《认知神经科学》课程教学资源（参考文献）[LeDoux, J. E.（2000）]Emotion circuits in the brain

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Annu. Rev. Neurosci. 2000. 23:155–184 Copyright q 2000 by Annual Reviews. All rights reserved 0147–006X/00/0301–0155$12.00 155 EMOTION CIRCUITS IN THE BRAIN Joseph E. LeDoux Center for Neural Science, New York University, New York, New York 10003; e-mail: ledoux@cns.nyu.edu Key Words fear, memory, learning, conditioning, amygdala, limbic system Abstract The field of neuroscience has, after a long period of looking the other way, again embraced emotion as an important research area. Much of the progress has come from studies of fear, and especially fear conditioning. This work has pinpointed the amygdala as an important component of the system involved in the acquisition, storage, and expression of fear memory and has elucidated in detail how stimuli enter, travel through, and exit the amygdala. Some progress has also been made in understanding the cellular and molecular mechanisms that underlie fear conditioning, and recent studies have also shown that the findings from experimental animals apply to the human brain. It is important to remember why this work on emotion succeeded where past efforts failed. It focused on a psychologically well-defined aspect of emotion, avoided vague and poorly defined concepts such as “affect,” “hedonic tone,” or “emotional feelings,” and used a simple and straightforward experimental approach. With so much research being done in this area today, it is important that the mistakes of the past not be made again. It is also time to expand from this foundation into broader aspects of mind and behavior INTRODUCTION After decades of neglect, neuroscience has again embraced emotion as a research topic. This new wave of interest raises the question of why emotion was overlooked for so long. It is instructive to consider this question before examining what has been learned about emotional circuits, as some of the factors that led brain researchers to turn away from this topic may again hamper progress unless they can be grappled with. Why Did Interest in Emotion Wane? During the first half of the twentieth century, brain researchers were immensely interested in the brain mechanisms of emotional behavior. Some of the early pioneers in neuroscience worked in this area, including Sherrington, Cannon, Papez, and Hebb. Responses that occur when we defend against danger, interact with sexual partners, fight with an enemy, or have a tasty bite to eat promote the survival of individuals and their species. Emotional responses are thus inherently

156 LeDOUX interesting and important. So what happened? Why did research on the brain mechanisms of emotion come to a halt after midcentury? For one thing, emotion research was a victim of the cognitive revolution. The emergence of cognitive science shifted the interest of those concerned with the relation between psychological functions and neural mechanisms toward processes (perception and memory, for example) that were readily thought of in terms of computer-like operations. From the start, cognitive scientists claimed that their field was not about emotion and other such topics (see Neisser 1967, Gardner 1987). The cognitive approach came to be the dominant approach in psychology and brain science, and research interest in emotion dwindled. Another factor that hindered work on emotions in neuroscience was that the problem of how the brain makes emotions seemed to have been solved in the early 1950s by the limbic system concept (MacLean 1949, 1952). This appealing and convincing theory was the culmination of research on the brain mechanisms of emotion by many researchers, extending back to the late nineteenth century (see LeDoux 1987, 1991). Studies of how the brain mediates cognitive processes seemingly had a long way to go to catch up with the deep understanding that had been achieved about emotions, and researchers flocked to the new and exciting topic of cognition and the brain to begin filling the gap. Cognitive questions also seemed more tractable than emotional ones, due in part to the dark cloud of subjectivity that hung over the topic of emotion. Although subjective experience and its relation to neural mechanisms is a potential difficulty for any area of psychology, cognitive scientists figured out how to study mental processes without having to solve the mind-body problem. They showed, for example, that it is possible to study how the brain processes (computes and represents) external stimuli without first resolving how the conscious perceptual experiences come about. In fact, it is widely recognized that most cognitive processes occur unconsciously, with only the end products reaching awareness, and then only sometimes (see Kihlstrom 1987). Emotion researchers, though, did not make this conceptual leap. They remained focused on subjective emotional experience. In spite of the fact that most research on emotions and the brain was, and still is, conducted with experimental animals, creatures in which subjective states are difficult if not impossible to prove, theoretical discussions of emotions and the brain typically reverted back to the age-old question of feelings. This approach puts the mind-body problem right smack in the middle of the path of progress. The main lesson to be learned from this brief excursion into history is that emotion researchers need to figure out how to escape from the shackles of subjectivity if emotion research is to thrive. It is ironic that cognitive science, which led to the neglect of emotion research, may also be able to help in its resurrection by providing a strategy that allows the study of emotion independent of subjective emotional experiences. It is possible, for example, to ask how the brain processes emotional information (i.e. detects and responds to danger) without necessarily first solving the question of where conscious feelings come from. Contrary to popular belief, conscious feelings are not required to produce emotional

EMOTION AND THE BRAIN 157 responses, which, like cognitive processes, involve unconscious processing mechanisms (see O¨ hman 1992, LeDoux 1996). If we want to understand feelings, it is likely going to be necessary to figure out how the more basic systems work. Failure to come to terms theoretically with the importance of processing systems that operate essentially unconsciously has been a major impediment to progress in understanding the neural basis of emotion. To overcome this, brain researchers need to be more savvy about the nature of emotions, rather than simply relying on common sense beliefs about emotions as subjective feeling states. Research on emotion can also help cognitive science. A pure cognitive approach, one that omits consideration of emotions, motivations, and the like, paints an artificial, highly unrealistic view of real minds. Minds are not either cognitive or emotional, they are both, and more. Inclusion of work on emotion within the cognitive framework can help rescue this field from its sterile approach to the mind as an information-processing device that lacks goals, strivings, desires, fears, and hopes. Once a processing approach to emotion is taken, emotion and cognition can be studied similarly: as unconscious processes that can, but do not necessarily, lead to conscious experiences. This would open the door for the integration of emotion and cognition, and such integration should be a major goal for the immediate future. Should We Integrate the Cognitive Brain with the Limbic System? The rise of cognitive science led to important advances in understanding the brain mechanisms of perception, attention, memory, and other cognitive processes. One might be tempted to say that the way to foster the synthesis of cognition and emotion into a new science of mind would be to put all this new information about the cognitive brain together with the definitive view of the emotional brain provided long ago by the limbic system concept. However, this would be a mistake. In spite of the fact that the limbic system concept remains the predominant view about how the brain makes emotions, it is a flawed and inadequate theory of the emotional brain. The limbic system concept was put forth in the context of an evolutionary explanation of mind and behavior (MacLean 1949, 1952, 1970; Isaacson 1982). It built upon the view, promoted by comparative anatomists earlier in the century, that the neocortex is a mammalian specialization—other vertebrates have primordial cortex but only mammals were believed to have neocortex. And because thinking, reasoning, memory, and problem solving are especially well developed in mammals, particularly in humans and other primates that have relatively more neocortical tissue, these cognitive processes must be mediated by the neocortex and not by the old cortex or other brain areas. In contrast, the old cortex and related subcortical ganglia form the limbic system, which was said to mediate the evolutionarily older aspects of mental life and behavior, our emotions. In this

158 LeDOUX way, cognition came to be thought of as the business of the neocortex and emotions of the limbic system. The limbic system theory began to run into trouble almost immediately when it was discovered, in the mid-1950s, that damage to the hippocampus, the centerpiece of the limbic system, led to severe deficits in a distinctly cognitive function, long-term memory (Scoville & Milner 1957). This was incompatible with the original idea that the primitive architecture of the limbic system, and especially of the hippocampus, was poorly suited to participate in cognitive functions (MacLean 1949, 1952). Subsequently, in the late 1960s, it was discovered that the equivalent of mammalian neocortex is present, though rudimentary, in nonmammallian vertebrates (see Nauta & Karten 1970). As a result, the old/new cortex distinction broke down, challenging the evolutionary basis of the assignment of emotion to the limbic system and cognition to the neocortex (Swanson 1983). The limbic system itself has been a moving target. Within a few years after inception, it expanded from the original notion of “old cortex” and related subcortical forebrain nuclei to include some areas of the midbrain (Nauta 1979), and even some regions of neocortex (Kaada 1960). Several attempts have been made to salvage the limbic system by defining it more precisely (see Isaacson 1982, Swanson 1983, Livingston & Escobar 1971). Nevertheless, after half a century of debate and discussion, there are still no agreed upon criteria that can be used to decide which areas of the brain belong to the limbic system. Some have suggested that the concept be abandoned (Brodal 1982; LeDoux 1987, 1991; Kotter & Meyer 1992). In spite of these difficulties, the limbic system continues to survive, both as an anatomical concept and as an explanation of emotions, in textbooks, research articles, and scientific lectures. This is in part attributable to the fact that both the anatomical concept and the emotional function it was supposed to mediate were defined so vaguely as to be irrefutable. For example, in most discussions of how the limbic system mediates emotion, the meaning of the term emotion is presumed to be something akin to the common English language use of the term (because no other definition is given). However, the common English use of the term emotion is at best a poor theoretical notion, for emotion is a rich and complex theoretical concept with many subtle aspects, some of which are nonintuitive and thus inconsistent with the common use of the term (for discussions see Lewis & Haviland 1992, Ekman & Davidson 1994, LeDoux 1996). On the neural side, the criteria for inclusion of brain areas in the limbic system remain undefined, and evidence that any limbic area, however defined, contributes to any aspect of any emotion has tended to validate the whole concept. Mountains of data on the role of limbic areas in emotion exist, but there is still little understanding of how our emotions might be the product of the limbic system. Particularly troubling is the fact that one cannot predict, on the basis of the original limbic theory of emotion or any of its descendants, how specific aspects of emotion work in the brain. The explanations are all post hoc. Nowhere is this

EMOTION AND THE BRAIN 159 more apparent than in recent work using functional imaging to study emotions in the human brain. Whenever a so-called emotional task is used, and a limbic area is activated, the activation is explained by reference to the fact that limbic areas mediate emotion. And when a limbic area is activated in a cognitive task, it is often assumed that there must have been some emotional undertone to the task. We are, in other words, at a point where the limbic theory has become an offthe-shelf explanation of how the brain works. However, this explanation is grounded in tradition rather than data. Deference to the concept is inhibiting creative thought about how mental life is mediated by the brain. Although the limbic system theory is inadequate as an explanation of the specific brain circuits of emotion, MacLean’s (1949, 1952, 1970) original ideas are very interesting in the context of a general evolutionary explanation of emotion and the brain. In particular, the notion that emotions involve relatively primitive circuits that are conserved throughout mammalian evolution seems right on target. Furthermore, the idea that cognitive processes might involve other circuits, and might function relatively independent of emotional circuits, at least in some circumstances, also seems correct. These functional ideas are worth holding on to, even if we abandon the limbic system as a structural theory of the emotional brain. ESCAPING THE LIMBIC SYSTEM LEGACY: FEAR CIRCUITS One of the main exceptions to the bleak state of affairs regarding the brain mechanisms of emotion is the body of research concerned with neural system underlying fear, especially in the context of the behavioral paradigm called fear conditioning. It has, in fact, been research on fear conditioning, and the progress that has been made on this topic, that has been largely responsible for the renaissance of interest of emotion within neuroscience. In this work, the fear system has been treated as a set of processing circuits that detect and respond to danger, rather than as a mechanism through which subjective states of fear are experienced. Through this approach, fear is operationalized, or made experimentally tractable. Some limbic areas turn out to be involved in the fear system, but the exact brain areas and the nature of their involvement would never have been predicted by the limbic system theory. Before describing research on fear, several other approaches to the study of emotion and the brain that are not discussed further should be mentioned. One involves stimulus-reward association learning (Aggleton & Mishkin 1986, Gaffan 1992, Everitt & Robbins 1992, Ono & Nishijo 1992, Rolls 1999, Gallagher & Holland 1994, Holland & Gallagher 1999). Another involves the role of septohippocampal circuits in anxiety (Gray 1982), and still another involves distinct hypothalamic and brainstem circuits for several different emotions (Panksepp 1998, Siegel & Edinger 1981, Siegel et al 1999)

EMOTION AND THE BRAIN 161 Neuroanatomy of Fear Conditioning Research from several laboratories combined in the 1980s to paint a relatively simple and remarkably clear picture of the neuroanatomy of conditioned fear (see Kapp et al 1992, LeDoux 1992, Davis 1992, Fanselow 1994). In short, conditioned fear is mediated by the transmission of information about the CS and US to the amygdala, and the control of fear reactions by way of output projections from the amygdala to the behavioral, autonomic, and endocrine response control systems located in the brainstem. Below, the input and output pathways, as well as the connections within the amygdala that link inputs and outputs, are described. The focus is on findings from rodents and other small mammals, as most of the work on fear conditioning has involved these species (for the contribution of the primate amygdala to fear and other emotions see Pribram et al 1979, Pribram & Melges 1969, Aggleton & Mishkin 1986, Ono & Nishijo 1992, Gaffan 1992, Rolls 1992, 1999). Amygdala Terminology and Connections The amygdala consists of approximately 12 different regions, each of which can be further divided into several subregions (Figure 2). Although a number of different schemes have been used to label amygdala areas (see Krettek & Price 1978, de Olmos et al 1985, Amaral et al 1992), the scheme adopted by Amaral et al (1992) for the primate brain and applied to the rat brain by Pitka¨nen et al (1997) is followed here. The areas of most relevance to fear conditioning are the lateral (LA), basal (B), accessory basal (AB), and central (CE) nuclei and the connections between these (Figure 2). In other classification schemes, B is known as the basolateral nucleus and AB as the basomedial nucleus. The term basolateral complex is sometimes used to refer to LA and B (and sometimes AB) together. Studies in several species, including rats, cats, and primates, are in close agreement about the connections of LA, B, AB, and CE (see Pitka¨nen et al 1997, Pare´ et al 1995, Amaral et al 1992, Cassell et al 1999). In brief, LA projects to B, AB, and CE, and both B and AB also project to CE. However, it is important to recognize that the connections of these areas are organzied at the level of subnuclei within each region rather than at the level of the nuclei themselves (see Pitka¨nen et al 1997). For simplicity, though, for the most part we focus below on nuclei rather than subnuclei. CS Pathways The pathways through which CS inputs reach the amygdala have been studied extensively in recent years. Much of the work has involved the auditory modality, which is focused on here. Auditory and other sensory inputs to the amygdala terminate mainly in LA (see LeDoux et al 1990b, Romanski & LeDoux 1993, Mascagni et al 1993, Amaral et al 1992, McDonald 1998), and damage to LA interferes with fear conditioning to an acoustic CS (LeDoux et al 1990a, Campeau & Davis 1995)

EMOTION AND THE BRAIN 163 CE Behavior ANS HPA Defense Responses LA MGm/ PIN Auditory Cortex TE1 TE3 MGv CS (tone) Auditory Pathways to Amygdala Circuits PRh Figure 3 The neural pathways involved in fear conditioning are well characterized. When the CS is an acoustic stimulus, the pathways involve transmission to the lateral nucleus of the lateral amygdala (LA) from auditory processing areas in the thalamus [medial division of the medial geniculate body (MGm/PIN)] and cortex [auditory association cortex (TE3)]. LA, in turn, projects to the central amygdala (CE), which controls the expression of fear responses by way of projections to brainstem areas. ANS, Autonomic nervous system; CS, conditioned stimulus; HPA, hypothalamic-pituitary axis; MGv, ventral division of the medial geniculate body; PRh, perirhinal cortex; TE1, primary auditory cortex. tioned the ability of the thalamic pathway to mediate conditioning (Campeau & Davis 1995, Shi & Davis 1998), single-unit recordings show that the cortical pathway learns more slowly over trials than does the thalamic pathway (Quirk et al 1995, 1997), thus indicating that plasticity in the amygdala occurs initially through the thalamic pathway. Recent functional magnetic resonance imaging studies in humans have found that the human amygdala shows activity changes during conditioning that correlate with activity in the thalamus but not the cortex (Morris et al 1999), further emphasizing the importance of the direct thalamoamygdala pathway. In addition to expressing fear responses to the CS, rats also exhibit these when returned to the chamber in which the tone and shock were paired, or a chamber in which shocks occur alone. This is called contextual fear conditioning and requires both the amygdala and the hippocampus (see Blanchard et al 1970, Phillips & LeDoux 1992, Maren et al 1997, Kim & Fanselow 1992, Frankland et al 1998). Areas of the ventral hippocampus (CA1 and subiculum) project to the B and AB nuclei of the amygdala (Canteras & Swanson 1992), and damage to these

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