The amygdala: vigilance and emotion

Abstract

Here we provide a review of the animal and human literature concerning the role of the amygdala in fear conditioning, considering its potential influence over autonomic and hormonal changes, motor behavior and attentional processes. A stimulus that predicts an aversive outcome will change neural transmission in the amygdala to produce the somatic, autonomic and endocrine signs of fear, as well as increased attention to that stimulus. It is now clear that the amygdala is also involved in learning about positively valenced stimuli as well as spatial and motor learning and this review strives to integrate this additional information. A review of available studies examining the human amygdala covers both lesion and electrical stimulation studies as well as the most recent functional neuroimaging studies. Where appropriate, we attempt to integrate basic information on normal amygdala function with our current understanding of psychiatric disorders, including pathological anxiety.

The amygdala

The term amygdala (Latin for almond) was first used in 1819 by the anatomist Burdach to describe an almond-shaped cell mass located deep in the human temporal cortex and is now used to describe a similar area in many species. As originally described, the amygdala is composed of several distinct groups of cells, usually termed the lateral, basal and accessory basal nuclei, and now collectively termed the basolateral amygdala. Several structures surrounding the basolateral amygdala, including the central, medial and cortical nuclei, are traditionally included in the ‘amygdaloid complex’. These surrounding structures, together with the basolateral amygdala, have come to be called ‘the amygdala’.

The extended amygdala

It is now clear that the basolateral amygdala is involved in negative and positive affect as well as spatial and motor learning. Moreover, including the basolateral nucleus with certain surrounding nuclei such as the central, medial, and cortical nuclei, into a single entity does not make anatomical sense. These neighboring structures are vastly different from the basolateral amygdala. In fact, in terms of cell shape, cell content and projection patterns, they are more similar to each other and other targets of the basolateral amygdala than they are to the basolateral amygdala itself. For example, the central nucleus of the amygdala (CeA), together with its rostral extension (lateral bed nucleus of stria terminalis), is organized on very similar lines to the dorsally situated striatopallidum. The cortical nuclei have strong olfactory relations and resemble adjacent olfactory cortical structures.

Thus, it is more useful to think of the amygdala as the ‘basolateral amygdala’ and to think of its several target areas as parts of a broader network that subserve more specialized functions (Figure 1 in Reference 1).1 The basolateral amygdala receives sensory information from the thalamus, hippocampus and cortex and then activates or modulates synaptic transmission in target areas appropriate for the reinforcement signal with which the sensory information has been associated. A light paired with food can serve as a positive reinforcer by changing neural transmission in the basolateral amygdala which sends signals to the striatum, leading to approach behavior. Outputs to the CeA are important for paying more attention to a stimulus paired with food.2 A light paired with shock may change neural transmission in the basolateral amygdala which projects to the CeA to produce the somatic, autonomic and endocrine signs of fear, as well as increased attention to that stimulus. These conditioned effects often depend on N-methyl-D-aspartate receptor activation within the basolateral amygdala when initially neutral stimuli, such as lights or tones, are paired with emotionally significant stimuli, such as shocks or food.34 More long-lasting fear-like effects, not necessarily dependent on conditioning, may involve outputs to the lateral bed nucleus of the stria terminalis (BNST) and may be more akin to anxiety than fear.5 Outputs to the striatum also may be involved in avoidance of stimuli paired with aversive events. Outputs to the hippocampus may influence the development of conscious memories of emotional events as well as modulating spatial learning. Finally, reciprocal connections with cortical areas may be involved in the representations of these positive or negative rewards in memory to guide appropriate choice behavior. Because most of the literature on the amygdala has analyzed the role of the basolateral amygdala and its adjacent target, the CeA, in aversive conditioning, this work will serve as the main focus of the present review. Brief summaries of the role of basolateral amygdala outputs to other targets shown in Figure 1 will follow.

Figure 1
figure1

Schematic diagram of the outputs of the basolateral nucleus of the amygdala to various target structures and possible functions of these connections.

The basolateral amygdala to CeA or BNST pathway as it relates to conditioned and unconditioned fear

The lateral and basolateral nuclei of the amygdala receive highly processed sensory information (for a highly comprehensive review in rats, monkeys and cats see McDonald).6 In turn, these nuclei project to the CeA which then projects in part to hypothalamic and brainstem target areas that directly mediate specific signs of fear and anxiety. A great deal of evidence now indicates that the basolateral amygdala to CeA connection along with the efferent projections of the CeA collectively represent a central fear system involved in both the expression and acquisition of conditioned fear.7891011121314 Figure 2 summarizes work done in many different laboratories indicating that the CeA has direct projections to a variety of anatomical areas that might be expected to be involved in many of the symptoms of fear or anxiety. This work has recently been reviewed where a full list of references can be found.15

Figure 2
figure2

Schematic diagram of the outputs of the central nucleus or the lateral division of the bed nucleus of the stria terminalis (BNST) to various target structures and possible functions of these connections.

Most of the literature on the amygdala involves an analysis of the role of the CeA using various measures of fear, primarily in rodents. Techniques have included mechanical and chemical lesions, electrical stimulation and local infusion of various compounds. A major caveat that needs to be kept in mind is that many effects attributed to the CeA may actually result from disconnecting the basolateral nucleus from the BNST because the fibers that connect the Bla to the BNST pass right through the CeA. This is illustrated in Figure 3 prepared by Dr Changjun Shi in which an anterograde tracer was infused into the posterior part of the basolateral nucleus of the amygdala and the brain was later sectioned so as to capture labeled terminals in both the CeA and the BNST. Many fibers synapse in the CeA but many pass through the CeA to terminate in the BNST. Hence, electrical stimulation or mechanical lesions of the CeA not only disrupt cells in the CeA, but also disconnect the basolateral nucleus from the BNST. Furthermore, the posterolateral division of the BNST has many of the same hypothalamic and brainstem projections as the CeA so that outputs from the basolateral nucleus of the amygdala to the BNST can eventually activate the same targets as the CeA does.

Figure 3
figure3

Photomicrographs of a horizontal section of the rat brain showing a deposit of biotinylated dextran amine (BDA) into the posterior basolateral nucleus of the amygdala (BLp). Panel (a) shows horizontal section more ventral than that shown in panel (b). Note that fibers originating from cells in the BLp stream through the more anterior part of the basolateral amygdala (Bla) to terminate in the medial (CM) and lateral (CL) divisions of the central nucleus of the amygdala. However, other fibers pass directly through the central nucleus on route to the anterior (BNSTal) and posterior (BNSTpl) regions of the lateral bed nucleus of the stria terminalis. Thus electrolytic lesions of the central nucleus of the amygdala would not only disrupt the function of the central nucleus but also disrupt input from the basolateral amygdala to the BNST. BDA was deposited via iontophoresis using a 5% solution in phosphate-buffered saline at a current of 4 μA over 10 min. The brain was blocked in such a way as to capture the amygdala and the more dorsally located bed nucleus of the stria terminalis in the same 30-μm section. Other abbreviations: ac, anterior commissure; BM, basomedial nucleus of the amygdala; L, lateral nucleus of the amygdala; ME, medial nucleus of the amygdala; opt, optic tract; SI, substantia innominata; VP, ventral pallidum. This very difficult procedure was carried out by Dr Changjun Shi who graciously allowed us to include this figure.

In addition, the CeA projects heavily to the lateral division of the BNST that collectively is known as the lateral extended amygdala.16 Thus, electrical or chemical stimulation of the CeA not only can activate CeA cells that project to the hypothalamus and brainstem but also CeA cells that project to the BNST. Similarly, chemical, fiber-sparing lesions of the CeA also can block inputs from the CeA to the BNST. Hence, manipulations of the CeA potentially will always have these dual effects on the CeA and the BNST. Because of this, the present review will conclude a role for either the CeA or BNST based on manipulations of the CeA.

Autonomic and hormonal measures of fear related to CeA/BNST projections

Anatomically, the CeA and the BNST are well situated to mediate the various components of the fear response. Both structures send prominent projections to areas such as the lateral hypothalamus which is involved in activation of the sympathetic autonomic nervous system seen during fear and anxiety.17 Direct projections to the dorsal motor nucleus of the vagus, nucleus of the solitary tract and ventrolateral medulla may be involved in lateral extended amygdala modulation of heart rate and blood pressure which are known to be regulated by these brainstem nuclei.18 Projections to the parabrachial nucleus may be involved in respiratory (as well as cardiovascular changes) during fear, because electrical stimulation or lesions of this nucleus are known to alter various measures of respiration. Indirect projections of the CeA to the paraventricular nucleus via the BNST and preoptic area may mediate the prominent neuroendocrine responses to fearful or stressful stimuli.

Attention and vigilance related to CeA/BNST projections

Projections from the CeA or BNST to the ventral tegmental area may mediate stress-induced increases in dopamine metabolites in the prefrontal cortex.19 Direct projections to the dendritic field of the locus coeruleus or indirect projections via the paragigantocellularis nucleus may mediate the response of cells in the locus coeruleus to conditioned fear stimuli as well as being linked to fear and anxiety.2021 Direct projections to the lateral dorsal tegmental nucleus and parabrachial nuclei, which have cholinergic neurons that project to the thalamus, may mediate increases in synaptic transmission in thalamic sensory relay neurons during states of fear. This cholinergic activation, along with increases in thalamic transmission accompanying activation of the locus coeruleus, may thus lead to increased vigilance and superior signal detection in a state of fear or anxiety.

As emphasized by Kapp et al,22 in addition to its direct connections to the hypothalamus and brainstem, the CeA also has the potential for indirect widespread effects on the cortex via its projections to cholinergic neurons that project to the cortex. In fact, the rapid development of conditioned bradycardia during Pavlovian aversive conditioning, critically dependent on the amygdala, may not be simply a marker of an emotional state of fear, but instead a more general process reflecting an increase in attention. In the rabbit, low voltage, fast EEG activity, generally considered a state of cortical readiness for processing sensory information, is acquired during Pavlovian aversive conditioning at the same rate as conditioned bradycardia.

Fear-induced changes in motor behavior related to CeA/BNST projections

Release of norepinephrine onto motor neurons via lateral extended amygdala activation of the locus coeruleus, or via projections to serotonin containing raphe neurons, could lead to enhanced motor performance during a state of fear, because both norepinephrine and serotonin facilitate excitation of motor neurons.2324 Direct projections to the nucleus reticularis pontis caudalis, as well as indirect projections to this nucleus via the central gray probably are involved in fear-potentiation of the startle reflex. Direct projections to the lateral tegmental field, including parts of the trigeminal and facial motor nuclei, may mediate some of the facial expressions of fear as well as potentiation of the eyeblink reflex. The lateral extended amygdala also projects to regions of the central gray that appear to be a critical part of a general defense system and which have been implicated in conditioned fear in a number of behavioral tests including freezing, sonic and ultrasonic vocalization and stress-induced hypoalgesia.172526272829

Elicitation of fear responses by electrical or chemical stimulation of the extended amygdala

Electrical stimulation or abnormal electrical activation of the amygdala (ie, via temporal lobe seizures) can produce a complex pattern of behavioral and autonomic changes that, taken together, highly resemble a state of fear. This probably results from simultaneous activation of many of the target areas seen in Figures 1 and 2 during focal stimulation of the amygdala. In fact, we have recently found in waking, alert rats, that low level electrical stimulation of the CeA leads to an increase in c-fos protein, a marker of neuronal activation, of many of these target areas in the same animal (Shi and Davis, unpublished observations).

Autonomic and hormonal measures

As outlined by Gloor30 ‘The most common affect produced by temporal lobe epileptic discharge is fear . . . It arises ‘out of the blue.’ Ictal fear may range from mild anxiety to intense terror. It is frequently, but not invariably, associated with a rising epigastric sensation, palpitation, mydriasis, and pallor and may be associated with a fearful hallucination, a frightful memory flashback, or both’ (p 513). In humans, electrical stimulation of the amygdala elicits feelings of fear or anxiety as well as autonomic reactions indicative of fear.3132 While other emotional reactions occasionally are produced, the major reaction is one of fear or apprehension. However, it is not clear whether these effects result from activation of the CeA or more widespread effects to other parts of the extended amygdala.

Electrical stimulation of the CeA or chemical activation via the cholinergic agonist carbachol or the neurotransmitter glutamate produces prominent cardiovascular effects that depend on the species, site of stimulation and state of the animal. CeA stimulation can also produce gastric ulceration and increase gastric acid, which can be associated with chronic fear or anxiety. It can also alter respiration, a prominent symptom of fear, especially in panic disorder.

Using very small infusion cannulas, Sanders and Shekhar33 found increases in blood pressure and heart rate when the GABA-A antagonist bicuculline was infused into the basolateral but not the central nucleus. Local infusion of NMDA or AMPA into the basolateral nucleus also increased blood pressure and heart rate.34 These effects, as well as those of bicuculline, could be blocked by local infusion of either NMDA or non-NMDA antagonists into the amygdala3435 or the dorsomedial hypothalamus.36

Repeated infusion of initially subthreshold doses of bicuculline into the anterior basolateral nucleus led to a ‘priming’ effect in which increases in heart rate and blood pressure were observed after 3–5 infusions.37 This change in threshold lasted at least 6 weeks and could not be ascribed to mechanical damage or generalized seizure activity based on EEG measurements. Similar changes in excitability were produced by repetitive infusion of very low doses of corticotropin releasing hormone (CRH) or urocortin.38 Once primed, these animals exhibited behavioral and cardiovascular responses to intravenous sodium lactate, a panic-inducing treatment in certain types of psychiatric patients. It is possible, therefore, that long-term stress or prior trauma could lead to similar priming effects that would make the amygdala, or structures to which it connects, more reactive to subsequent stressors, thereby leading to certain types of psychiatric disorders.

Alternatively, genetic differences in GABA or CRH tone in the amygdala could render individuals hyper-responsive to stress or anxiety (see excellent recent reviews by Adamec39 and Rosen and Schulkin40 for more on this idea).

In general, electrical stimulation of the amygdala causes an increase in plasma levels of corticosterone. The effect of electrical stimulation appears to depend on both norepinephrine and serotonin in the paraventricular nucleus. Depletion of these transmitters via local infusions of 6-OHDA or 5,7-DHT, or local infusion of the norepinephrine or serotonin antagonists prazosin or ketanserin, in the paraventricular nucleus attenuated the effects of electrical stimulation.41

Attention and vigilance

Studies in several species indicate that electrical stimulation of the CeA increases attention or processes associated with increased attention. For example, stimulation of sites in the CeA that produce bradycardia12 also produce low voltage fast EEG activity in both rabbits42 and rats.43 In fact, an attention or orienting reflex was the most common response elicited by electrical stimulation of the amygdala.4445 These and other observations have led Kapp et al22 to hypothesize that the ‘CeA and its associated structures function, at least in part, in the acquisition of an increased state of nonspecific attention or arousal manifested in a variety of CRs which function to enhance sensory processing. This mechanism is rapidly acquired, perhaps via an inherent plasticity within the nucleus and associated structures in situations of uncertainty but of potential import; for example, when a neutral stimulus (CS) precedes either a positive or negative reinforcing, unexpected event (US)’ (p 241). Electrical stimulation of the amygdala can also activate cholinergic cells that are involved in arousal-like effects depending on the state of sleep and perhaps the species.

Motor behavior

Electrical or chemical stimulation of the CeA produces a cessation of ongoing behavior, a critical component in several animal models such as freezing, the operant conflict test, the conditioned emotional response, and the social interaction test. Electrical stimulation of the amygdala also elicits jaw movements and activation of facial motoneurons, which probably mediate some of the facial expressions seen during the fear reaction. These motor effects may be indicative of a more general effect of amygdala stimulation, namely that of modulating brainstem reflexes such as the massenteric, baroreceptor nictitating membrane, eyeblink and the startle reflex.

Summary of the effects of stimulation of the amygdala

Viewed in this way, the pattern of behaviors seen during fear may result from activation of a single area of the brain (the extended amygdala), which then projects to a variety of target areas, each of which are critical for the specific symptoms of fear (the expression of fear), as well, perhaps, for the experience of fear. Moreover, it must be assumed that these connections are already formed in an adult organism, because electrical stimulation produces these effects in the absence of prior explicit fear conditioning. Thus, much of the complex behavioral pattern seen during a state of ‘conditioned fear’ has already been ‘hard wired’ during evolution. For a formerly neutral stimulus to produce the constellation of behavioral effects used to define a state of fear or anxiety, it is only necessary for that stimulus to activate the amygdala following aversive conditioning. In turn this will produce the complex pattern of behavioral changes by virtue of the innate connections between the amygdala and these different brain target sites. Hence, plasticity during fear conditioning probably results from a change in synaptic inputs prior to or in the basolateral amygdala,464748 rather than from a change in its efferent target areas. The ability to produce LTP in the basolateral amygdala495051525354 that can lead to an increase in responsiveness to a physiological stimulus,55 and the finding that local infusion of NMDA antagonists into the amygdala block the acquisition of fear conditioning15 are consistent with this hypothesis.

Effects of lesions of the amygdala on conditioned fear

The Kluver–Bucy syndrome

In 1939, following earlier work, Kluver and Bucy56 described the now classic behavioral syndrome of monkeys with bilateral removal of the temporal lobes including the amygdala, hippocampus and surrounding cortical areas. Following such lesions the monkeys developed ‘psychic blindness’ where they would approach animate and inanimate objects without hesitation and examine these objects by mouth rather than by hand, be they a piece of food, feces, a snake or a light bulb. They also had a strong tendency, almost a compulsion, to attend to and examine every visual stimulus that came into their field of view and showed a marked change in emotional behavior. These monkeys had a striking absence of emotional motor and vocal reactions normally associated with stimuli or situations eliciting fear and anger. As described by Kluver and Bucy, ‘The typical reaction of a ‘wild’ monkey when suddenly turned loose in a room consists in getting away from the experimenter as rapidly as possible. It will try to find a secure place near the ceiling or hide in an inaccessible corner where it cannot be seen. If seen, it will either crouch and, without uttering a sound, remain in a state of almost complete immobility or suddenly dash away to an apparently safer place. This behavior is frequently accompanied by other signs of strong emotional excitement. In general, all such reactions are absent in the bilateral temporal monkey. Instead of trying to escape, it will contact and examine one object after another or other parts of the objects, including the experimenter, stranger or other animals . . . Expressions of emotions, such a vocal behavior, ‘chattering’ and different facial expressions, are generally lost for several months. In some cases, the loss of fear and anger is complete’ (p 991). Finally, many monkeys showed striking increases in heterosexual and homosexual behavior never previously observed in this monkey colony.

Lesions of the temporal lobe also were reported to cause profound changes in social behavior of monkeys both in the laboratory and the wild. Following temporal lobe lesions, monkeys rapidly fell in rank within dominance hierarchies established in monkey colonies (for review see Kling and Brothers).57 Lesioned monkeys now tried to fight with more dominant, larger monkeys, leading to frequent and often severe wounds. In the wild, these inappropriate interactions with other monkeys led to repeated attacks, social isolation and eventual death.5859

Subsequent studies have shown that all of the emotional components of the Kluver–Bucy syndrome can be reproduced by removal of the amygdala and surrounding perirhinal and entorhinal cortex.606162636465 The tameness and excessive orality can be reproduced by lesions restricted to only the amygdala.66 Zola-Morgan et al67 found that lesions of the amygdala disrupted emotional behavior to a set of novel objects whereas lesions of the hippocampus or surrounding cortical areas, did not. Conversely, damage to the hippocampus and the anatomically related perirhinal and parahippocampal cortex impaired memory but not emotional behavior. Moreover, combined damage to the amygdala and hippocampus had no greater effect on memory or emotion than damage to either structure alone.

Although the Kluver–Bucy syndrome has been enormously important for focussing attention onto the amygdala, more recent studies using techniques that selectively destroy amygdala neurons rather than ones that destroy both cells and fibers that pass through the amygdala have had much more subtle effects. For example, ibotenic-induced lesions of even relatively large parts of the amygdala do not reproduce the Kluver–Bucy syndrome in rhesus monkeys. However, these animals appear less fearful of snakes because they will reach for an object next to a toy snake at a shorter latency than non-lesioned monkeys.68 Moreover, these animals appear to be less weary and less vigilant because other, non-lesioned, monkeys are more apt to brush up against the lesioned monkeys and mount and play with them (Kalin, personal communication).

Humans only rarely show the full-blown Kluver–Bucy syndrome following lesions restricted to the amygdala, although they consistently show a blunting of emotional reactivity. This finding, along with the frequent change in emotional behaviors seen in Alzheimer's disease, and other neurological diseases associated with amygdala pathology, is further evidence for the role of the amygdala in human emotion.6970 It is not surprising, therefore, that several authors have seen a connection between the social inappropriateness following temporal lobe damage in monkeys and some of the negative or deficit symptoms in schizophrenia. These include inappropriate mood, flat affect, social isolation, poverty of speech and difficulty in identifying the emotional status of other people.6971

Face recognition and classical fear conditioning in humans

In non-human primates727374 and humans,7576 cells have been found that respond selectively to faces or direction of gaze.77 In humans, removal of the amygdala has been associated with an impairment of memory for faces78798081 and deficits in recognition of emotion in people's faces and interpretation of gaze angle.8182292 In a very rare case involving bilateral calcification confined to the amygdala (Urbach–Wiethe disease), Patient SM046 could not identify the emotion of fear in pictures of human faces. Moreover, she could not draw a fearful face, even though other emotions such as happy, sad, angry and disgusted were identified and drawn within the normal range. Furthermore, she had no difficulty in identifying the names of familiar faces.8384 Based on these and other data, Adolphs et al84 proposed that ‘the amygdala is required to link visual representation of facial expression, on the one hand, with representation that constitute the concept of fear, on the other’ (p 5879). This patient and two others also tended to view even the most threatening faces as trustworthy and approachable.85

A more detailed evaluation of patient SM046 showed that she correctly identified valence (eg pleasant vs unpleasant) in faces displaying happy, surprised, afraid, angry, disgusted, or sad emotion but was highly abnormal in rating the level of arousal to the afraid, angry, disgusted and sad faces.86 Interestingly, her arousal ratings for the happy and surprised faces were in the normal range. She also had a very similar pattern when judging the valence or arousal of sentences and words. The authors suggest these deficits may reflect a blockade of acquisition rather than retrieval of knowledge about the arousing aspects of negative emotions because patients who sustained amygdala damage late in life showed normal recognition of fear in human faces.87 In contrast, SMO46’s lesion occurred very early in life, perhaps at birth. In fact, a deficit in arousal could explain a decrease in fear acquisition because patients with long-standing bilateral amygdala damage failed to show the normal enhancement in memory for emotional material.888990 This is known from preclinical studies to be dependent on activation of B-noradrenergic receptors in the amygdala91 as a result of arousal-induced activation of noradrenergic-containing cells.

Another patient (SP) with extensive bilateral amygdala damage also showed a major deficit in her ability to rate levels of fear in human faces, yet was perfectly normal in generating a fearful facial expression in comparison to normal subjects, based on the ratings of three judges.92 Moreover, she also had preserved evaluation of vocal expressions of fear93 and patient SM046 had no deficit in judging the emotional quality of music.94 These data suggest the amygdala lesions in these patients affected the ability to process the social signals of fear rather than altering the experience or feeling of fear.

Autonomic and hormonal measures

Patients with unilateral95 or bilateral96 lesions of the amygdala also have been reported to have deficits in classical fear conditioning using the galvanic skin response as a measure. In monkeys, removal of the amygdala decreases reactivity to sensory stimuli measured with the galvanic skin response.9798 In rodents lesions of the amygdala block conditioned changes in heart rate and blood pressure. Ablation of the amygdala can reduce the secretion of ACTH or corticosteroids as well as reducing stress-induced increases in dopamine release in the frontal cortex. Lesions of the CeA have been found to significantly attenuate ulceration produced by restraint or shock stress or elevated levels of plasma corticosterone produced by restraint stress. Lesions of the amygdala have been reported to block the ability of high levels of noise, which may be an unconditioned fear stimulus, to produce hypertension,

Motor behavior

Numerous studies have shown that lesions of the amygdala eliminate or attenuate conditioned freezing normally seen in response to a stimulus formerly paired with shock (cf Ref 15). Lesions of the amygdala counteract the normal reduction of bar pressing or licking in the operant conflict test and the conditioned emotional response paradigms. They also can block high-frequency vocalizations as well as reflex facilitation such as fear-potentiated startle. Lesions of the amygdala also produce a dramatic decrease in shock-probe avoidance.

Lesions of the amygdala are known to block several measures of innate fear in different species.99100 Lesions of the cortical amygdaloid nucleus and perhaps the central nucleus markedly reduce emotionality in wild rats measured in terms of flight and defensive behaviors. Large amygdala lesions dramatically increase the number of contacts a rat will make with a sedated cat.99 In fact, some of these lesioned animals crawl all over the cat and even nibble its ear, a behavior never shown by the non-lesioned animals. Following lesions of the archistriatum birds become docile and show little tendency to escape from humans, consistent with a general taming effect of amygdala lesions reported in many species101 and perhaps related to the increase in trust following lesions in humans (see above). Recently, patients who underwent bilateral amygdalotomy for intractable aggression showed a reduction in autonomic arousal levels to stressful stimuli and in the number of aggressive outbursts, although they continued to have difficulty controlling aggression.102

This, along with a large literature implicating the amygdala in many other measures of fear such as active and passive avoidance1491100103104105 and evaluation and memory of emotionally significant sensory stimuli,91106107108109110111112113114115116117118 provides strong evidence for a crucial role of the amygdala in fear.

Attention and vigilance

Because the CeA is so important for the expression of fear conditioning its role in attention is difficult to evaluate using a lesion approach and measuring fear conditioning. However, using an appetitive procedure, Michela Gallagher and Peter Holland have found results consistent with an attentional role of the CeA. In these studies,119 a CS such as a light or a tone is paired with receipt of food. Initially rats rear when the light goes on or show small orienting responses when the tone goes on, both of which habituate with stimulus repetition. When these stimuli are then paired with food, these initial orienting responses return (CS-generated CRs) along with approach behavior to the food cup (US-generated responses). Neurotoxic lesions of the CeA severely impair CS-generated responses without having any effect on unconditioned orienting responses or US-generated responses. Based on these data, the authors conclude that the CeA modulates attention to a stimulus that signals a change in reinforcement. Further work seemed to confirm this hypothesis. For example, rats with lesions of the central nucleus fail to benefit from procedures that normally facilitate attention to conditioned stimuli.120121

Differential roles of the central and basolateral nuclei have been found in a phenomenon known as taste-potentiated odor aversion learning. In this test, which requires processing information in two sensory modalities, rats develop aversions to a novel odor paired with illness only when the odor is presented in compound with a distinctive gustatory stimulus. Electrolytic122 or chemical lesions123 of the basolateral but not the CeA blocked taste-potentiated odor aversion learning even though they had no effect on taste aversion learning itself. Depletion of dopamine and norepinephrine in the amygdala via local infusion of 6-hydroxydopamine also blocked odor aversion but not taste aversion.124 Local infusion of NMDA antagonists into the basolateral nucleus also blocked the acquisition but not the expression of taste-potentiated odor aversion but had no effect on taste aversion learning itself.125 Based on these and other data, Hatfield et al126 suggest their data support the view that the CeA ‘regulates attentional processing of cues during associative conditioning’ (p 5265),126 whereas the basolateral nucleus of the amygdala is critically involved in ‘associative learning processes that give conditioned stimuli access to the motivation value of their associated unconditioned stimuli’ (p 5264).126

A role for the amygdala in attention also has been implicated in studies that recorded stimulus-evoked electrical activity in the amygdala in epileptic patients.127 In these studies subjects were presented with a series of visual or auditory stimuli, some of which they were instructed to ignore and others to attend. Averaged evoked responses showed a prominent negative-positive component occuring roughly 200–300 ms after stimulus onset (N200/P300). These components, especially N200, were prominent within the amygdala and much larger when elicited by a stimulus to which the subject was asked to attend. Halgren summarizes the cognitive conditions that evoke the N200/P300 as being stimuli that are novel or signals for behavioral tasks and hence necessary to attend and process. Moreover, these components, along with other autonomic measures of the orienting reflex, seem to form an overall reaction of humans to stimuli that demand their evaluation.

Effects of local infusion of drugs into the amygdala on measures of fear and anxiety

Figure 2 suggests that spontaneous activation of the amygdala would produce a state resembling fear or anxiety in the absence of any obvious eliciting stimulus. In fact, fear and anxiety often precede temporal lobe epileptic seizures3032 which are usually associated with abnormal electrical activity of the amygdala.128 If the amygdala is critically involved in fear and anxiety, then drugs that reduce fear or anxiety clinically may well act within the amygdala. It is also probable that certain neurotransmitters within the amygdala especially may be involved in fear and anxiety. For example, the amygdala has a high density of CRH receptors129 and CRH nerve endings130 and several recent papers indicate that stress, as well as conditioned fear, can induce a release of CRH in the amygdala which results in various anxiogenic effects. In fact, a large number of studies indicate that local infusion of GABA or GABA agonists, benzodiazepines, CRH antagonists, opiate agonists, neuropeptide Y, dopamine antagonists or glutamate antagonists decrease measures of fear and anxiety in several animal species. Table 1 gives selected examples of some of these studies. Conversely, local infusion of GABA antagonists, CRH or CRH analogues, vasopressin, TRH, opiate antagonists, CCK or CCK analogues tend to have anxiogenic effects. Table 2 shows selected examples of such studies, which, along with those in Table 1, are reviewed in Davis.15

Table 1 Effects of local infusion into the amygdala of various neurotransmitter agonists on selected measures of fear and anxiety
Table 2 Effects of local infusion into the amygdala of various neurotransmitter antagonists on selected measures of fear and anxiety

In summary, connections between the basolateral amygdala and the central nucleus or the bed nucleus of the stria terminalis are critically involved in various autonomic and motor responses seen during a state of fear or anxiety. However, it is also the case that connections between the basolateral nucleus and other target areas are involved in emotional behavior (Figure 1).

The basolateral amygdala to ventral striatum pathway as it relates to emotion

Although a full description of the role of this pathway is beyond the scope of this paper, it is clear that projections from the amygdala to the ventral striatum are involved in certain forms of appetitive behavior and perhaps positive affect in general. The basolateral nucleus of the amygdala projects directly to the nucleus accumbens in the ventral striatum,181 in close apposition to dopamine terminals of A10 cell bodies in the ventral tegmental area.182 Morgenson and colleagues suggested that the ventral striatum was the site where affective processes in the limbic forebrain gained access to subcortical elements of the motor system that resulted in appetitive actions.183 Local infusion into the nucleus accumbens of drugs such as d-amphetamine, which release dopamine, increase the magnitude of conditioned reinforcement in operant tasks, ie pressing a bar to turn on a light that previously was paired with food.184 These facilitative effects can be blocked by local infusion of 6-OHDA185 or glutamate antagonists such as CNQX or AP5.186 However, 6-OHDA did not block the expression of conditioned reinforcement itself, suggesting that the reinforcement signal comes from some other brain area that projects to the nucleus accumbens. In fact, excitotoxic lesions of the basolateral amygdala significantly reduced bar pressing for the conditioned reinforcer but local infusion of d-amphetamine in these lesioned rats still facilitated performance, albeit at a lower baseline level or responding.187 These results suggest that two relatively independent processes operate during conditioned reinforcement. First, information from the amygdala concerning the CS-US association is sent to the nucleus accumbens that leads to approach behavior to the conditioned reinforcer. Second, dopamine in the nucleus accumbens amplifies these signals from the amygdala. Perhaps similarly, acoustic startle amplitude is reduced when elicited in the presence of cues previously paired with food188 and pre-training local infusion of 6-OHDA into the nucleus accumbens blocks this effect.188 Connections between the basolateral amygdala and the ventral striatum also are involved in conditioned place preference.189

The basolateral amygdala to dorsal striatum pathway as it relates to conditioned and unconditioned fear

As emphasized by McGaugh, Packard, and others, the amygdala modulates memory in a variety of tasks such as inhibitory avoidance, motor or spatial learning.104190191192193 For example, post-training intra-caudate injections of amphetamine enhanced memory in a visible platform water maze task but had no effect in the hidden platform, spatially guided task.192193 Conversely post-training intra-hippocampal infusion of amphetamine enhanced memory in the hidden platform water maze task but not in the visible platform task. However, post-training intra-amygdala injections of amphetamine enhanced memory in both water maze tasks.192193 Moreover, pre-retention intra-hippocampal lidocaine injections blocked expression of the memory-enhancing effects of post-training intra-hippocampal amphetamine injections in the hidden platform task, and pre-retention intra-caudate lidocaine injections blocked expression of the memory-enhancing effects of post-training intra-caudate amphetamine injections in the visible platform task. However, pre-retention intra-amygdala lidocaine injections did not block the memory-enhancing effect of post-training intra-amygdala amphetamine injections on either task. Finally, in the hidden platform tasks, post-training intrahippocampal, but not intracaudate, lidocaine injections blocked the memory-enhancing effects of post-training intra-amygdala amphetamine. In the visible platform task, post-training intra-caudate, but not intra-hippocampal, lidocaine injections blocked the memory-enhancing effects of post-training intra-amygdala amphetamine. The findings indicate a double dissociation between the roles of the hippocampus and caudate-putamen in memory and suggest that the amygdala exerts a modulatory influence on both the hippocampal and caudate-putamen memory systems.

Perhaps similarly, lesions of the CeA block freezing but not escape to a tone previously paired with shock, whereas lesions of the basal nucleus of the basolateral complex have just the opposite effect.194 However, lesions of the lateral nucleus, which receive sensory information required by both measures, block both freezing and escape. Lesions of the basolateral, but not the central nucleus, also block avoidance of a bar associated with shock.195 It is possible that basolateral outputs to the dorsal or the ventral striatum mediate the escape behavior given the importance of the striatum in several measures of escape or avoidance learning. However, combined, unilateral lesions of each structure on opposite sides of the brain would be required to evaluate whether this results from serial transmission from the basolateral nucleus to the striatum.

The basolateral amygdala to hippocampus pathway as it relates to conditioned and unconditioned fear

As mentioned above, post-training intra-hippocampal as well as intra-amygdala injections of amphetamine selectively enhance memory in a hidden platform water maze task.192193 Post training infusion of norepinephrine into the basolateral nucleus enhanced retention in the hidden platform water maze task whereas post training infusion of propranolol had the opposite effect.196 These results suggest that the amygdala exerts a modulatory influence on hippocampal-dependent memory systems, presumably via direct projections from the basolateral nucleus of the amygdala, perhaps via modulation of long-term potentiation in the hippocampus. Lesions,197 NMDA antagonists198 or local anesthetics199 infused into the basolateral amygdala decrease long-term potentiation in the dentate gyrus of the hippocampus. Conversely, high frequency stimulation of the amygdala facilitates induction of LTP in the dentate gyrus.200201 However, combined, unilateral lesions of each structure on opposite sides of the brain would be required to evaluate whether this results from serial transmission from the basolateral nucleus to the hippocampus.

The basolateral amygdala to frontal cortex pathway as it relates to emotion

The importance of the basolateral amygdala in US representation

Following Pavlovian conditioning, presentation of a conditioned stimulus elicits some neural representation of the unconditioned stimulus (US) with which it was paired. For example, the sound of a refrigerator door opening or an electric can opener may bring the family cat into the kitchen in expectation of dinner. Several studies suggest that the Bla, perhaps via connections with cortical areas such as the perirhinal cortex,202 is critical for these US representations based on studies using a procedure called ‘US devaluation’. In these experiments a neutral stimulus (eg a light) is first paired with food so that a conditioned response can be measured. Some animals then have the food paired with something that makes them sick (US devaluation). Following such treatment these animals show a reduction in the conditioned response to the light compared to animals that did not experience US devaluation. This suggests that after conditioning animals have a representation of the value of a reinforcement that is elicited by the cue paired with that US. When that representation is changed, then the behavior elicited by the cue also is changed in the same direction. Lesions of the basolateral, but not the CeA, block US devaluation.126 In a related paradigm, rats are trained to be fearful of a weak shock in the presence of a tone. When this is followed by presentation of a stronger shock, without further tone-shock pairing, more freezing occurs to the tone. Temporary inactivation of the basolateral amygdala during this inflation procedure blocks this effect when testing subsequently occurs with a normal, unlesioned, amygdala.203

Second order conditioning also depends on an emotional representation elicited by a conditioned stimulus. In this procedure, cue 1 is paired with a particular US (eg shock or food) and cue 2 is paired with cue 1. After such training, cue 2 elicits a similar behavior as that elicited by cue 1, depending on the US with which cue 1 was paired. Thus it might elicit approach behavior if cue 1 was formerly paired with food, and avoidance if cue 1 was paired with shock. This indicates that cue 1 elicits a representation of the US that then becomes associated with cue 2. Lesions of the basolateral amygdala, but not the CeA, block second order conditioning,126189204 as do local infusions of NMDA antagonists into the basolateral amygdala.205

The importance of the basolateral amygdala projection to the frontal cortex in using US representations to guide behavior

Converging evidence now suggests that the connection between the basolateral amygdala and the prefrontal cortex is critically involved in the way in which a US representation (eg very good, pretty good, very bad, pretty bad) guides approach or avoidance behavior. Patients with late or early onset lesions of the orbital regions of the prefrontal cortex fail to use important information to guide their actions and decision making.206207208 For example, on a gambling task they choose high, immediate reward associated with long-term loss rather than low, immediate reward associated with positive long-term gains. They also show severe deficits in social behavior and make poor life decisions.

Studies using single unit recording techniques in rats indicate that cells in both the basolateral amygdala and the orbitofrontal cortex fire differentially to an odor, depending on whether the odor predicts a positive (eg sucrose) or negative (eg quinine) US. These differential responses emerge before the development of consistent approach or avoidance behavior elicited by that odor.209 Many cells in the basolateral amygdala reverse their firing pattern during reversal training (ie the cue that used to predict sucrose now predicts quinine and vice versa),210 although this has not always been observed.211 In contrast, many fewer cells in the orbitofrontal cortex showed selectivity before the behavioral criterion was reached and many fewer reversed their selectivity during reversal training.210 These investigators suggests that cells in the basolateral amygdala encode the associative significance of cues, whereas cells in the orbitofrontal cortex are active when that information, relayed from the basolateral amygdala, is required to guide choice behavior.

Taken together, these data suggest that the connection between the basolateral amygdala and the frontal cortex may be involved in determining choice behavior based on how an expected US is represented in memory. The necessity for communication between the amygdala and frontal cortex recently has been shown in monkeys using a ‘disconnection approach’ in which the amygdala on one side of the brain and the frontal cortex on the other side are lesioned together.212 Because the reciprocal connections between the two structures are ipsilateral, this procedure completely eliminates activity of the network connections while preserving partial function of each structure. Using this approach in rhesus monkeys Baxter et al212 found a decrease in US devaluation after unilateral neurotoxic lesions of the basolateal nucleus in combination with unilateral aspiration of orbital prefrontal cortex. These monkeys continued to approach a food on which they had recently been satiated whereas control monkeys consistently switched to the other food.

Neuroimaging studies of the amygdala in humans

The emergence of neuroimaging technologies such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) allows the study of the intact, normal amygdala in humans. Analysis of human subjects offers an opportunity to study a component of fear not attainable in animals because in humans it is possible to ask ‘Are you afraid?’ while presenting stimuli aimed at activating the amygdala. Table 3 presents a list of recent neuroimaging studies demonstrating activation of the human amygdala. It is important to emphasize that the effective spatial resolution of the neuroimaging studies discussed here does not allow for the differentiation of the separate amygdala subnuclei, though the amygdala's role in the modulation of vigilance is most often associated with the CeA (see discussion below).

Table 3 Neuroimaging studies assessing amygdala response in normal human subjects (I–III) and patient groups (IV)

We will take this opportunity to speculate on what we see as some interesting effects presented in Table 3. Consistent with the animal and human lesion data, presented above, 5 years of human neuroimaging studies support a greater role for the amygdala in the processing of negatively valenced stimuli. Importantly, like much of the animal literature, these early neuroimaging studies are probably limited by the fact that it is difficult to match negatively and positively valenced stimuli for the level of arousal they will evoke. When positively valenced facial expressions have been presented, signal decreases in the amygdala have been reported.214217 These data gain support from neuroimaging studies of acupuncture251 and meditation252 that also observe signal decreases in the amygdala to these manipulations that could also be categorized as positively valenced. At least two studies have reported that presentation of positively valenced stimuli may be associated with signal increases in the amygdala.213231 We note that the Talairach coordinates reported in these two studies were at the dorsal border of the amygdala where it meets the substantia innominata. Signal decreases to positively valenced stimuli observed in other studies were located more ventrally in the traditionally defined amygdala.214217 Indeed, a single study has observed both ventral signal decreases and more dorsal signal increases to positively valenced stimuli in the same group of subjects.217 Clearly, complex responses are occurring to both positively and negatively valenced stimuli throughout the amygdala and the functionally contiguous substantia innominata that will be a challenge to capture with the spatial resolution of current neuroimaging technology.

Given the above discussion concerning signal decreases in the amygdala to positively valenced stimuli it is surprising that studies of amygdala response to the presentation of painful stimuli listed in Table 3 report signal decreases in the amygdala.253254 To explain this most interesting finding, we would suggest that perhaps when human subjects have been fully informed about the painful stimulus they are about to receive, eventual presentation of what might be considered a relatively mildly painful stimulus is less negative than what they had anticipated. This interpretation is consistent with the notion that the amygdala is especially sensitive to the uncertainty of stimulus contingencies222264 (see discussion below). Indeed, anticipation of shock often leads to more fear, measured with the fear potentiated startle test in humans, compared to the actual receipt of shock.265

Overall, one can see that amygdala activation appears to be reliably produced by presentation of biologically-relevant sensory stimuli, many of which probably induce strong negative emotional states. For example, fMRI signal intensity is greater when subjects view graphic photographs of negative material (eg, mutilated human bodies) compared to when they view neutral pictures.266 PET metabolic activity within the amygdala increases to negative material presented via film clips227 and the amount of amygdala activity during film clips predicts later recall.230 More recently, human amygdala fMRI signal intensities have been shown to be increased during Pavlovian fear conditioning in response to stimuli that predict an aversive event.241242243244

Compared to the above mentioned stimuli, the presentation of pictures of facial expressions may represent a strategy for observing amygdala response in the absence of strong emotional response. Human subjects presented with pictures of fearful faces do not report being ‘afraid’ and yet amygdala activity is modulated as a result, suggesting that reported emotion and amygdala activation should not be equated. Indeed, brain regions other than the amygdala (eg insula cortex) demonstrate responses that are more closely correlated with the intensity of fearful facial expressions.267 In addition, a recent neuroimaging study demonstrated that while presentation of negative sensory stimuli activated the amygdala to a greater degree than an internal negative state induction, it was the internal state induction that produced greater subjective reports of emotion compared to the sensory stimulus presentations.227 These data are consistent with the fact that initial human neuroimaging studies which have sought to induce negative emotional states do not provide strong support for the notion that the amygdala is a neural substrate for such feelings. The studies that have been most successful in observing amygdala activation during the induction of emotional state, have also utilized presentations of external stimuli (eg facial expressions).227246247248 Also see Ref 268, emphazising the role of the amygdala in the encoding of stimulus contingencies vs the generation of strong emotional states.264

Numerous studies presented in Table 3 suggest that sensory stimuli demonstrating some predictive validity in terms of biological import (eg possible threat) appear sufficient to engage the amygdala, even though these stimuli may not be highly arousing. More than affect itself, amygdala activation in response to subtle emotional stimuli such as photographs of facial expressions might represent affective information processing.

In an attempt to further explore this line of reasoning, facial expressions were presented in a manner intended to isolate amygdala involvement during the earliest stages of facial expression processing.217 A backward masking technique perfected by Öhman and colleagues was used.269 Very brief presentations of fearful and happy facial expressions (33 ms) were ‘masked’—that is, immediately followed by presentations (167 ms) of neutral faces. Most subjects reported seeing neutral ‘expressionless’ faces, but not any afraid or smiling faces. Despite this lack of recognition, the amygdala demonstrated greater fMRI signal intensity to masked fearful faces compared to masked happy faces. Thus, the response of the amygdala to these social signals was preferential and automatic. In addition, subjects reported that these masked stimuli did not induce any noticeable changes in their state of emotional arousal. Because subjects were unaware that such stimuli would be presented, this study offers preliminary support for the notion that the amygdala constantly monitors the environment for such signals. More than functioning primarily for the production of strong emotional states, the amygdala would be poised to modulate the moment-to-moment vigilance level of an organism.

The role of the amygdala in modulating vigilance

As mentioned earlier, Kapp, Gallager, Holland and colleagues222 have emphasized the importance of the amygdala in attention and vigilance, of which fear may simply be a special, although especially potent example. To elaborate, the same neurons in the CeA that show changes in firing rates to a tone that predicts a shock, also show changes in firing rates that correlate with spontaneous fluctuations in cortical neuronal excitability as measured by cortical EEG in animals.270271 This is even seen in experimentally-naive animals.

As reviewed exensively by Whalen264 these data suggest that the amygdala may be especially involved in increasing vigilance by lowering neuronal thresholds in sensory systems. This may occur via activation of cholinergic neurons in the basal forebrain that lower response thresholds of widespread sensory cortical areas through release of acetylcholine.272273274275276277278 In addition, activation of cholinergic, dopaminergic, serotonergic and noradrenergic neurons in the brainstem may have widespread influences on thalamic and subthalamic sensory as well as motor transmission (see Figure 2). If one assumes that an ambiguous stimulus requires the brain to gather more information to decide to approach or avoid that stimulus, one can imagine that a system designed to promote vigilance and attention would show greater activation, the more ambiguous the stimulus. As suggested by Whalen264 the fact that fearful faces are especially effective in activating the amygdala may reflect the inherent ambiguity of a fearful face, compared for example to an angry face, rather than the exact content of the emotion itself. Thus, angry faces provide information about the presence of threat, but they also give some information about the source of that threat. Fearful faces provide information about the presence of threat, but give less information about the source of that threat. If, as emphasized by Kapp et al1222 projections from the amygdala to the basal forebrain function to potentiate additional cortical information processing, then a more ambiguous face should produce greater amygdala activation. Indeed, preliminary neuroimaging data support this hypothesis.279 When fearful and angry faces were presented to subjects within the same imaging session, responses in the amygdala and basal forebrain were larger to fearful faces when compared directly to angry faces.

If amygdala activation increases vigilance outside of strong emotional states it may serve this same function when observed during strong emotional states.264 This line of reasoning would suggest that amygdala activation should be greatest early in training or when reinforcement schedules are variable or when stimulus contingencies change. In each case these stimulus situations are more ambiguous and in need of greater vigilance and attention. In fact, in both non-human and human subjects, several amygdala-mediated responses44280 reach their peak during early conditioning trials and subside thereafter.12281282283 Powell and colleagues284 have documented that amygdala-mediated conditioned responses (eg bradycardia) are larger and are maintained longer to partial reinforcement schedules compared to continuous reinforcement schedules.285 Even more telling is the observation that when stimulus contingencies change (eg when a CS is suddenly not followed by shock at the beginning of extinction), single unit activity in the lateral amygdala nucleus in rats47 or blood flow in human amygdala241 re-emerge. This conceptualization would also suggest that animal and human subjects with amygdala lesions should exhibit deficits in their ability to regulate vigilance or generalized arousal in response to biologically-relevant stimuli, consistent with recent findings.86

Although these studies indicate that the amygdala is especially activated under conditions of uncertainty, it can continue to be activated, although perhaps to a lesser degree, when conditions or surroundings are considerably less novel. For example, even after 12 daily exposures to a novel startle test cage, c-fos mRNA was significantly elevated in the basolateral and central nucleus of the amygdala.286 Furthermore, even after extensive over-training, when rats clearly have learned the temporal relationship between light onset and shock onset in training,287 lesions of the amygdala completely block the expression of conditioned fear.288289 Thus, although the amygdala may be especially important early in training, it may still continue to play an important role later on, depending on the task. Perhaps the blood flow and blood oxygen-dependent measures utilized in human neuroimaging studies are more sensitive to neuronal activity associated with response to uncertainty compared to cellular and/or neuronal activity changes resulting from overtraining.290

An emphasis on the role of the amygdala in modulating moment-to-moment levels of vigilance in response to uncertainty has important implications for the study of human psychopathology. Hypervigilance is a key symptom of the anxiety disorders. Pathological anxiety may not be a disorder of fear, but a disorder of vigilance. Indeed, early neuroimaging studies implicate the amygdala in psychiatric disorders such as anxiety255256257258259262263 and depression.260261 Highlighting the present argument that amygdala activation should not be equated with the amount of anxiety that these subjects feel, individuals with social phobia demonstrated exaggerated amygdala response to neutral facial expressions though they reported that these expressions did not make them more afraid.262 Experimental paradigms specifically aimed at highlighting the role of the amygdala in the modulation of vigilance and subsequent affective information processing may implicate the amygdala in the etiology of these disorders. Animal studies attempting to differentiate brain areas involved in stimulus-specific fear vs anxiety161291 are especially needed.

References

  1. 1

    Davis M, Shi C-J . The amygdala Curr Biol 2000 10: R131

    CAS  PubMed  Google Scholar 

  2. 2

    Holland PC, Gallagher M . Amygdala circuitry in attentional and representational processes [Review] Trends Cogn Sci 1999 3: 65–73

    CAS  PubMed  Google Scholar 

  3. 3

    Baldwin AE, Holahan MR, Sadeghian K, Kelley AE . N-methyl-D-aspartate receptor-dependent plasticity within a distributed corticostriatal network mediates appetitive instrumental learning Behav Neurosci 2000 114: 84–98

    CAS  PubMed  Google Scholar 

  4. 4

    Miserendino MJD, Sananes CB, Melia KR, Davis M . Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala Nature 1990 345: 716–718

    CAS  PubMed  Google Scholar 

  5. 5

    Davis M, Walker DL, Lee Y . Roles of the amygdala and bed nucleus of the stria terminalis in fear and anxiety measured with the acoustic startle reflex: possible relevance to PTSD Ann NY Acad Sci 1997 821: 305–331

    CAS  PubMed  Google Scholar 

  6. 6

    McDonald AJ . Cortical pathways to the mammalian amygdala Prog Neurobiol 1998 55: 257–332

    CAS  PubMed  Google Scholar 

  7. 7

    Davis M . Neurobiology of fear responses: the role of the amygdala J Neuropsy Clin Neurosci 1997 9: 382–402

    CAS  Google Scholar 

  8. 8

    Gray TS . Autonomic neuropeptide connections of the amygdala. In: Tache Y, Morley JE, Brown MR (eds) Neuropeptides and Stress Springer Verlag: New York 1989 pp 92–106

    Google Scholar 

  9. 9

    Gloor P . Amygdala. In: Field J (ed) Handbook of Physiology: Sec. I. Neurophysiology American Physiological Society: Washington, DC 1960 pp 1395–1420

    Google Scholar 

  10. 10

    Kapp BS, Pascoe JP, Bixler MA . The amygdala: a neuroanatomical systems approach to its contribution to aversive conditioning. In: Butters N, Squire LS (eds) The Neuropsychology of Memory The Guilford Press: New York 1984 pp 473–488

    Google Scholar 

  11. 11

    Kapp BS, Pascoe JP . Correlation aspects of learning and memory: vertebrate model systems. In: Martinez JL, Kesner RP (eds) Learning and Memory: A Biological View Academic Press: New York 1986 pp 399–440

    Google Scholar 

  12. 12

    Kapp BS, Wilson A, Pascoe JP, Supple WF, Whalen PJ . A neuroanatomical systems analysis of conditioned bradycardia in the rabbit. In: Gabriel M, Moore J (eds) Neurocomputation and Learning: Foundations of Adaptive Networks Bradford Books: New York 1990 pp 55–90

    Google Scholar 

  13. 13

    LeDoux JE. Emotion. In: Plum F (ed) . Handbook of Physiology, Sec. 1, Neurophysiology: Vol. 5. Higher Functions of the Brain American Psychological Society: Bethesda 1987 pp 416–459

  14. 14

    Sarter M, Markowitsch HJ . Involvement of the amygdala in learning and memory: a critical review, with emphasis on anatomical relations Behav Neurosci 1985 99: 342–380

    CAS  PubMed  Google Scholar 

  15. 15

    Davis M . The role of the amygdala in conditioned and unconditioned fear and anxiety. In: Aggleton JP (ed) The Amygdala, A Functional Analysis Oxford University Press: Oxford, UK 2000 213–287

    Google Scholar 

  16. 16

    Alheid G, deOlmos JS, Beltramino CA . Amygdala and extended amygdala. In: Paxinos G (ed) The Rat Nervous System Academic Press: New York 1995 pp 495–578

    Google Scholar 

  17. 17

    LeDoux JE, Iwata J, Cicchetti P, Reis DJ . Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear J Neurosci 1988 8: 2517–2529

    CAS  PubMed  Google Scholar 

  18. 18

    Schwaber JS, Kapp BS, Higgins GA, Rapp PR . Amygdaloid basal forebrain direct connections with the nucleus of the solitary tract and the dorsal motor nucleus J Neurosci 1982 2: 1424–1438

    CAS  PubMed  Google Scholar 

  19. 19

    Goldstein LE, Rasmusson AM, Bunney BS, Roth RH . Role of the amygdala in the coordination of behavioral, neuroendocrine, and prefrontal cortical monoamine responses to psychological stress in the rat J Neurosci 1996 16: 4787–4798

    CAS  PubMed  Google Scholar 

  20. 20

    Aston-Jones G, Rajkowski J, Kubiak P, Valentino RJ, Shipley MT . Role of the locus coeruleus in emotional activation Prog Brain Res 1996 107: 379–402

    CAS  PubMed  Google Scholar 

  21. 21

    Redmond DE Jr . Alteration in the function of the nucleus locus: a possible model for studies on anxiety. In: Hanin IE, Usdin E (eds) Animal Models in Psychiatry and Neurology Pergamon Press: Oxford UK 1977 pp 292–304

    Google Scholar 

  22. 22

    Kapp BS, Whalen PJ, Supple WF, Pascoe JP . Amygdaloid contributions to conditioned arousal and sensory information processing. In: Aggleton JP (ed) The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction Wiley-Liss: New York 1992 pp 229–254

    Google Scholar 

  23. 23

    McCall RB, Aghajanian GK . Serotonergic facilitation of facial motoneuron excitation Brain Res 1979 169: 11–27

    CAS  PubMed  Google Scholar 

  24. 24

    White SR, Neuman RS . Facilitation of spinal motoneuron excitability by 5-hydroxytryptamine and noradrenaline Brain Res 1980 185: 1–9

    Google Scholar 

  25. 25

    Bandler R, Carrive P . Integrated defence reaction elicted by excitatory amino acid microinjection in the midbrain periaqueductal grey region of the unrestrained cat Brain Res 1988 439: 95–106

    CAS  PubMed  Google Scholar 

  26. 26

    Blanchard DC, Williams G, Lee EMC, Blanchard RJ . Taming of wild Rattus norvegicus by lesions of the mesencephalic central gray Physiol Psychol 1981 9: 157–163

    Google Scholar 

  27. 27

    Fanselow MS . The midbrain periaqueductal gray as a coordinator of action in response to fear and anxiety. In: Depaulis A, Bandler R (eds) The Midbrain Periaqueductal Gray Matter: Functional, Anatomical and Neurochemical Organization Plenum Publishing: New York 1991 pp 151–173

    Google Scholar 

  28. 28

    Graeff FG . Animal models of aversion. In: Simon P, Soubrie P, Wildlocher D (eds) Selected Models of Anxiety, Depression and Psychosis Karger: Basel, Switzerland 1988 pp 115–141

    Google Scholar 

  29. 29

    Helmstetter FJ, Tershner SA, Poore LH, Bellgowan PSF . Antinociception following opioid stimulation of the basolateral amygdala is expressed through the periaqueductal gray and rostral ventromedial medulla Brain Res 1998 779: 104–118

    CAS  PubMed  Google Scholar 

  30. 30

    Gloor P . Role of the amygdala in temporal lobe epilepsy. In: Aggleton JP (ed) The Amygdala: Neurobiological Aspects of Emotion, Memory and Mental Dysfunction Wiley-Liss: New York 1992 pp 505–538

    Google Scholar 

  31. 31

    Chapman WP, Schroeder HR, Guyer G, Brazier MAB, Fager C, Poppen JL et al. Physiological evidence concerning the importance of the amygdaloid nuclear region in the integration of circulating function and emotion in man Science 1954 129: 949–950

    Google Scholar 

  32. 32

    Gloor P, Olivier A, Quesney LF . The role of the amygdala in the expression of psychic phenomena in temporal lobe seizures. In: Ben-Ari Y (ed) The Amygdaloid Complex Elsevier/North Holland: New York 1981 pp 489–507

    Google Scholar 

  33. 33

    Sanders SK, Shekhar A . Blockade of GABAA receptors in the region of the anterior basolateral amygdala of rats elicits increases in heart rate and blood pressure Brain Res 1991 576: 101–110

    Google Scholar 

  34. 34

    Soltis RP, Cook JC, Gregg AE, Sanders BJ . Interaction of GABA and excitatory amino acids in the basolateral amygdala: role in cardiovascular regulation J Neurosci 1997 17: 9367–9374

    CAS  PubMed  Google Scholar 

  35. 35

    Sajdyk TJ, Shekhar A . Excitatory amino acid receptor antagonists block the cardiovascular and anxiety responses elicited by γ-aminobutyric acid—a receptor blockade in the basolateral amygdala of rats J Pharmacol Exp Therapeut 1997 283: 969–977

    CAS  Google Scholar 

  36. 36

    Soltis RP, Cook JC, Gregg AE, Stratton JM, Flickinger KA . EAA receptors in the dorsomedial hypothalamic area mediate the cardiovascular response to activation of the amygdala Am J Physiol 1998 275: R624–R631

    CAS  PubMed  Google Scholar 

  37. 37

    Sanders SK, Shekhar A . Regulation of anxiety by GABAA receptors in the rat amygdala Pharmacol Biochem Behav 1995 52: 701–706

    CAS  PubMed  Google Scholar 

  38. 38

    Sajdyk TJ, Schober DA, Gehlert DR, Shekhar A . Role of corticotropin-releasing factor and urocortin within the basolateral amygdala of rats in anxiety and panic responses Behav Brain Res 1999 100: 207–215

    CAS  PubMed  Google Scholar 

  39. 39

    Adamec R . Transmitter systems involved in neural plasticity underlying increased anxiety and defense—implications for understanding anxiety following traumatic stress Neurosci Biobehav Rev 1997 21: 755–765

    CAS  PubMed  Google Scholar 

  40. 40

    Rosen JB, Schulkin J . From normal fear to pathological anxiety Psychol Rev 1998 105: 325–350

    CAS  PubMed  Google Scholar 

  41. 41

    Feldman S, Weidenfeld J . The excitatory effects of the amygdala on hypothalamo-pituitary-adrenocortical responses are mediated by hypothalamic norepinephrine, serotonin, and CRF-41 Brain Res Bull 1998 45: 389–393

    CAS  PubMed  Google Scholar 

  42. 42

    Kapp BS, Supple WF, Whalen PJ . Effects of electrical stimulation of the amygdaloid central nucleus on neocortical arousal in the rabbit Behav Neurosci 1994 108: 81–93

    CAS  PubMed  Google Scholar 

  43. 43

    Dringenberg HC, Vanderwolf CH . Cholinergic activation of the electrocorticogram: an amygdaloid activating system Exp Brain Res 1996 108: 285–296

    CAS  PubMed  Google Scholar 

  44. 44

    Applegate CD, Kapp BS, Underwood MD, McNall CL . Autonomic and somatomotor effects of amygdala central n. stimulation in awake rabbits Physiol Behav 1983 31: 353–360

    CAS  PubMed  Google Scholar 

  45. 45

    Ursin H, Kaada BR . Functional localization within the amygdaloid complex in the cat Electroencephalogr Clin Neurophysiol 1960 12: 109–122

    Google Scholar 

  46. 46

    McKernan MG, Shinnick-Gallagher P . Fear conditioning induces a lasting potentiation of synaptic currents in vitro Nature 1997 390: 607–611

    CAS  PubMed  Google Scholar 

  47. 47

    Quirk GJ, Repa JC, LeDoux JE . Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: parallel recordings in the freely behaving rat Neuron 1995 15: 1029–1039

    CAS  PubMed  Google Scholar 

  48. 48

    Rogan MT, Staubli UV, LeDoux JE . Fear conditioning induces associative long-term potentiation in the amygdala Nature 1997 390: 604–607

    CAS  PubMed  Google Scholar 

  49. 49

    Clugnet MC, LeDoux JE . Synaptic plasticity in fear conditioning circuits: induction of LTP in the lateral nucleus of the amygdala by stimulation of the medial geniculate body J Neurosci 1990 10: 2818–2824

    CAS  PubMed  Google Scholar 

  50. 50

    Chapman PF, Kairiss EW, Keenan CL, Brown TH . Long-term synaptic potentiation in the amygdala Synapse 1990 6: 271–278

    CAS  PubMed  Google Scholar 

  51. 51

    Chapman PF, Bellavance LL . Induction of long-term potentiation in the basolateral amygdala does not depend on NMDA receptor activation Synapse 1992 11: 310–318

    CAS  PubMed  Google Scholar 

  52. 52

    Gean PW, Chang FC, Huang CC, Lin JH, Way LJ . Long-term enhancement of EPSP and NMDA receptor-mediated synaptic transmission in the amygdala Brain Res Bull 1993 31: 7–11

    CAS  PubMed  Google Scholar 

  53. 53

    Huang YY, Kandel ER . Postsynaptic induction and PKA-dependent expression of LTP in the lateral amygdala Neuron 1998 21: 169–178

    CAS  PubMed  Google Scholar 

  54. 54

    Shindou T, Watanabe S, Yamamoto K, Nakanishi H . NMDA receptor-dependent formation of long-term potentiation in the rat medial amygdala neuron in an in vitro slice preparation Brain Res Bull 1993 31: 667–672

    CAS  PubMed  Google Scholar 

  55. 55

    Rogan MT, LeDoux JE . LTP is accompanied by commensurate enhancement of auditory-evoked responses in a fear conditioning circuit Neuron 1995 15: 127–136

    CAS  PubMed  Google Scholar 

  56. 56

    Kluver H, Bucy PC . Preliminary analysis of functions of the temporal lobes in monkeys Arch Neurol Psychiatry 1939 42: 979–1000

    Google Scholar 

  57. 57

    Kling AS, Brothers LA . The amygdala and social behavior. In: Aggleton J (ed) The Amygdala: Neurobiological Aspects of Emotion, Memory and Mental Dysfunction John Wiley & Sons: New York 1992 pp 353–377

    Google Scholar 

  58. 58

    Dicks D, Meyers RE, Kling A . Uncus and amygdala lesions: effects on social behavior in the free-ranging rhesus monkey Science 1969 165: 69–71

    CAS  PubMed  Google Scholar 

  59. 59

    Kling A, Lancaster J, Benitone J . Amygdalectomy in the free-ranging vervet J Psychiatr Res 1970 7: 191–199

    CAS  PubMed  Google Scholar 

  60. 60

    Horel JA, Keating EG, Misantone LJ . Partial Kluver–Bucy syndrome produced by destroying termporal neocortex and amygdala Brain Res 1975 94: 347–359

    CAS  PubMed  Google Scholar 

  61. 61

    Meyers RE, Swett C . Social behaviour deficits of free-ranging monkeys after anterior temporal cortex removals: a preliminary report Brain Res 1970 19: 39

    Google Scholar 

  62. 62

    Mishkin M, Pribram KH . Visual discrimination performance following partial ablations of the temporal lobe. I. Ventral vs lateral J Comp Physiol Psychol 1954 47: 14–20

    CAS  PubMed  Google Scholar 

  63. 63

    Pribram KH, Bagshaw M . Further analysis of the temporal lobe syndrome utilizing fronto-temporal ablations J Comp Neurol 1953 99: 347–374

    CAS  PubMed  Google Scholar 

  64. 64

    Schwartzbaum JS . Discrimination behavior after amygdalectomy in monkeys: learning set and discrimination reversals J Comp Physiol Psychol 1965 60: 314–319

    CAS  PubMed  Google Scholar 

  65. 65

    Weiskrantz L . Behavioral changes associated with ablation of the amygdaloid complex in monkeys J Comp Physiol Psychol 1956 49: 381–391

    CAS  PubMed  Google Scholar 

  66. 66

    Aggleton JP, Passingham RE . Syndrome produced by lesions of the amygdala in monkeys (Macaca mulatta) J Comp Physiol Psychol 1981 95: 961–977

    CAS  PubMed  Google Scholar 

  67. 67

    Zola-Morgan S, Squire LR, Alvarez-Royo P, Clower RP . Independence of memory functions and emotional behavior: separate contributions of the hippocampal formation and the amygdala Hippocampus 1991 1: 207–220

    CAS  PubMed  Google Scholar 

  68. 68

    Nelson EE, Shelton SE, Kelley AE, Kalin NH . Innate snake fear in rhesus monkeys: role of the amygdala Soc Neurosci Abs 1999 25: 2151

    Google Scholar 

  69. 69

    Aggleton J . The contribution of the amygdala to normal and abnormal emotional states Trends Neurosci 1993 8: 328–333

    Google Scholar 

  70. 70

    Kromer Vogt LJ, Hyman BT, Van Hoesen GW, Damasio AR . Pathological alterations in the amygdala in Alzheimer's disease Neuroscience 1990 37: 377–385

    CAS  PubMed  Google Scholar 

  71. 71

    Kirkpatrick B, Buchanan RW . The neural basis of the deficit syndrome of schizophrenia J Nerv Ment Dis 1990 178: 545–555

    CAS  PubMed  Google Scholar 

  72. 72

    Leonard CM, Rolls ET, Wilson FAW, Baylis GC . Neurons in the amygdala of the monkey with responses selective for faces Behav Brain Res 1985 15: 159–176

    CAS  PubMed  Google Scholar 

  73. 73

    Nakamura K, Mikami A, Kubota K . Activity of single neurons in the monkey amygdala during performance of a visual discrimination task J Neurophysiol 1992 67: 1447–1463

    CAS  PubMed  Google Scholar 

  74. 74

    Rolls ET . Neurons in the cortex of the temporal lobe and in the amygdala of the monkey with responses selective for faces Hum Neurobiol 1984 3: 209–222

    CAS  PubMed  Google Scholar 

  75. 75

    Allison T, McCarthy G, Nobre A, Puce A, Belger A . Human extrastriate visual cortex and the perception of faces, words, numbers, and colors Cereb Cortex 1994 4: 544–554

    CAS  PubMed  Google Scholar 

  76. 76

    Heit G, Smith ME, Halgren E . Neural encoding of individual words and faces by the human hippocampus and amygdala Nature 1988 333: 773–775

    CAS  PubMed  Google Scholar 

  77. 77

    Brothers L, Ring B . Mesial temporal neurons in the macaque monkey with responses selective for aspects of social stimuli Behav Brain Res 1993 57: 53–61

    CAS  PubMed  Google Scholar 

  78. 78

    Aggleton JP . The functional effects of amygdala lesions in humans: a comparison with findings from monkeys. In: Aggleton JP (ed) The Amygdala: Neurobiological Aspects of Emotion, Memory and Mental Dysfunction Wiley-Liss: New York 1992 pp 485–503

    Google Scholar 

  79. 79

    Jacobson R . Disorders of facial recognition, social behaviour and affect after combined bilateral amygdalotomy and subcaudate tractotomy—a clinical and experimental study Psychol Med 1986 16: 439–450

    CAS  PubMed  Google Scholar 

  80. 80

    Tranel D, Hyman BT . Neuropsychological correlates of bilateral amygdala damage Arch Neurol 1990 47: 349–355

    CAS  PubMed  Google Scholar 

  81. 81

    Young AW, Aggleton JP, Hellawell DJ, Johnson M, Broks P, Hanley JR . Face processing impairments after amygdalotomy Brain 1995 118: 15–24

    PubMed  Google Scholar 

  82. 82

    Calder AJ, Young AW, Rowland D, Perrett DI, Hodges JR, Etcoff NL . Facial emotion recognition after bilateral amygdala damage: differentially severe impairment of fear Cogn Neuropsychol 1996 13: 699–745

    Google Scholar 

  83. 83

    Adolphs R, Tranel D, Damasio H, Damasio AR . Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala Nature 1994 372: 669–672

    CAS  PubMed  Google Scholar 

  84. 84

    Adolphs R, Tranel D, Damasio H, Damasio AR . Fear and the human amygdala J Neurosci 1995 15: 5879–5891

    CAS  PubMed  Google Scholar 

  85. 85

    Adolphs R, Tranel D, Damasio AR . The human amygdala in social judgment Nature 1998 393: 470–447

    CAS  PubMed  Google Scholar 

  86. 86

    Adolphs R, Russell JA, Tranel D . A role for the human amygdala in recognizing emotion arousal from unpleasant stimuli Psychol Sci 1999 10: 167–171

    Google Scholar 

  87. 87

    Hamann SB, Stefanacci L, Squire LR, Adolphs R, Tranel D, Damasio H et al. Recognizing facial emotion Nature 1996 379: 497

    CAS  PubMed  Google Scholar 

  88. 88

    Adolphs R, Cahill L, Schul R, Babinsky R . Impaired declarative memory for emotional material following bilateral amygdala damage in humans Learning and Memory 1997 4: 291–300

    CAS  PubMed  Google Scholar 

  89. 89

    Cahill L, Babinsky R, Markowitsch HJ, McGaugh JL . The amygdala and emotional memory Nature 1995 377: 295–296

    CAS  PubMed  Google Scholar 

  90. 90

    Markowitsch HJ, Calabrese P, Wurker M, Durwen HF, Kessler J, Babinsky R et al. The amygdala's contribution to memory—a study on two patients with Urbach–Wiethe disease NeuroReport 1994 5: 1349–1352

    CAS  PubMed  Google Scholar 

  91. 91

    McGaugh JL, Introini-Collison IB, Nagahara AH, Cahill L, Brioni JD, Castellano C . Involvement of the amygdaloid complex in neuromodulatory influences on memory storage Neurosci Biobehav Rev 1990 14: 425–432

    CAS  PubMed  Google Scholar 

  92. 92

    Anderson AK, Phelps EA . Expression without recognition: contributions of the human amygdala to emotional communication Psychol Sci 2000 11: 106–111

    CAS  PubMed  Google Scholar 

  93. 93

    Anderson AK, Phelps EA . Intact recognition of vocal expressions of fear following bilateral lesions of the human amygdala Neuroreport 1998 9: 3607–3613

    CAS  PubMed  Google Scholar 

  94. 94

    Adolphs R, Tranel D . Intact recognition of emotional prosody following amygdala damage Neuropsychologia 1999 37: 1285–1292

    CAS  PubMed  Google Scholar 

  95. 95

    LeBar KS, LeDoux JE, Spencer DD, Phelps EA . Impaired fear conditioning following unilateral temporal lobectomy in humans J Neurosci 1995 15: 6846–6855

    Google Scholar 

  96. 96

    Bechara A, Tranel D, Damasio H, Adolphs R, Rockland C, Damasio AR . Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans Science 1995 269: 1115–1118

    CAS  PubMed  Google Scholar 

  97. 97

    Bagshaw MH, Kimble DP, Pribram KH . The GSR of monkeys during orienting and habituation and after ablation of the amygdala, hippocampus and inferotemporal cortex Neuropsychologia 1965 3: 111–119

    Google Scholar 

  98. 98

    Bagshaw MH, Benzies S . Multiple measures of the orienting reaction and their dissociation after amygdalectomy in monkeys Exp Neurol 1968 20: 175–187

    CAS  PubMed  Google Scholar 

  99. 99

    Blanchard DC, Blanchard RJ . Innate and conditioned reactions to threat in rats with amygdaloid lesions J Comp Physiol Psychol 1972 81: 281–290

    CAS  PubMed  Google Scholar 

  100. 100

    Ursin H, Jellestad F, Cabrera IG . The amygdala, exploration and fear. In: Ben-Ari Y (ed) The Amygdaloid Complex Elsevier North Holland Press: Amsterdam 1981 pp 317–329

    Google Scholar 

  101. 101

    Goddard GV . Functions of the amygdala Psychol Bull 1964 62: 89–109

    CAS  PubMed  Google Scholar 

  102. 102

    Lee GP, Bechara A, Adolphs R, Arena J, Meador KJ, Loring DW, et al. Clinical and physiological effects of stereotaxic bilateral amygdalotomy for intractable aggression J Neuropsy Clin Neurosci 1998 10: 413–420

    CAS  Google Scholar 

  103. 103

    Kaada BR . Stimulation and regional ablation of the amygdaloid complex with reference to functional representations. In: Eleftheriou BE (ed) The Neurobiology of the Amygdala Plenum Press: New York 1972 pp 205–281

    Google Scholar 

  104. 104

    McGaugh JL, Introini-Collison IB, Cahill L, Castellano C, Dalmaz C, Parent MB et al. Neuromodulatory systems and memory storage: role of the amygdala Behav Brain Res 1993 58: 81–90

    CAS  PubMed  Google Scholar 

  105. 105

    McGaugh J, Cahill L, Parent MB, Mesches MH, Coleman-Mesches K, Salinas JA . Involvement of the amygdala in the regulation of memory storage. In: McGaugh J, Bermudez-Rattoni F, Praco-Alcala RA (eds) Plasticity in the Central Nervous System Lawrence Erlbaum Associates: Hillsdale, NJ 1995 pp 17–40

    Google Scholar 

  106. 106

    Bennett C, Liang KC, McGaugh JL . Depletion of adrenal catecholamines alters the amnestic effect of amygdala stimulation Behav Brain Res 1985 15: 83–91

    CAS  PubMed  Google Scholar 

  107. 107

    Bresnahan E, Routtenberg A . Memory disruption by unilateral low level, sub-seizure stimulation of the medial amygdaloid nucleus Physiol Behav 1972 9: 513–525

    CAS  PubMed  Google Scholar 

  108. 108

    Ellis ME, Kesner RP . The noradrenergic system of the amygdala and aversive information processing Behav Neurosci 1983 97: 399–415

    CAS  PubMed  Google Scholar 

  109. 109

    Gallagher M, Kapp BS, Frysinger RC, Rapp PR . b-Adrenergic manipulation in amygdala central n. alters rabbit heart rate conditioning Pharmacol Biochem Behav 1980 12: 419–426

    CAS  PubMed  Google Scholar 

  110. 110

    Gallagher M, Kapp BS . Effect of phentolamine administration into the amygdala complex of rats on time-dependent memory processes Behav Neural Biol 1981 31: 90–95

    CAS  PubMed  Google Scholar 

  111. 111

    Gallagher M, Kapp BS, McNall CL, Pascoe JP . Opiate effects in the amygdala central nucleus on heart rate conditioning in rabbits Pharmacol Biochem Behav 1981 14: 497–505

    CAS  PubMed  Google Scholar 

  112. 112

    Gallagher M, Kapp BS . Manipulation of opiate activity in the amygdala alters memory processes Life Sci 1978 23: 1973–1978

    CAS  PubMed  Google Scholar 

  113. 113

    Gold PE, Hankins L, Edwards RM, Chester J, McGaugh JL . Memory inference and facilitation with post-trial amygdala stimulation: effect varies with footshock level Brain Res 1975 86: 509–513

    CAS  PubMed  Google Scholar 

  114. 114

    Handwerker MJ, Gold PE, McGaugh JL . Impairment of active avoidance learning with posttraining amygdala stimulation Brain Res 1974 75: 324–327

    CAS  PubMed  Google Scholar 

  115. 115

    Kesner RP . Brain stimulation: effects on memory Behav Neural Biol 1982 36: 315–367

    CAS  PubMed  Google Scholar 

  116. 116

    Liang KC, Bennett C, McGaugh JL . Peripheral epinephrine modulates the effects of post-training amygdala stimulation on memory Behav Brain Res 1985 15: 93–100

    CAS  PubMed  Google Scholar 

  117. 117

    Liang KC, Juler RG, McGaugh JL . Modulating effects of post-training epinephrine on memory: involvement of the amygdala noradrenergic systems Brain Res 1986 368: 125–133

    CAS  PubMed  Google Scholar 

  118. 118

    Mishkin M, Aggleton J . Multiple function contributions of the amygdala in the monkey. In: Ben-Ari Y (ed) The Amygdaloid Complex Elsevier/North Holland: New York 1981 pp 409–420

    Google Scholar 

  119. 119

    Gallagher M, Graham PW, Holland PC . The amygdala central nucleus and appetitive pavlovian conditioning: lesions impair one class of conditioned behavior J Neurosci 1990 10: 1906–1911

    CAS  PubMed  Google Scholar 

  120. 120

    Holland PC, Gallagher M . The effects of amygdala central nucleus lesions on blocking and unblocking Behav Neurosci 1993 107: 235–245

    CAS  PubMed  Google Scholar 

  121. 121

    Holland PC, Gallagher M . Amygdala central nucleus lesions disrupt increments, but not decrement, in conditioned stimulus processing Behav Neurosci 1993 107: 246–253

    CAS  PubMed  Google Scholar 

  122. 122

    Bermudez-Rattoni F, Grijalva CV, Kiefer SW, Garcia J . Flavor-illness aversion: the role of the amygdala in acquisition of taste-potentiated odor aversions Physiol Behav 1986 38: 503–508

    CAS  PubMed  Google Scholar 

  123. 123

    Hatfield T, Graham PW, Gallagher M . Taste-potentiated odor aversion: role of the amygdaloid basolateral complex and central nucleus Behav Neurosci 1992 106: 286–293

    CAS  PubMed  Google Scholar 

  124. 124

    Fernandez-Ruiz J, Miranda MI, Bermudez-Rattoni F, Drucker-Colin R . Effects of catecholaminergic depletion of the amygdala and insular cortex on the potentiation of odor by taste aversions Behav Neural Biol 1993 60: 189–191

    CAS  PubMed  Google Scholar 

  125. 125

    Hatfield T, Gallagher M . Taste-potentiated odor conditioning: impairment produced by infusion of an N-methyl-D-aspartate antagonist into basolateral amygdala Behav Neurosci 1995 109: 663–668

    CAS  PubMed  Google Scholar 

  126. 126

    Hatfield T, Han J-S, Conley M, Gallagher M, Holland P . Neurotoxic lesions of basolateral, but not central, amygdala interfere with Pavlovian second-order conditioning and reinforcer devaluation effects J Neurosci 1996 16: 5256–5265

    CAS  PubMed  Google Scholar 

  127. 127

    Halgren E . Emotional neurophysiology of the amygdala within the context of human cognition. In: Aggleton JP (ed) The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction Wiley-Liss: New York 1992 pp 191–228

    Google Scholar 

  128. 128

    Crandall PH, Walter RD, Dymond A . The ictal electroencephalographic signal identifying limbic system seizure foci Proc Am Assoc Neurol Surg 1971 1: 1

    Google Scholar 

  129. 129

    DeSouza EB, Insel TR, Perrin MH, Rivier J, Vale WW, Kuhar MJ . Corticotropin-releasing factor receptors are widely distributed within the rat central nervous system: an autoradiographic study J Neurosci 1985 5: 3189–3203

    CAS  Google Scholar 

  130. 130

    Uryu K, Okumura T, Shibasaki T, Sakanaka M . Fine structure and possible origins of nerve fibers with corticotropin-releasing factor-like immunoreactivity in the rat central amygdaloid nucleus Brain Res 1992 577: 175–179

    CAS  PubMed  Google Scholar 

  131. 131

    Sullivan RM, Henke PG, Ray A, Hebert MA, Trimper JM . The GABA/benzodiazepine receptor complex in the central amygdalar nucleus and stress ulcers in rats Behav Neural Biol 1989 51: 262–269

    CAS  PubMed  Google Scholar 

  132. 132

    Green S, Vale AL . Role of amygdaloid nuclei in the anxiolytic effects of benzodiazepines in rats Behav Pharmacol 1992 3: 261–264

    CAS  PubMed  Google Scholar 

  133. 133

    Hodges H, Green S, Glenn B . Evidence that the amygdala is involved in benzodiazepine and serotonergic effects on punished responding but not on discrimination Psychopharmacology 1987 92: 491–504

    CAS  PubMed  Google Scholar 

  134. 134

    Petersen EN, Braestrup C, Scheel-Kruger J . Evidence that the anticonflict effect of midazolam in amygdala is mediated by the specific benzodiazepine receptor Neuroscience Lett 1985 53: 285–288

    CAS  Google Scholar 

  135. 135

    Scheel-Kruger J, Petersen EN . Anticonflict effect of the benzodiazepines mediated by a GABAergic mechanism in the amygdala Eur J Pharmacol 1982 82: 115–116

    CAS  PubMed  Google Scholar 

  136. 136

    Thomas SR, Lewis ME, Iversen SD . Correlation of [3H]diazepam binding density with anxiolytic locus in the amygdaloid complex of the rat Brain Res 1985 342: 85–90

    CAS  PubMed  Google Scholar 

  137. 137

    Shibata K, Kataoka Y, Yamashita K, Ueki S . An important role of the central amygdaloid nucleus and mammillary body in the mediation of conflict behavior in rats Brain Res 1986 372: 159–162

    CAS  PubMed  Google Scholar 

  138. 138

    Takao K, Nagatani T, Kasahara K-I, Hashimoto S . Role of the central serotonergic system in the anticonflict effect of d-AP159 Pharmacol Biochem Behav 1992 43: 503–508

    CAS  PubMed  Google Scholar 

  139. 139

    Pesold C, Treit D . The central and basolateral amygdala differentially mediate the anxiolytic effects of benzodiazepines Brain Res 1995 671: 213–221

    CAS  PubMed  Google Scholar 

  140. 140

    Helmstetter FJ . Stress-induced hypoalgesia and defensive freezing are attenuated by application of diazepam to the amygdala Pharmacol Biochem Behav 1993 44: 433–438

    CAS  PubMed  Google Scholar 

  141. 141

    Young BJ, Helmstetter FJ, Rabchenuk SA, Leaton RN . Effects of systemic and intra-amygdaloid diazepam on long-term habituation of acoustic startle in rats Pharmacol Biochem Behav 1991 39: 903–909

    CAS  PubMed  Google Scholar 

  142. 142

    Costall B, Kelly ME, Naylor RJ, Onaivi ES, Tyers MB . Neuroanatomical sites of action of 5-HT3 receptor agonist and antagonists for alteration of aversive behaviour in the mouse Br J Pharmacol 1989 96: 325–332

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Boadle-Biber MC, Singh VB, Corley KC, Phan TH, Dilts RP . Evidence that corticotropin-releasing factor within the extended amygdala mediates the activation of tryptophan hydroxylase produced by sound stress in the rat Brain Res 1993 628: 105–114

    CAS  PubMed  Google Scholar 

  144. 144

    Heinrichs SC, Pich EM, Miczek KA, Britton KT, Koob GF . Corticotropin-releasing factor antagonist reduces emotionality in socially defeated rats via direct neurotropic action Brain Res 1992 581: 190–197

    CAS  PubMed  Google Scholar 

  145. 145

    Rassnick S, Heinrichs SC, Britton KT, Koob GF . Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal Brain Res 1993 605: 25–32

    CAS  PubMed  Google Scholar 

  146. 146

    Heinrichs SC, Menzaghi F, Schulteis G, Koob GF, Stinus L . Suppression of corticotropoin-releasing factor in the amygdala attenuates aversive consequences of morphine withdrawal Behav Pharmacol 1995 6: 74–80

    CAS  PubMed  Google Scholar 

  147. 147

    Liebsch G, Landgraf R, Gerstberger R, Probst JC, Wotjak CT, Engelmann M et al. Chronic infusion of a CRH1 receptor antisense oligodeoxynucleotide into the central nucleus of the amygdala reduced anxiety-related behavior in socially defeated rats Regul Peptides 1995 59: 229–239

    CAS  Google Scholar 

  148. 148

    Swiergiel AH, Takahashi LK, Kalin NH . Attenuation of stress-induced behavior by antagonism of corticotropin-releasing factor in the central amygdala of the rat Brain Res 1993 623: 229–234

    CAS  PubMed  Google Scholar 

  149. 149

    Wiersma A, Baauw AD, Bohus B, Koolhaas JM . Behavioural activation produced by CRH but not a-helical CRH (CRH-receptor antagonist) when microinfused into the central nucleus of the amygdala under stress-free conditions Psychoneuroendocrinology 1995 20: 423–432

    CAS  PubMed  Google Scholar 

  150. 150

    Ray A, Sullivan RM, Henke PG . Interactions of thyrotropin-releasing hormone (TRH) with neurotensin and dopamine in the central nucleus of the amygdala during stress ulcer formation in rats Neurosci Lett 1988 91: 95–100

    PubMed  Google Scholar 

  151. 151

    Ray A, Henke PG . Enkephalin-dopamine interactions in the central amygdalar nucleus during gastric stress ulcer formation in rats Behav Brain Res 1990 36: 179–183

    CAS  PubMed  Google Scholar 

  152. 152

    Ray A, Henke PG . TRH-enkephalin interactions in the amygdaloid complex during gastric stress ulcer formation in rats Regul Peptides 1991 35: 11–17

    CAS  Google Scholar 

  153. 153

    Gallagher M, Kapp BS, Pascoe JP . Enkephalin analogue effects in the amygdala central nucleus on conditioned heart rate Pharmacol Biochem Behav 1982 17: 217–222

    CAS  PubMed  Google Scholar 

  154. 154

    File SE, Rodgers RJ . Partial anxiolytic actions of morphine sulphate following microinjection into the central nucleus of the amygdala in rats Pharmacol Biochem Behav 1979 11: 313–318

    CAS  PubMed  Google Scholar 

  155. 155

    Sajdyk TJ, Vandergriff MG, Gehlert DR . Amygdalar neuropeptide Y Y-1 receptors mediate the anxiolytic-like actions of neuropeptide Y in the social interaction test Eur J Pharmacol 1999 368: 143–147

    CAS  PubMed  Google Scholar 

  156. 156

    Heilig M, McLeod S, Brot M, Henrichs SC, Menzaghi F, Koob GF et al. Anxiolytic-like action of neuropeptide Y: mediation by Y1 receptors in amygdala, and dissociation from food intake effects Neuropsychopharmacology 1993 8: 357–363

    CAS  PubMed  Google Scholar 

  157. 157

    Roozendaal B, Wiersma A, Driscoll P, Koolhaas JM, Bohus B . Vasopressinergic modulation of stress responses in the central amygdala of the Roman high-avoidance and low-avoidance rat Brain Res 1992 596: 35–40

    CAS  PubMed  Google Scholar 

  158. 158

    Lamont EW, Kokkinidis L . Infusion of the dopamine D1 receptor antagonist SCH 23390 into the amygdala blocks fear expression in a potentiated startle paradigm Brain Res 1998 795: 128–136

    CAS  PubMed  Google Scholar 

  159. 159

    Guarraci FA, Frohardt RJ, Kapp BS . Amygdaloid D1 dopamine receptor involvement in Pavlovian fear conditioning Brain Res 1999 827: 28–40

    CAS  PubMed  Google Scholar 

  160. 160

    Kim M, Campeau S, Falls WA, Davis M . Infusion of the non-NMDA receptor antagonist CNQX into the amygdala blocks the expression of fear-potentiated startle Behav Neural Biol 1993 59: 5–8

    CAS  PubMed  Google Scholar 

  161. 161

    Walker DL, Davis M . Double dissociation between the involvement of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in light-enhanced versus fear-potentiated startle J Neurosci 1997 17: 9375–9383

    CAS  PubMed  Google Scholar 

  162. 162

    Shors TJ, Mathew PR . NMDA receptor antagonism in the lateral/basolateral but not central nucleus of the amygdala prevents the induction of facilitated learning in response to stress Learning and Memory 1998 5: 220–230

    CAS  PubMed  Google Scholar 

  163. 163

    Sajdyk TJ, Shekhar A . Excitatory amino acid receptors in the basolateral amygdala regulate anxiety responses in the social interaction test Brain Res 1997 764: 262–264

    CAS  PubMed  Google Scholar 

  164. 164

    Taylor JR, Punch LJ, Elsworth JD . A comparison of the effects of clonidine and CNQX infusion into the locus coeruleus and the amygdala on naloxone-precipitated opiate withdrawal in the rat Psychopharmacology 1998 138: 133–142

    CAS  PubMed  Google Scholar 

  165. 165

    Wiersma A, Bohus B, Koolhaas JM . Corticotropin-releasing hormone microinfusion in the central amygdala diminishes a cardiac parasympathetic outflow under stress-free conditions Brain Res 1993 625: 219–227

    CAS  PubMed  Google Scholar 

  166. 166

    Brown MR, Gray TS . Peptide injections into the amygdala of conscious rats: effects on blood pressure, heart rate and plasma catecholamines Regul Peptides 1988 21: 95–106

    CAS  Google Scholar 

  167. 167

    Wiersma A, Tuinstra T, Koolhaas JM . Corticotropin-releasing hormone microinfusion into the basolateral nucleus of the amygdala does not induce any changes in cardiovascular, neuroendocrine or behavioural output in a stress-free condition Unpublished dissertation, University of Groningen, The Netherlands 1997

    Google Scholar 

  168. 168

    Wiersma A, Bohus B, Koolhaas JM . Corticotropin-releasing hormone microinfusion in the central amygdala enhances active behaviour responses in the conditioned burying paradigm Stress 1997 1: 113–122

    Google Scholar 

  169. 169

    Roozendaal B, Schoorlemmer GH, Koolhaas JM, Bohus B . Cardiac, neuroendocrine, and behavioral effects of central amygdaloid vasopressinergic and oxytocinergic mechanisms under stress-free conditions in rats Brain Res Bull 1993 32: 573–579

    CAS  PubMed  Google Scholar 

  170. 170

    Willcox BJ, Poulin P, Veale WL, Pittman QJ . Vasopressin-induced motor effects: localization of a sensitive site in the amygdala Brain Res 1992 596: 58–64

    CAS  PubMed  Google Scholar 

  171. 171

    Ray A, Henke PG, Sullivan RM . Effects of intra-amygdalar thyrotropin releasing hormone (TRH) and its antagonism by atropine and benzodiazepines during stress ulcer formation in rats Pharmacol Biochem Behav 1990 36: 597–601

    CAS  PubMed  Google Scholar 

  172. 172

    Morrow NS, Hodgson DM, Garrick T . Microinjection of thyrotropin-releasing hormone analogue into the central nucleus of the amygdala stimulates gastric contractility in rats Brain Res 1996 735: 141–148

    CAS  PubMed  Google Scholar 

  173. 173

    Hernandez DE, Salaiz AB, Morin P, Moreira MA . Administration of thyrotropin-releasing hormone into the central nucleus of the amygdala induces gastric lesions in rats Brain Res Bull 1990 24: 697–699

    CAS  PubMed  Google Scholar 

  174. 174

    Ishikawa T, Yang H, Tache Y . Medullary sites of action of the TRH analogue, RX 77368, for stimulation of gastric acid secretion in the rat Gastroenterology 1988 95: 1470–1476

    CAS  PubMed  Google Scholar 

  175. 175

    Calvino B, Lagowska J, Ben-Ari Y . Morphine withdrawal syndrome: differential participation of structures located within the amygdaloid complex and striatum of the rat Brain Res 1979 177: 19–34

    CAS  PubMed  Google Scholar 

  176. 176

    Stinus L, LeMoal M, Koob GF . Nucleus accumbens and amygdala are possible substrates for the aversive stimulus effects of opiate withdrawal Neuroscience 1990 37: 767–773

    CAS  PubMed  Google Scholar 

  177. 177

    Maldonado R, Stinus L, Gold LH, Koob GF . Role of different brain structures in the expression of the physical morphine withdrawal syndrome J Pharmacol Exp Therapeut 1992 261: 669–677

    CAS  Google Scholar 

  178. 178

    Fendt M, Koch M, Schnitzler HU . Amygdaloid noradrenaline is involved in the sensitization of the acoustic startle response in rats Pharmacol Biochem Behav 1994 48: 307–314

    CAS  PubMed  Google Scholar 

  179. 179

    Belcheva I, Belcheva S, Petkov VV, Petkov VD . Asymmetry in behavioral responses to cholecystokinin microinjected into rat nucleus accumbens and amygdala Neuropharmacology 1994 33: 995–1002

    CAS  PubMed  Google Scholar 

  180. 180

    Frankland PW, Josselyn SA, Bradwejn J, Vaccarino FJ, Yeomans JS . Activation of amygdala cholecystokininB receptors potentiates the acoustic startle response in the rat J Neurosci 1997 17: 1838–1847

    CAS  PubMed  Google Scholar 

  181. 181

    McDonald J . Topographic organization of amgdaloid projections to the caudatoputamen, nucleus accumbens, and related striateal-like areas of the rat brain Neuroscience 1991 44: 15–33

    CAS  PubMed  Google Scholar 

  182. 182

    Everitt BJ, Robbins TV . Amygdala-ventral striatal interactions and reward related processes. In: Aggleton JP (ed) The Amygdala: Neurobiological Aspects of Emotion, Memory and Mental Dysfunction Wiley-Liss: New York 1992 p 401–429

    Google Scholar 

  183. 183

    Morgenson GM . Limbic-motor intergration. In: Epstein A, Morrison AR (eds) Progress in Psychobiology and Physiological Psychology Academic Press: New York 1987 pp 117–170

    Google Scholar 

  184. 184

    Taylor JR, Robbins TW . Enhanced behavioral control by conditioned reinforcers following microinjections of d-amphetamine into the nucleus accumbens Psychopharmacology 1984 84: 405–412

    CAS  PubMed  Google Scholar 

  185. 185

    Taylor JR, Robbins TW . 6-hydroxydopamine lesions of the nucleus accumbens, but not the caudate nucleus, attenuate enhanced responding with reward-related stimuli produced by intra-accumbens d-amphetamine Psychopharmacology 1986 90: 390–397

    CAS  PubMed  Google Scholar 

  186. 186

    Burns LH, Everitt BJ, Kelly AE, Robbins TW . Glutamate-dopamine interactions in the ventral striatum: role in locomotor activity and responding with conditioned reinforcement Psychopharmacology 1994 115: 516–528

    CAS  PubMed  Google Scholar 

  187. 187

    Cador M, Robbins TW, Everitt BJ . Involvement of the amygdala in stimulus-reward associations: interactions with the ventral striatum Neuroscience 1989 30: 77–86

    CAS  PubMed  Google Scholar 

  188. 188

    Koch M, Schmid A, Schnitzler H-U . Pleasure-attenuation of startle is disrupted by lesions of the nucleus accumbens Neuroreport 1996 7: 1442–1446

    CAS  PubMed  Google Scholar 

  189. 189

    Everitt BJ, Morris KA, O'Brien A, Robbins TW . The basolateral amygdala-ventral striatal system and conditioned place preference: further evidence of limbic-striatal interactions underlying reward-related processes Neuroscience 1991 42: 1–18

    CAS  PubMed  Google Scholar 

  190. 190

    Cahill L, McGaugh JL . Mechanisms of emotional arousal and lasting declarative memory Trends Neurosci 1998 21: 294–299

    CAS  PubMed  Google Scholar 

  191. 191

    McGaugh JL, Introini-Collison IB, Cahill L, Kim M, Liang KC . Involvement of the amygdala in neuromodulatory influences on memory storage. In: Aggleton JP (ed) The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction Wiley-Liss: New York 1992 pp 431–451

    Google Scholar 

  192. 192

    Packard MG, Teather LA . Amygdala modulation of multiple memory systems: hippocampus and caudate-putamen Neurobiol Learning Memory 1998 69: 163–203

    CAS  Google Scholar 

  193. 193

    Packard MG, Cahill L, McGaugh JL . Amygdala modulation of hippocampal-dependent and caudate nucleus-dependent memory processes Proc Nat Acad Sci USA 1994 91: 8477–8481

    CAS  PubMed  Google Scholar 

  194. 194

    Amorapanth P, LeDoux JE, Nader K . Different lateral amygdala outputs mediate reactions and actions elicited by a fear-arousing stimulus Nature Neurosci 2000 3: 74–79

    CAS  PubMed  Google Scholar 

  195. 195

    Killcross S, Robbins TW, Everitt BJ . Different types of fear-conditioned behaviour mediated by separate nuclei within amygdala Nature 1997 388: 377–380

    CAS  PubMed  Google Scholar 

  196. 196

    Hatfield T, McGaugh JL . Norepinephrine infused into the basolateral amygdala posttraining enhances retention in the spatial water maze task Neurobiol Learning Memory 1999 71: 232–239

    CAS  Google Scholar 

  197. 197

    Ikegaya Y, Saito H, Abe K . Attenuated hippocampal long-term potentiation in basolateral amygdala-lesioned rats Brain Res 1994 1994: 157–164

    Google Scholar 

  198. 198

    Ikegaya Y, Saito H, Abe K . Amygdala N-methyl-D-aspartate receptors participate in the induction of long-term potentiation in the dentate gyrus in vivo Neurosci Lett 1995 192: 193–196

    CAS  PubMed  Google Scholar 

  199. 199

    Ikegaya Y, Saito H, Abe K . Requirement of basolateral amygdala neuron activity for the induction of long-term potentiation in the dentate gyrus in vivo Brain Res 1995 671: 351–354

    CAS  PubMed  Google Scholar 

  200. 200

    Ikegaya Y, Abe K, Saito H, Nishiyama N . Medial amygdala enhances synaptic transmission and synaptic plasticity in the dentate gyrus of rats in vivo J Neurophysiol 1995 74: 2201–2203

    CAS  PubMed  Google Scholar 

  201. 201

    Ikegaya Y, Saito H, Abe K . High-frequency stimulation of the basolateral amygdala facilitates the induction of long-term potentiation in the dentate gyrus in vivo Neuroscience Res 1995 22: 203–207

    CAS  Google Scholar 

  202. 202

    Gewirtz JC, Davis M . Application of Pavlovian higher-order conditioning to the analysis of the neural substrates of learning and memory Neuropharmacology 1998 37: 453–460

    CAS  PubMed  Google Scholar 

  203. 203

    Akbari Y, Mongeau R, Maren S, Fanselow MS . Reversible inactivation of the basolateral amygdala prevents inflation of fear conditioning in rats In: Society for Neuroscience: New Orleans 1997

    Google Scholar 

  204. 204

    Everitt BJ, Cador M, Robbins TW . Interactions between the amygdala and ventral striatum in stimulus-reward associations: studies using a second-order schedule of sexual reinforcement Neuroscience 1989 30: 63–75

    CAS  PubMed  Google Scholar 

  205. 205

    Gewirtz J, Davis M . Second order fear conditioning prevented by blocking NMDA receptors in the amygdala Nature 1997 388: 471–474

    CAS  PubMed  Google Scholar 

  206. 206

    Anderson SW, Bechara A, Damasio H, Tranel D, Damasio AR . Impairment of social and moral behavior related to early damage in human prefrontal cortex Nature Neurosci 1999 2: 1032–1037

    CAS  PubMed  Google Scholar 

  207. 207

    Damasio AR . Descartes’ Error Grosset/Putnam: New York 1994

    Google Scholar 

  208. 208

    Bechara A, Damasio H, Tranel D, Damasio AR . Deciding advantageously before knowing the advantageous strategy Science 1997 275: 1293–1294

    CAS  PubMed  Google Scholar 

  209. 209

    Schoenbaum G, Chiba AA, Gallagher M . Orbitofrontal cortex and basolateral amygdala encode expected outcomes during learning Nature Neurosci 1998 1: 155–159

    CAS  PubMed  Google Scholar 

  210. 210

    Schoenbaum G, Chiba AA, Gallagher M . Neural encoding in orbitofrontal cortex and basolateral amygdala during olfactory discrimination learning J Neurosci 1999 19: 1876–1884

    CAS  PubMed  Google Scholar 

  211. 211

    Sanghera MK, Rolls ET, Roper-Hall A . Visual responses of neurons in the dorsolateral amygdala of the alert monkey Exp Neurol 1979 63: 610–626

    CAS  PubMed  Google Scholar 

  212. 212

    Baxter MG, Parker A, Lindner CCC, Izquierdo AD, Murray EA . Control of response selection by reinforcer value requires interaction of amygdala and orbital prefrontal cortex J Neurosci 2000 20: 4311–4319

    CAS  PubMed  Google Scholar 

  213. 213

    Breiter HC, Etcoff NL, Whalen PJ, Kennedy WA, Rauch SL, Buckner RL et al. Response and habituation of the human amygdala during visual processing of facial expression Neuron 1996 17: 875–887

    CAS  PubMed  Google Scholar 

  214. 214

    Morris JS, Frith CD, Perrett DI, Rowland D, Young AW, Calder AJ et al. A differential neural response in the human amygdala to fearful and happy facial expressions Nature 1996 383: 812–815

    CAS  PubMed  Google Scholar 

  215. 215

    Phillips ML, Young AW, Senior C, Brammer M, Andrew C, Calder AJ et al. A specific neural substrate for perceiving facial expressions of disgust Nature 1997 389: 495–498

    CAS  PubMed  Google Scholar 

  216. 216

    Phillips ML, Young AW, Scott SK, Calderm AJ, Andrew C, Giampietro V et al. Neural responses to facial and vocal expressions of fear and disgust Proc R Soc Lond B 1998 265: 1809–1817

    CAS  Google Scholar 

  217. 217

    Whalen PJ, Rauch SL, Etcoff NL, McInerney SC, Lee MB, Jenike MA . Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge J Neurosci 1998 18: 411–418

    CAS  PubMed  Google Scholar 

  218. 218

    Baird AA, Gruber SA, Fein DA, Maas LC, Steingard RJ, Renshaw PF et al. Functional magnetic resonance imaging of facial affect recognition in children and adolescents J Am Acad Child Adolesc Psychiatry 1999 38: 195–199

    CAS  PubMed  Google Scholar 

  219. 219

    Blair RJ, Morris JS, Frith CD, Perrett DI, Dolan RJ . Dissociable neural responses to facial expressions of sadness and anger Brain 1999 122: 883–893

    PubMed  Google Scholar 

  220. 220

    Hariri AR, Bookheimer SY, Mazziotta JC . Modulating emotional responses: effects of a neocortical network on the limbic system Neuroreport 2000 11: 43–48

    CAS  PubMed  Google Scholar 

  221. 221

    Critchley H, Daly E, Phillips M, Brammer M, Bullmore E, Williams S et al. Explicit and implicit neural mechanisms for processing of social information from facial expressions: a functional magnetic resonance imaging study Hum Brain Mapp 2000 9: 93–105

    CAS  PubMed  Google Scholar 

  222. 222

    DuBois S, Rossion B, Schlitz C, Bodart JM, Michel C, Bruyer R et al. Effect of familiarity on the processing of human faces Neuroimage 1999 9: 278–289

    CAS  PubMed  Google Scholar 

  223. 223

    Kawashima R, Sugiura M, Kato T, Nakamura A, Hatano K, Ito K et al. The human amygdala plays an important role in gaze monitoring: a PET study Brain 1999 122: 779–783

    PubMed  Google Scholar 

  224. 224

    Sprengelmeyer R, Rausch M, Eysel UT, Przuntek H . Neural structures associated with recognition of facial expressions of basic emotions Proc R Soc Lond B 1998 265: 1927–1931

    CAS  Google Scholar 

  225. 225

    Lane RD, Reiman EM, Bradley MM, Lang PJ, Ahern GL, Davidson RJ et al. Neuroanatomical correlates of pleasant and unpleasant emotion Neuropsychologia 1997 35: 1437–1444

    CAS  PubMed  Google Scholar 

  226. 226

    Taylor SF, Liberzon I, Fig LM, Decker LR, Minoshima S, Koeppe RA . The effect of emotional content on visual recognition memory: a PET activation study Neuroimage 1998 8: 188–197

    CAS  PubMed  Google Scholar 

  227. 227

    Reiman EM, Lane RD, Ahern GL, Schwartz GE, Davidson RJ, Friston KJ et al. Neuroanatomical correlates of externally and internally generated human emotion Am J Psychiatry 1997 54: 918–925

    Google Scholar 

  228. 228

    Paradiso S, Johnson DL, Andreasen NC, O'Leary DS, Watkins GL, Boles Ponto LL et al. Cerebral blood flow changes associated with attribution of emotional valence to pleasant, unpleasant, and neutral visual stimuli in a PET study of normal subjects Am J Psychiatry 1999 156: 1618–1629

    CAS  PubMed  Google Scholar 

  229. 229

    Fischer H, Furmark T, Wik G, Fredrikson M . Brain representation of habituation to repeated complex visual stimulation studied with PET Neuroreport 2000 11: 123–126

    CAS  PubMed  Google Scholar 

  230. 230

    Cahill L, Haier RJ, Fallon J, Alkire MT, Tang C, Keator D et al. Amygdala activity at encoding correlated with long-term, free recall of emotional information Proc Nat Acad Sci USA 1996 93: 8016–8021

    CAS  PubMed  Google Scholar 

  231. 231

    Hamann SB, Ely TD, Grafton ST, Kilts CD . Amygdala activity related to enhanced memory for pleasant and aversive stimuli Nature Neurosci 1999 2: 289–293

    CAS  PubMed  Google Scholar 

  232. 232

    Dolan RJ, Lane R, Chua P, Fletcher P . Dissociable temporal lobe activations during emotional episodic memory retrieval Neuroimage 2000 11: 203–209

    CAS  PubMed  Google Scholar 

  233. 233

    Zald DH, Pardo JV . Emotion, olfaction, and the human amygdala: amygdala activation during aversive olfactory stimulation Proc Nat Acad Sci USA 1997 94: 4119–4124

    CAS  PubMed  Google Scholar 

  234. 234

    Zald DH, Lee JT, Fluegel KW, Pardo JV . Aversive gustatory stimulation activates limbic circuits in humans Brain 1998 121: 1143–1154

    PubMed  Google Scholar 

  235. 235

    Isenberg N, Silbersweig D, Engelien A, Emmerich S, Malavade K, Beattie B et al. Linguistic threat activates the human amygdala Proc Natl Acad Sci 1999 96: 10456–10459

    CAS  PubMed  Google Scholar 

  236. 236

    Whalen PJ, Bush G, McNally RJ, Wilhelm S, McInerney SC, Jenike MA et al. The emotional counting Stroop paradigm: a functional magnetic resonance imaging probe of the anterior cingulate affective division Biol Psychiatry 1998 44: 1219–1228

    CAS  PubMed  Google Scholar 

  237. 237

    Morris JS, Scott SK, Dolan RJ . Saying it with feeling: neural responses to emotional vocalizations Neuropsychologia 1999 37: 1155–1163

    CAS  PubMed  Google Scholar 

  238. 238

    Schneider F, Gur RE, Alavi, A, Seligman MEP, Mozley LH, Smith RJ et al. Cerebral blood flow changes in limbic regions induced by unsolvable anagram tasks Am J Psychiatry 1996 153: 206–212

    CAS  PubMed  Google Scholar 

  239. 239

    Bonda E, Petrides M, Ostry D, Evans A . Specific involvement of human parietal systems and the amygdala in the perception of biological motion J Neurosci 1996 16: 3737–3744

    CAS  PubMed  Google Scholar 

  240. 240

    Furmark T, Fischer H, Wirk G, Larsson M, Fredrikson M . The amygdala and individual differences in human fear conditioning NeuroReport 1997 8: 3957–3960

    CAS  PubMed  Google Scholar 

  241. 241

    LaBar KS, Gatenby JC, Gore JC, LeDoux JE, Phelps EA . Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study Neuron 1998 20: 937–945

    CAS  PubMed  Google Scholar 

  242. 242

    Büchel C, Morris J, Dolan RJ, Friston KJ . Brain systems mediating aversive conditioning: an event-related fMRI study Neuron 1998 20: 947–957

    PubMed  Google Scholar 

  243. 243

    Morris JS, Öhman A, Dolan RJ . Conscious and unconscious emotional learning in the human amygdala Nature 1998 393: 467–470

    CAS  PubMed  Google Scholar 

  244. 244

    Büchel C, Dolan RJ, Armony JL, Friston KJ . Amygdala-hippocampal involvement in human aversive trace conditioning revealed through event-related functional magnetic resonance imaging J Neurosci 1999 19: 10869–10876

    PubMed  Google Scholar 

  245. 245

    Phelps EA, O'Connor KJ, Gatenby JC, Gore JC, Grillon C, Davis M . Activation of the left amygdala to a cognitive representation of fear Nature Neurosci (in press)

  246. 246

    Schneider F, Gur RE, Harper Mozley L, Smith RJ, Mosley PD, Censits DM et al. Mood effects on limbic blood flow correlate with emotional self-rating: a PET study with oxygen-15 labeled water Psychiatry Res: Neuroimaging 1995 61: 265–283

    CAS  PubMed  Google Scholar 

  247. 247

    Schneider F, Grodd W, Weiss U, Klos U, Mayer KR, Nagele T et al. Functional MRI reveals left amygdala activation during emotion Psychiatry Res 1997 76: 75–82

    CAS  PubMed  Google Scholar 

  248. 248

    Grodd W, Schneider F, Klose U, Nägele T . Functional magnetic resonance tomography of psychological functions with experimentally induced emotions [German] Radiologe 1995 35: 283–289

    CAS  PubMed  Google Scholar 

  249. 249

    Ketter TA, Andreason PJ, George MS, Lee C, Gill DS, Parekh PI et al. Anterior paralimbic mediation of procaine-induced emotional and psychosensory experiences Arch Gen Psychiatry 1996 53: 59–69

    CAS  PubMed  Google Scholar 

  250. 250

    Servan-Schreiber DS, Perlstein WM, Cohen JD, Mintun M . Selective pharmacological activation of limbic structures in human volunteers: a positron emission tomography study J Neuropsychiatry Clin Neurosci 1998 10: 148–159

    CAS  PubMed  Google Scholar 

  251. 251

    Hui KKS, Liu J, Makris N, Gollub RL, Chen AJW, Moore CI et al. Acupuncture modulates the limbic system and subcortical gray structures of the human brain: evidence from fMRI studies in normal subjects Hum Brain Mapp 2000 9: 13–25

    CAS  PubMed  Google Scholar 

  252. 252

    Lazar SW, Bush G, Gollub RL, Fricchione GL, Khalsa G, Benson H . Functional brain mapping of the relaxation response and meditation Neuroreport 2000 11: 1581–1585

    CAS  PubMed  Google Scholar 

  253. 253

    Becerra L, Breiter HC, Stojanovic M, Fishman S, Edwards A, Comite AR et al. Human brain activation under controlled thermal stimulation and habituation to noxious heat: an fMRI study Magn Reson Med 1999 41: 1044–1057

    CAS  PubMed  Google Scholar 

  254. 254

    Derbyshire S, Jones A, Gyulai F, Clark S, Townsend D, Firestone L . Pain processing during three levels of noxious stimulation produces differential patterns of central activity Pain 1997 73: 431–445

    CAS  PubMed  Google Scholar 

  255. 255

    Rauch SL, van der Kolk BA, Fisler RE, Alpert NM, Orr SP, Savage CR et al. A symptom provocation study of posttraumatic stress disorder using positron emission tomography and script-driven imagery Arch Gen Psychiatry 1996 53: 380–387

    CAS  PubMed  Google Scholar 

  256. 256

    Shin LM, Kosslyn SM, McNally RJ, Alpert NM, Thompson WL, Rauch SL et al. Visual imagery and perception in posttraumatic stress disorder: a positron emission tomographic investigation Arch Gen Psychiatry 1997 54: 233–241

    CAS  PubMed  Google Scholar 

  257. 257

    Liberzon I, Taylor SF, Amdur R, Jung TD, Chamberlain KR, Minoshima S et al. Brain activation in PTSD in response to trauma-related stimuli Biol Psychiatry 1999 45: 817–826

    CAS  PubMed  Google Scholar 

  258. 258

    Rauch SL, Whalen PJ, Shin LM, McInerney SC, Macklin ML, Lasko NB et al. Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder Biol Psychiatry 2000 47: 769–776

    CAS  PubMed  Google Scholar 

  259. 259

    Semple WE, Goyer PF, McCormick R, Donovan B, Muzic RF, Rugle L et al. Higher brain blood flow at amygdala and lower frontal cortex blood flow in PTSD patients with comorbid cocaine and alcohol abuse compared with normals Psychiatry 2000 63: 65–74

    CAS  PubMed  Google Scholar 

  260. 260

    Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME . A functional anatomical study of unipolar depression J Neurosci 1992 12: 3628–3641

    CAS  PubMed  Google Scholar 

  261. 261

    Abercrombie HC, Schaefer SM, Larson CL, Oakes TRL, Lindgren KA, Holden JE et al. Metabolic rate in the right amygdala predicts negative affect in depressed patients Neuroreport 1998 9: 3301–3307

    CAS  PubMed  Google Scholar 

  262. 262

    Birbaumer N, Grodd W, Diedrich O, Klose U, Erb M, Lotze M et al. fMRI reveals amygdala activation to human faces in social phobics NeuroReport 1998 9: 1223–1226

    CAS  PubMed  Google Scholar 

  263. 263

    Schneider F, Weiss U, Kessler C, Müller-Gärtner H-W, Posse S, Salloum JB et al. Subcortical correlates of differential classical conditioning of aversive emotional reactions in social phobia Biol Psychiatry 1999 45: 863–871

    CAS  PubMed  Google Scholar 

  264. 264

    Whalen PJ . Fear, vigilance, and ambiguity: initial neuroimaging studies of the human amygdala Curr Direct Psychol Sci 1998 7: 177–188

    Google Scholar 

  265. 265

    Grillon C, Ameli R, Woods SW, Merikangas K, Davis M . Fear-potentiated startle in humans: effects of anticipatory anxiety on the acoustic blink reflex Psychophysiology 1991 28: 588–595

    CAS  PubMed  Google Scholar 

  266. 266

    Irwin W, Davidson RJ, Lowe MJ, Mock BJ, Sorenson JA, Turski PA . Human amygdala activation detected with echo-planar functional magnetic resonance imaging NeuroReport 1996 7: 1765–1769

    CAS  PubMed  Google Scholar 

  267. 267

    Morris JS, Friston KJ, Büchel C, Frith CD, Young AW, Calder AJ et al. A neuromodulatory role for the human amygdala in processing emotional facial expressions Brain 1998 121: 47–57

    PubMed  Google Scholar 

  268. 268

    Drevets WC, Raichle M . Reciprocal suppression of regional cerebral blood flow during emotional versus higher cognitive processes: implications for interactions between emotion and cognition Cognition and Emotion 1998 12: 353–385

    Google Scholar 

  269. 269

    Esteves F, Öhman A . Masking the face: recognition of emotional facial expressions as a function of the parameters of backward masking Scand J Psychol 1993 34: 1–18

    CAS  PubMed  Google Scholar 

  270. 270

    Kapp BS, Silvestri AJ, Guarraci FA . Amygdaloid central nucleus neuronal activity: correlations with EEG arousal Neurosci Abs 1996 22: 2049

    Google Scholar 

  271. 271

    Kapp BS, Silvestri AJ, Guarraci FA, Moynihan JE, Cain ME . Associative and EEG arousal-related characteristics of amygdaloid central nucleus neurons in the rabbit Neurosci Abs 1997 23: 787

    Google Scholar 

  272. 272

    Metherate R, Ashe JH . Basal forebrain stimulation modifies auditory cortex responsiveness by an action at muscarinic receptors Brain Res 1991 559: 163–167

    CAS  PubMed  Google Scholar 

  273. 273

    Sillitto AM, Kemp JA . Cholinergic modulation of the functional organization of the cat visual cortex Brain Res 1983 289: 143–155

    Google Scholar 

  274. 274

    Weinberger NM, Ashe JH, Metherate R, McKenna TM, Diamond DM, Bakin JS et al. Neural adaptive information processing: a preliminary model of receptive-field plasticity in auditory cortex during Pavlovian conditioning. In: Gabriel M, Moore J (eds). Learning and Computational Neuroscience: Foundations of Adaptive Networks MIT Press: Cambridge MA 1990

  275. 275

    Chiba AA, Bucci DJ, Holland PC, Gallagher M . Basal forebrain cholinergic lesions disrupt increments but not decrements in conditioned stimulus processing J Neurosci 1995 15: 7315–7322

    CAS  PubMed  Google Scholar 

  276. 276

    Bucci DJ, Holland PC, Gallagher M . Removal of cholinergic input to rat posterior parietal cortex disrupts incremental processing of conditioned stimuli J Neurosci 1998 18: 8038–8046

    CAS  PubMed  Google Scholar 

  277. 277

    Everitt BJ, Robbins TW . Central cholinergic systems and cognition Ann Rev Psychol 1997 48: 649–684

    CAS  Google Scholar 

  278. 278

    Robbins TW, Everitt BJ, Marston HM, Wilkinson J, Jones GH, Page KJ . Comparative effects of ibotenic acid- and quisqualic acid-induced lesions of the substantia innominata on attentional function in the rat: further implications for the role of the cholinergic neurons of the nucleus basalis in cognitive processes Behav Brain Res 1989 35: 221–240

    CAS  PubMed  Google Scholar 

  279. 279

    Whalen PJ, Shin LM, McInerney SC, Rauch SL . Greater fMRI activation to fearful vs angry facial expression in the amygdaloid region Neurosci Abs 1998 24: 692

    Google Scholar 

  280. 280

    Whalen PJ, Kapp BS . Contributions of the amygdaloid central nucleus to the modulation of the nictitating membrane reflex in the rabbit Behav Neurosci 1991 105: 141–153

    CAS  PubMed  Google Scholar 

  281. 281

    Masur JD, Dienst FT, O'Neal EC . The acquisition of a Pavlovian conditioned response in septally damaged rabbits: role of a competing response Physiol Psychol 1974 2: 133–136

    Google Scholar 

  282. 282

    Schneiderman N . Response system divergencies in aversive classical conditioning. In: Black AH, Prokasy WF (eds). Classical Conditioning, Vol. III: Current Research and Theory Appleton-Century-Crofts: New York 1972

  283. 283

    Weisz DJ, McInerney J . An associative process maintains reflex facilitation of the unconditioned nictitating membrane response during the early stages of training Behav Neurosci 1990 104: 21–27

    CAS  PubMed  Google Scholar 

  284. 284

    Powell DA, Milligan WL . Effects of partial and continuous reinforcement on conditioned heart rate and corneoretinal potential responses in the rabbit (Oryctolagus cuniculus) Psychol Record 1975 25: 419–426

    Google Scholar 

  285. 285

    Fitzgerald RD, Vardaris RM, Brown JS . Classical conditioning of heart-rate deceleration in the rat with continuous and partial reinforcement Psychon Sci 1966 6: 437–438

    Google Scholar 

  286. 286

    Campeau S, Falls WA, Cullinan WE, Helmreich DL, Davis M, Watson SJ . Elicitation and reduction of fear: behavioral and neuroendocrine indices and brain induction of the immediate-early gene c-fos Neuroscience 1997 78: 1087–1104

    CAS  PubMed  Google Scholar 

  287. 287

    Davis M, Schlesinger LS, Sorenson CA . Temporal specificity of fear-conditioning: effects of different conditioned stimulus-unconditioned stimulus intervals on the fear-potentiated startle effect J Exp Psychol: Anim Behav Proc 1989 15: 295–310

    CAS  Google Scholar 

  288. 288

    Kim M, Davis M . Electrolytic lesions of the amygdala block acquisition and expression of fear-potentiated startle even with extensive training, but do not prevent re-acquisition Behav Neurosci 1993 107: 580–595

    CAS  PubMed  Google Scholar 

  289. 289

    Maren S . Overtraining does not mitigate contextual fear conditioning deficits produced by neurotoxic lesions of the basolateral amygdala J Neurosci 1998 18: 3088–3097

    CAS  PubMed  Google Scholar 

  290. 290

    Scannell JW, Young MP . Neuronal population activity and functional imaging Proc Royal Soc London B 1999 266: 875–881

    CAS  Google Scholar 

  291. 291

    Lee Y, Davis M . Role of the hippocampus, bed nucleus of the stria terminalis and amygdala in the excitatory effect of corticotropin releasing (CRH) hormone on the acoustic startle reflex J Neurosci 1997 17: 6434–6446

    CAS  PubMed  Google Scholar 

  292. 292

    Broks P, Young AW, Maratos EJ, Coffey PL, Calder AJ, Isaac C et al. Face processing impairments after encephalitis: amygdala damage and recognition of fear Neuropsychologia 1998 36: 59–70

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by NIH Grants MH 47840, MH 57250, MH 58922, MH 52384, MH 59906 and the Woodruff Foundation to MD and NIH Grant MH 01866 and a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award to PJW. Special thanks are given to Dr Changjun Shi who prepared Figure 3 based on his own work.

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Davis, M., Whalen, P. The amygdala: vigilance and emotion. Mol Psychiatry 6, 13–34 (2001). https://doi.org/10.1038/sj.mp.4000812

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Keywords

  • fear
  • anxiety
  • conditioning
  • amygdala
  • bed nucleus stria terminalis
  • lesions
  • functional neuroimaging
  • basolateral nucleus
  • central nucleus
  • animal
  • human

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