Neural Substrates of Emotional Memory

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Emotions are an integral part of our psychological life. For years, neuroscientists have largely ignored emotion, in part because it was believed that emotions were difficult to objectively define and measure, and therefore were outside the realm of legitimate scientific investigation. In recent years, however, great strides have been made in our understanding the brain pathways and structures underlying one especially important emotion: fear. In particular, much has been learned about how the brain learns to fear an object or situation, how learned fears can guide the acquisition of behaviors that are instrumental in avoiding danger, and how fear can augment the strength of memory formation of significant life events.

Classical Fear Conditioning

The fear learning system of the brain has been most extensively studied in the laboratory rat using a simple, robust form of associative learning known as classical or Pavlovian fear conditioning (LeDoux, 2000; 2002). In this behavioral paradigm, an animal learns to respond defensively to an initially neutral stimulus (the conditioned stimulus ; CS) after it has been associated or paired with a noxious stimulus (the unconditioned stimulus ; US). In rats, presentation of the CS after conditioning elicits defensive behavior (freezing) and supporting autonomic and endocrine adjustments. This is an implicit form of memory, which means that the brain system involved functions independently of conscious mediation (LeDoux, 2000, 2002). Nevertheless, conscious (or explicit) memories of the emotional experience can and often are formed in parallel.

In auditory fear conditioning, the most thoroughly studied form of implicit fear learning, a tone (CS) is paired with brief electrical shock to the feet (US). This form of fear conditioning involves transmission of auditory and somatic sensory information to the lateral nucleus of the amygdala (LA), an area that is critical for fear conditioning. During fear conditioning, individual neurons in the LA are well suited to integrate information about tone and foot shock. Cells in the LA, for example, receive direct projections from areas of the auditory thalamus and cortex. Inputs from each of these auditory areas converge onto single neurons in the LA, and these same cells are also responsive to the foot shock US. Further, auditory fear conditioning is disrupted either by permanent lesions or reversible functional inactivation targeted to the LA and adjacent areas (LeDoux, 2000; 2002; Maren, 2001).

The LA is not only the principle site of sensory input in the amygdala; it also appears to be an essential locus of plasticity during fear conditioning. For example, individual cells in the LA alter their response properties when CS and US are paired during fear conditioning; specifically, LA neurons that are initially weakly responsive to auditory input respond vigorously to the same input after fear conditioning (Quirk, Armony, Repa, Li, and LeDoux, 1997; Repa et al., 2001). Thus, a change occurs in the function of LA cells as the result of training, a finding that has contributed to the view that neural plasticity in the LA encodes key aspects of fear learning and memory storage (Blair et al., 2001; Fanselow and LeDoux, 1999; Maren, 1999; Quirk et al., 1997).

What mechanism may mediate the change that occurs in the LA as a result of conditioning? One of the leading candidates is long-term potentiation (LTP), an activity-dependent form of plasticity initially discovered in the hippocampus (Bliss and Lomø, 1973). LTP is an attractive candidate for a cellular mechanism of learning and memory during fear conditioning for several reasons. For one, LTP has been observed in each of the major sensory input pathways to the LA, including the thalamic and cortical auditory pathways (Maren, 1999, 2001). Second, fear conditioning itself has been shown to lead to electrophysiological changes in the LA similar to those observed following artificial LTP induction, and these changes persist over days (Maren, 1999). Third, associative LTP in the LA has been shown to be sensitive to the same contingencies as fear conditioning (Bauer, LeDoux, and Nader, 2001). That is, LTP in the LA appears to depend on the contingency between pre- and postsynaptic activity rather than simply on temporal contiguity, a hallmark of associative learning. Finally, amygdala LTP and fear conditioning have been shown to be subserved by similar biochemical or molecular mechanisms (Schafe, Nader, Blair, and LeDoux, 2001).

The LA is also critically involved in the expression of conditioned fear by way of its projections to the nearby central nucleus of the amygdala ([CE]; Amorapanth, LeDoux, and Nader, 2000; Nader, Majidishad, Amorapanth, and LeDoux, 2001; Pitkänen, Savander, and LeDoux, 1997). The CE is known to project to areas of the forebrain, hypothalamus, and brain stem that control behavioral, endocrine, and autonomic conditioned responses (CRs) associated with fear learning. Projections from the CE to the midbrain periacqueductal gray, for example, have been shown to be particularly important for mediating behavioral and endocrine responses such as freezing and hypoalgesia (De Oca, DeCola, Maren, and Fanselow, 1998; Helmstetter and Tershner, 1994), whereas projections to the lateral hypothalamus have been implicated in the control of conditioned cardiovascular responses (Iwata, LeDoux, and Reis, 1986). Importantly, while lesions of these individual areas can selectively impair expression of individual CRs, damage to the CE interferes with the expression of all fear CRs (LeDoux, 2000, 2002). Thus, the CE is typically thought of as the principal output nucleus of the fear system that acts to orchestrate the collection of hardwired, and typically species-specific, responses that underlie defensive behavior.

Instrumental Fear Learning

In addition to its role in Pavlovian fear conditioning, the amygdala contributes to other fear-related aspects of behavior. For example, Pavlovian fear conditioning is useful for learning to detect a dangerous object or situation, but the animal must also be able to use this information to guide ongoing behavior that is instrumental in avoiding that danger. In some situations, the animal must learn to make a response (i.e., move away, press a bar, or turn a wheel) that will allow it to avoid presentation of a shock or danger signal, a form of learning known as active avoidance. In other situations, the animal must learn not to respond, also known as passive avoidance. Both of these are examples of instrumental conditioning, and the amygdala plays a vital role in each.

The role of different amygdala nuclei, including the LA, CE, and the basal nucleus, in learning tasks that involve both classical and instrumental fear learning components has recently been examined (Amorapanth, LeDoux, and Nader, 2000; Killcross, Robbins, and Everitt, 1997). In one such study, for example, the animal was first trained to associate a tone with foot shock (the Pavlovian component). Next, the animal learned to move from one side of a two-compartment box to the other to avoid presentation of the tone (the instrumental component). In summary, while lesions of the LA appear to impair both the classical and instrumental aspects of fear learning, lesions of the CE impair only the Pavlovian component (i.e., the tone-shock association). Conversely, lesions of the basal nucleus impair only the instrumental component (learning to move to the second compartment). Thus, different outputs of the LA appear to mediate Pavlovian and instrumental behaviors elicited by a fear-arousing stimulus (Amorapanth, LeDoux, and Nader, 2000; Nader and LeDoux, 1998). This is not to say, however, that the basal nucleus is a site of motor control or a locus of memory storage for instrumental learning. Rather, it likely guides fear-related behavior and reinforcement via its projections to nearby striatal regions that are known to be necessary for reinforcement learning (Everitt, Cador, and Robbins, 1989; Everitt et al., 1999; Robbins, Cador, Taylor, and Everitt, 1989).

In spite of the fact that fear conditioning itself is an implicit form of learning and memory, during most emotional experiences explicit or conscious memories are also formed (LeDoux, 2000; 2002). These occur through the operation of the medial temporal lobe memory system involving the hippo-campus and related cortical areas (Eichenbaum, 2000; Milner, Squire, and Kandel, 1998). The role of the hippocampus in the explicit memory of an emotional experience is similar to its role in other kinds of experiences, with one important exception. During fearful emotional experiences, the amygdala activates neuromodulatory systems in the brain and hormonal systems in the brain and body. Chemicals released by these systems modulate the function of forebrain areas such as the hippocampus and serve to enhance the storage of the memory in these areas (McGaugh, 2000). The primary support for this model comes from studies of inhibitory avoidance learning, where the animal must learn not to enter a chamber in which it has previously received shock. In this paradigm, various pharmacological manipulations of the amygdala that affect neurotransmitter or neurohormonal systems modulate the strength of the memory. For example, immediate posttraining blockade of adrenergic or glucocorticoid receptors in the amygdala impairs memory retention of inhibitory avoidance, while facilitation of these systems in the amygdala enhances acquisition and memory storage (McGaugh, 2000; McGaugh et al., 1993).

Thus, a picture has begun to emerge of the role of the amygdala and its different subnuclei in emotional memory processes. The amygdala, and particularly the LA, participates both in reflexive or reactive forms of fear learning, where the animal learns to fear one stimulus that has been associated with another. However, the amygdala also appears to participate in instrumental or active forms of fear learning, where the animal must learn to cope behaviorally in the presence of fearful stimuli. In addition, the amygdala modulates the formation of memories in other systems of the brain, such as systems involved in explicit or conscious memory.



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Joseph E.LeDoux

Revised byGlenn E.Schafe

andJoseph E.LeDoux