Joseph E. LeDoux: “Emotion, Memory and the Brain” “The neural routes underlying the formation of memories about primitive emotional experiences, such as fear, have been traced” ‘Scientific American’, April 2002, pp. 62-71. *** “Despite millennia of preoccupation with every facet of human emotion, we are still far from explaining in a rigorous physiological sense this part of our mental experience. Neuroscientists have, in modern times, been especially concerned with the neural basis of such cognitive processes as perception and memory. They have for the most part ignored the brain’s role in emotion. Yet in recent years, interest in this mysterious mental terrain has surged.... “One quite rewarding area of research has been the inquiry into the relation between memory and emotion. Much of this examination has involved studies of one particular emotion—fear—and the manner in which specific events or stimuli come, through individual learning experiences, to evoke this state. Scientists, myself included, have been able to determine the way in which the brain shapes how we form memories about this basic, but significant, emotional event. We call this process ‘emotional memory.’ “By uncovering the neural pathways through which a situation causes a creature to learn about fear, we hope to elucidate the general mechanisms of this form of memory. Because many human mental disorders—including anxiety, phobia, post-traumatic stress syndrome and panic attack—involve malfunctions in the brain’s ability to control fear, studies of the neural basis of this emotion may help us further understand and treat these disturbances. “Most of our knowledge about how the brain links memory and emotion has been gleaned through the study of so-called classical fear conditioning. In this process the subject, usually a rat, hears a noise or sees a flashing light that is paired with a brief, mild electric shock to its feet. After a few such experiences, the rat responds automatically to the sound or light, even in the absence of the shock. Its reactions are typical to any threatening situation: the animal freezes, its blood pressure and heart rate increase, and it startles easily.... “Conditioning of this kind happens quickly in rats—indeed, it takes place as rapidly as it does in humans. A single pairing of the shock to the sound or sight can bring on the conditioned effect. Once established, the fearful reaction is relatively permanent. If the noise or light is administered many times without an accompanying electric shock, the rat’s response diminishes. This change is called extinction. But considerable evidence suggests that this behavioral alteration is the result of the brain’s controlling the fear response rather than the elimination of the emotional memory. For example, an apparently extinguished fear response can recover spontaneously or can be reinstated by an irrelevant stressful experience.... Fear and Emotional Memory “FEAR CONDITIONING has proved an ideal starting point for studies of emotional memory for several reasons. First, it occurs in nearly every animal group in which it has been examined: fruit flies, snails, birds, lizards, fish, rabbits, rats, monkeys and people. Although no one claims that the mechanisms are precisely the same in all these creatures, it seems clear from studies to date that the pathways are very similar in mammals and possibly in all vertebrates. We therefore are confident in believing that many of the findings in animals apply to humans.... “At the same time, such cues do not require complicated cognitive processing from the brain. Consequently, the stimuli permit us to study emotional mechanisms relatively directly. Finally, our extensive knowledge of the neural pathways involved in processing acoustic and visual information serves as an excellent starting point for examining the neurological foundations of fear elicited by such stimuli. “...As do most other investigators in the field, I assume that fear conditioning occurs because the shock modifies the way in which neurons in certain important regions of the brain interpret the sound stimulus.... “...But our lesion experiments in rats confirmed what a series of other studies had already suggested: the auditory cortex is not needed in order to learn many things about simple acoustic stimuli. “We then went on to make lesions in the auditory thalamus and auditory midbrain, sites lying below the auditory cortex. Both these areas process auditory signals: the midbrain provides the major input to the thalamus; the thalamus supplies the major input to the cortex. Lesions in both regions eliminated the rat’s susceptibility to conditioning. This discovery suggested that a sound stimulus is transmitted through the auditory system to the level of the auditory thalamus but that it does not have to reach the cortex for fear conditioning to occur. “...So David A. Ruggiero, Donald J. Reis and I looked again and found that cells in some regions of the auditory thalamus also give rise to fibers that reach several subcortical locations. Could these neural projections be the connections through which the stimulus elicits the response we identify with fear? We tested this hypothesis by making lesions in each one of the subcortical regions with which these fibers connect. The damage had an effect in only one area: the amygdala. Filling in the Picture “THAT OBSERVATION suddenly created a place for our findings in an already accepted picture of emotional processing. For a long time, the amygdala has been considered an important brain region in various forms of emotional behavior. In 1979 Bruce S. Kapp and his colleagues at the University of Vermont reported that lesions in the amygdala’s central nucleus interfered with a rabbit’s conditioned heart rate response once the animal had been given a shock paired with a sound. The central nucleus connects with areas in the brain stem involved in the control of heart rate, respiration and vasodilation. Kapp’s work suggested that the central nucleus was a crucial part of the system through which autonomic conditioned responses are expressed. ... “The findings from various laboratories studying different species and measuring fear in different ways all implicated the central nucleus as a pivotal component of fear-conditioning circuitry. It provides connections to the various brain stem areas involved in the control of a spectrum of responses. “Despite our deeper understanding of this site in the amygdala, many details of the pathway remained hidden. Does sound, for example, reach the central nucleus directly from the auditory thalamus? We found that it does not. The central nucleus receives projections from thalamic areas next to, but not in, the auditory part of the thalamus; an entirely different area of the amygdala, the lateral nucleus, receives inputs from the auditory thalamus. Lesions of the lateral nucleus prevented fear conditioning. Because this site gets information directly from the sensory system, we now consider it the sensory interface of the amygdala in fear conditioning.... ... “The emotional significance of such a stimulus is determined by the sound itself and by the environment in which it occurs. Rats must therefore learn not only that a sound or visual cue is dangerous but under what conditions it is so. Russell G. Phillips and I examined the response of rats to the chamber, or context, in which they had been conditioned. We found that lesions of the amygdala interfered with the animals’ response to both the tone and the chamber. But lesions of the hippocampus—a brain region involved in declarative memory—interfered only with response to the chamber, not the tone. Declarative memory involves explicit, consciously accessible information, as well as spatial memory.... Emotional Significance “THESE FINDINGS were consistent with the generally accepted view that the hippocampus plays an important role in processing complex information, such as details about the spatial environment where activity is taking place.... “Although our experiments had identified a subcortical sensory pathway that gave rise to fear conditioning, we did not dismiss the importance of the cortex. The interaction of subcortical and cortical mechanisms in emotion remains a hotly debated topic.... “...Norman M. Weinberger and his colleagues at the University of California at Irvine performed elegant studies showing that neurons in the auditory cortex undergo specific physiological changes in their reaction to sounds as a result of conditioning. This finding indicates that the cortex is establishing its own record of the event. “Experiments by Lizabeth M. Romanski in my laboratory determined that in the absence of the auditory cortex, rats can learn to respond fearfully to a single tone. If, however, projections from the thalamus to the amygdala are removed, projections from the thalamus to the cortex and then to the amygdala are sufficient. Romanski went on to establish that the lateral nucleus can receive input from both the thalamus and the cortex. Her work with rats complements earlier research in primates. Molecular Mechanisms “ONCE WE HAD a clear understanding of the mechanism through which fear conditioning is learned, we tried to find out how emotional memories are established and stored on a molecular level. Farb and I showed that the excitatory amino acid transmitter glutamate is present in the thalamic cells that reach the lateral nucleus. Chiye J. Aoki and I showed that it is also present at synapses in the lateral nucleus. Because glutamate transmission is implicated in memory formation, we seemed to be on the right track. “Glutamate has been observed in a process called long-term potentiation, or LTP, that has emerged as a model for the creation of memories.... “Various studies have found LTP in the fear-conditioning pathway.... “Studies by Fabio Bordi, also in my laboratory, have suggested hypotheses about what is going on in the neurons of the lateral nucleus during learning. Bordi monitored the electrical state of individual neurons in this area when a rat was listening to the sound and receiving the shock. He and Romanski found that essentially every cell responding to the auditory stimuli also responded to the shock. The basic ingredient of conditioning is thus present in the lateral nucleus. “Bordi was able to divide the acoustically stimulated cells into two classes: habituating and consistently responsive. Habituating cells eventually stopped responding to the repeated sound, suggesting that they might serve to detect any sound that was unusual or different. They could permit the amygdala to ignore a stimulus once it became familiar. Sound and shock pairing at these cells might reduce habituation, thereby allowing the cells to respond to, rather than ignore, significant stimuli. “The consistently responsive cells had high-intensity thresholds: only loud sounds could activate them. That finding is interesting because of the role volume plays in judging distance. Nearby sounds are presumably more dangerous than those that are far away. Sound coupled with shock might act on these cells to lower their threshold, increasing the cells’ sensitivity to the same stimulus.... “The apparent permanence of these memories raises an important clinical question: Can emotional learning be eliminated, and, if not, how can it be toned down? It appears to be quite difficult to get rid of emotional memories, and at best we can hope only to keep them under wraps. Studies by Maria A. “Morgan in my laboratory have illuminated how the brain regulates emotional expressions. Morgan showed that when part of the prefrontal cortex is damaged, emotional memory is very hard to extinguish. This discovery indicates that the prefrontal areas— possibly by way of the amygdala— normally control expression of emotional memory and prevent emotional responses once they are no longer useful. A similar conclusion was proposed by Edmund T. Rolls and his colleagues at the University of Oxford during primate studies. The researchers studied the electrical activity of neurons in the frontal cortex of the animals. “Functional variation in the pathway between this region of the cortex and the amygdala may make it more difficult for some people to change their emotional behavior. Davis and his colleagues found that blocking NMDA receptors in the amygdala interferes with extinction, which hints that it is an active learning process.... “Placing a basic emotional memory process in the amygdalic pathway yields obvious benefits. The amygdala is a critical site of learning because of its central location between input and output stations. Each route that leads to the amygdala— sensory thalamus, sensory cortex and hippocampus—delivers unique information. Pathways originating in the sensory thalamus provide only a crude perception of the external world, but because they involve only one neural link, they are quite fast. In contrast, pathways from the cortex offer detailed and accurate representations, allowing us to recognize an object by sight or sound. But these pathways, which run from the thalamus to the sensory cortex to the amygdala, involve several neural links. And each link in the chain adds time. “Conserving time may be the reason there are two routes—one cortical and one subcortical—for emotional learning. Animals, and humans, need a quick-anddirty reaction mechanism. The thalamus activates the amygdala at about the same time as it activates the cortex. The arrangement may enable emotional responses to begin in the amygdala before we completely recognize what it is we are reacting to or what we are feeling. “The thalamic pathway may be particularly useful in situations requiring a rapid response. Failing to respond to danger is more costly than responding inappropriately to a benign stimulus. For instance, the sound of rustling leaves is enough to alert us when we are walking in the woods without our first having to identify what is causing the sound. Similarly, the sight of a slender curved shape lying flat on the path ahead of us is sufficient to elicit defensive fear responses... We do not need to go through a detailed analysis of whether or not what we are seeing is a snake.... Later, coordination of this basic information with the cortex permits verification (yes, this is a snake) or brings the response (screaming, sprinting) to a stop. Storing Emotional Memory “ALTHOUGH THE AMYGDALA stores primitive information, we should not consider it the only learning center. The establishment of memories is a function of the entire network, not just of one component.... “Memory is generally thought to be the process by which we bring back to mind some earlier conscious experience. The original learning and the remembering, in this case, are both conscious events. Researchers have determined that declarative memory is mediated by the hippocampus and the cortex. But removal of the hippocampus has little effect on fear conditioning—except conditioning to context. “In contrast, emotional learning that comes through fear conditioning is not declarative learning. Rather it is mediated by a different system, which may operate independently of conscious awareness. Emotional information may be stored within declarative memory, but it is kept there as a cold declarative fact. For example, if a person is injured in an auto accident in which the horn gets stuck, he or she may later react when hearing the blare of car horns. The person may remember the details of the accident, such as where and when it occurred and who was involved. These are declarative memories that are dependent on the hippocampus. The individual may also become tense, anxious and depressed as the emotional memory is reactivated through the amygdalic system. The declarative system has stored the emotional content of the experience, but it has done so as a fact. “Emotional and declarative memories are stored and retrieved in parallel, and their activities are joined seamlessly in our conscious experience. That does not mean that we have direct conscious access to our emotional memory; it means instead that we have access to the consequences— such as the way we behave or the way our bodies feel. These consequences combine with current declarative memory to form a new declarative memory. Emotion is not just unconscious memory: it exerts a powerful influence on declarative memory and other thought processes.... “The distinction between declarative memory and emotional memory is an important one. W. J. Jacobs of the University of British Columbia and Lynn Nadel of the University of Arizona have argued that we are unable to remember traumatic early-life events because the hippocampus has not yet matured enough to consciously form accessible memories. The emotional memory system, which may develop earlier, clearly forms and stores its unconscious memories of these events. For this reason, the trauma may affect mental and behavioral functions in later life through processes that remain inaccessible to consciousness. “Because pairing a tone and a shock can bring about conditioned responses in animals throughout the phyla, it is clear that fear conditioning cannot be dependent on consciousness. Fruit flies and snails, for example, are not creatures known for their conscious mental processes. My way of interpreting this phenomenon is to consider fear a subjective state of awareness brought about when brain systems react to danger. Only if the organism possesses a sufficiently advanced neural mechanism does conscious fear accompany bodily response. This is not to say that only humans experience fear but, rather, that consciousness is a prerequisite to subjective emotional states. “Thus, emotions or feelings are conscious products of unconscious processes. It is crucial to remember that the subjective experiences we call feelings are not the primary business of the system that generates them. Emotional experiences are the result of triggering systems of behavioral adaptation that have been preserved by evolution.... Postscript “MUCH HAS HAPPENED in the study of emotion, memory and the brain since this article was written in 1994, some of which I will summarize. ... “The molecular mechanisms underlying fear learning and memory have been pursued through studies of LTP [i.e., long-term potentiation, Y.O.] in brain slices of the lateral amygdala.... “...Because similar molecular steps are involved in different forms of memory in different species, it seems that the uniqueness of different kinds of memory has less to do with the underlying molecules than with the circuits in which they act. “Protein synthesis is not only involved in the initial formation of the memory of an aversive experience but is also called into play when these memories are recalled, which suggests that each time such a memory is activated it has to be restored (reconsolidated) by new protein synthesis. This may be a process by which memories are updated in light of experiences that occurred after the initial memory. “...And functional imaging has shown that the human amygdala is activated during fear conditioning, even under conditions where the CS [i.e., conditioned stimulus, Y.O.] is prevented from entering consciousness, showing that fear memories can be established unconsciously. “…” ----------------- Joseph E. LeDoux is the Henry and Lucy Moses Professor of Science at New York University. His research is focused on brain mechanisms of emotion and memory. He is the recipient of two National Institute of Mental Health distinctions: a Merit Award and a Research Scientist Development Award. people.brandeis.edu/~teuber/emotion.pdf
Posted on: Wed, 10 Sep 2014 18:39:55 +0000
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