cannot deal with negative feelings about someone who is important, needed, and valued, they handle those feelings by repressing them and uncon...

He found that depressed patients exhibited not more, but less hostility than other patients.

Beck found that rather than expressing hostility, depressed people express a systematic negative bias in the way they think about life.

They almost invariably have unrealistically high expectations of themselves, overreact dramatically to any disappointment, put themselves down whenever possible, and are pessimistic about their future....

Beck made the radical suggestion that by identifying and addressing the negative beliefs, thought processes, and behaviors, one might be able to help patients replace them with healthy, positive beliefs. Moreover, one could do so independent of personality factors and the unconscious conflicts that may underlie them.

This positive result led Beck to develop a systematic, short-term psychological treatment for depression that focuses not on a patient’s unconscious conflict, but on his or her conscious cognitive style and distorted way of thinking.

They found that cognitive behavioral therapy is usually as effective as antidepressant medication in treating people with mild and moderate depression; in some studies, it appeared superior at preventing relapses. In later controlled clinical trials, cognitive behavioral therapy was successfully extended to anxiety disorders, especially panic attacks, post-traumatic stress disorders, social phobias, eating disorders, and obsessive-compulsive disorders.

Cognitive behavioral therapy

interpersonal psychotherapy. This treatment focuses on correcting patients’ mistaken beliefs and on changing the nature of their communications in various interactions with others. Like cognitive behavioral therapy, it has proven efficacious in controlled trials for mild and moderate depression and has been codified in teaching manuals. Interpersonal therapy seems to be particularly effective in situational crises, such as the loss of a partner or a child, whereas cognitive therapy appears to be particularly effective in treating chronic disorders. Similarly, although not yet as extensively studied, Peter Sifneous and Habib Davanloo have formalized a third short-term treatment, brief dynamic therapy, which focuses on the patient’s defenses and resistance, and Otto Kernberg has introduced a psychotherapy focused on transference.

Interpersonal therapy , otto kernberg

The long-term effects of the new psychotherapies are still uncertain, however. Although they often achieve results, both therapeutically and in terms of basic understanding, within five to fifteen sessions, the improvement is not always long-lasting. Indeed, it would appear that for some patients to achieve sustained improvement, therapy must continue for one or two years, perhaps because treating symptoms of their disorder without addressing the underlying conflicts is not always efficacious. Even more important from a scientific viewpoint is the fact that Beck and most other proponents of evidence-based therapeutics come from a psychoanalytic tradition of observation, not from a biological tradition of experimentation. With rare exceptions, the leaders of this trend in psychotherapy have not yet turned to biology to try to understand the underlying basis of observed behavior.

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In fact, if psychotherapeutic changes are maintained over time, it is

reasonable to conclude that different forms of psychotherapy lead to different structural changes in the brain, just as other forms of learning do.

The idea of using brain imaging to evaluate the outcome of different forms of psychotherapy is not an impossible dream, as studies of obsessive-compulsive disorder have shown. This disorder has long been thought to reflect a disturbance of the basal ganglia, a group of structures that lies deep in the brain and plays a key role in modulating behavior. One of the structures of the basal ganglia, the caudate nucleus, is the primary recipient of information coming from the cerebral cortex and other regions of the brain. Brain imaging has found that obsessive-compulsive disorder is associated with increased metabolism in the caudate nucleus. Lewis R. Baxter, Jr., and his colleagues at the University of California, Los Angeles have found that obsessive-compulsive disorder can be reversed by cognitive behavioral psychotherapy. It can also be reversed pharmacologically by inhibiting the reuptake of serotonin. Both the drugs and psychotherapy reverse the increased metabolism of the caudate nucleus. Brain-imaging studies of patients with depression commonly reveal a decrease in activity in the dorsal side of the prefrontal cortex but an increase in activity in the ventral side. Again, bo...