User:Ledouxje/amygdala
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The amygdala (Latin, also corpus amygdaloideum, plural amygdalae, from Greek αμυγδαλή, amygdalē, 'almond') [1] is located deep in the temporal lobe in each hemisphere. The existence of the amygdala was first formally recognized in the early 19th century [2]. It is often described as an almond-shaped structure, but the shape from which the amygdala gets its name is only one of several subdivisions, as described below. The amygdala plays a key role in emotions, such as fear, and in the emotional coloration of cognitive processes, such as attention, perception, and memory.
Anatomical Organization There has been considerable debate about what the amygdala is, how it should be subdivided, and how the subdivisions relate to other major regions of the brain. One long-standing idea is the amygdala consists of evolutionarily primitive areas associated with the olfactory system (cortical, medial and central nuclei) and evolutionarily newer areas associated with the neocortex (lateral, basal, and accessory basal nuclei) [3]. The areas of the older division are sometimes grouped as the cortico-medidal region (cortical and medial nuclei) and sometimes as the centro-medial region (the central and medial nuclei). In contrast, the newer structures related to the neocortex are often referred to as the basolateral region. The almond shaped structure that originally defined the amygdala included the basaolateral region rather than the whole structure now considered to constitute the amygdala.
It is easy to be confused by the terminology used to describe amygdala nuclei, as different sets of terms are used by different authors [4]. This problem is especially acute with regards to the basolateral region of the amygdala. As noted, the basolateral region consists of the lateral, basal and accessory basal nuclei. However, the basal and accessory basal nuclei are also known as the basolateral and basomedial nuclei, respectively. Particularly confusing is the use of the term basolateral to refer to both a specific nucleus (the basal or basolateral nucleus) and to the larger region that includes the lateral, basal and accessory basal nuclei (the basolateral complex). Another confusing point involves the cortical nucleus. Being a cortical structure, albeit a primitive olfactory one, it is sometimes associated with the basolateral region, but is also often grouped with the medial nucleus to form the cortico-medial amygdala. Each amygdala nucleus can be further partitioned into subnuclei [5]. For example, the lateral nucleus has three major divisions: dorsal, ventrolateral, and medial. Further division is also possible: the dorsal subdivsion has a superior and an inferior region. The central nucleus, on the other hand, has lateral, capsular, and medial divisions. These subnuclear partitions of the lateral and central nuclei have turned out to have important functional significance, as mentioned below.
There have been a number of attempts to reclassify the amygdala and its relation to other areas. For example, on the basis of connectivity and neurochemical observations, Heimer has argued for the concept of an extended amygdala in which the central and medial amygdala form continuous structures with the lateral and medial divisions of the bed nucleus of the stria terminalis [6]. A more radical notion comes from Swanson and Petrovich, who propose that idea that “the amygdala,” whether extended or not, does not exist as a structural unit [7]. Instead, they argue that the amygdala consists of regions that belong to other regions or systems of the brain and that the designation “the amygdala” is not necessary. For example, in this scheme, the lateral and basal amygdala are viewed as nuclear extensions of the neocortex (rather than amygdala regions related to the neocortex), the central and medial amygdala are said to be ventral extensions of the striatum, and the cortical nucleus is part of the olfactory system. It is certainly true that “the amygdala’ has no function. Functions are carried out by cells and synapses at the nuclear (and subnuclear) level. Thus, the key issue is how nuclei that are traditionally part of the amygdala perform their functions, regardless of whether they are part of the cortex, striatum, amygdala, or other gross designations. Connections
Each nucleus of the amygdala has unique inputs and outputs [8]. The lateral nucleus is generally viewed as sensory interface of the amygdala [9]. It is the major site receiving inputs from the visual, auditory, somatosensory (including pain), olfactory, and taste systems (olfactory and taste information is also transmitted other nuclei as well). The cortical nucleus also receives sensory input, in particular from the olfactory system, and is involved in the sexual and other behaviors that utilize odor and pheromone signaling.
Connections of the central nucleus make it an important output region for the expression of emotional responses and associated physiological adjustments in the brain and body. It connects with hypothalamic and brainstem areas involved in the control of the autonomic nervous system, hormones released from the pituitary and adrenal glands, and emotional behavior, including the facial expressions [10]. Other outputs of the central nucleus connect with amine modulatory systems in the brainstem that release dopamine, norepinephrine, acetylcholine and serotonin throughout the forebrain [11].
Given that the lateral nucleus is the sensory interface and that the central nucleus contributes to the control of emotional responses, there is considerable interest in the internal connectivity between the lateral and central nuclei [12]. While some direct connections exist from the lateral nucleus to the central nucleus, these are relatively sparse. The main channels of communication between the lateral and the central nucleus are thus thought to involve connections with other amygdala nuclei that then connect with the central nucleus. For example, the lateral nucleus projects to the basal nucleus which projects to the central nucleus. In addition, both the lateral and basal nuclei project to the intercalated cell masses, which then connect with the central nucleus [13].
The basal nucleus, in addition to receiving inputs from the lateral nucleus and connecting with the central nucleus, has extensive connectivity with other forebrain areas, including the neocortex, hippocampus, basal ganglia [14]. Through these connections information processing in the amygdala can influence perception, memory, and decision making, and can also contribute to the control of instrumental goal-directed behavior.
The connections of other amygdala areas (including the accessory basal, medial and cortical nuclei) are summarized in several publications [15].
Cellular Mechanisms The cellular architecture and physiology of the lateral and basal nuclei have been studied more extensively than that of other amygdala areas. These nuclei, like neocortical areas, have two basic cell types: principal and internurons [16]. Principal neurons are relatively large, pyramidal-like cells that project outside of the nucleus in which the soma resides. Interneurons are smaller and tend to project locally. Most principal neurons are excitatory while most interneruons are inhibitory [17].
The amygdala is a relatively “silent” area of the brain [18]. It contains a strong inhibitory network of interneurons that keeps spontaneous cellular activity low and that prevents excitatory principal cells from firing action potentials to irrelevant stimuli [19]. Novel stimuli elicit responses, but these rapidly habituate if the stimulus is repeated [20]. This inhibition can be overcome when a novel stimulus is presented in association with a significant event, leading to the potentiation rather than dissipation of the response [21].
Most of the inputs to the amygdala involve excitatory pathways that use glutamate as a transmitter [22]. These inputs form synaptic connections on the dendrites of excitatory principal neurons that transmit signals to other regions or subregions of the amygdala or to extrinsic regions [23]. However, axons of principal neurons also give rise to local connections to inhibitory interneurons that then provide feedback inhibition to the principal neurons [24]. In addition to terminating on projection neurons, some of the excitatory inputs to the amygdala terminate on local inhibitory interneurons that in turn connect with principal neurons, giving rise to feedforward inhibition [25]. These connections allow stimulus-driven inhibition to build up and account for the decrease in responses when stimuli are repeated.
The scheme of inputs and connections just described applies to the neurons of the basolateral region (lateral and basal nuclei) more so than to neurons within the corticomedial group. For example, the projection neurons in the central nucleus tend to be inhibitory in nature [26]. Thus, excitation of these leads to inhibition of output activity, while inhibition of these gives rise to increased output activity. How, then, might these inbibitory outputs lead to the expression of emotional responses? One possibility is that activation of the inhibitory intercalated cells by the lateral and basal amygdala may inhibit the central amygdala output cells, thus disinhibiting their targets and leading to the expression of responses.
The flow of information through amygdala circuits is modulated by a variety of neurotransmitter systems [27]. Thus, norepinephrine, dopamine, serotonin, and acetylcholine released in the amygdala influences how excitatory and inhibitory neurons interact. Importantly, output connections of the central nucleus terminate on these cells as well as in response control regions. Thus, activation of the amygdala leads to the release of these neurotransmitters throughout the forebrain, including within the amygdala.
Receptors for the various neuromodulators are differentially distributed in the various amygdala nuclei [28]. Also differentially distributed are receptors for various hormones, including glucocorticoid and estrogen hormones [29]. Numerous peptides receptors are also present in the amygdala, including receptors for opioid peptides, oxytocin, vasopressin, corticotriopin releasing factor, and neuropetide Y, to name a few [30].
An important challenge for the future is to understand how these various chemical systems interact to set the overall tone of the amydgala. For example, it is known that release of serotonnin inhbits cellular activity in the lateral nucleus. However, this is achieved by serotinin exciting GABAergic cells that inhibit projection neurons [31]. Further, the glucocorticoid hormones corticosterone is necessary for these effects of serotonin [32]. Many possible interactions are likely to exist amongst the various chemical systems in the amygdala.
Functions The amygdala has long been associated with emotional functions of the brain. While the contribution of the amygdala to emotional functions is often said to be due to its involvement in the limbic system [33], the validity of the limbic system concept as an explanation of the emotional functions of the brain has been questioned [34]. This does not imply that the amygdala is the only structure involved in emotional processing, or that it functions independent of other areas in the mediation of emotional or other functions. It simply means that little is added by deferring to the vague limbic system concept in the attempt to understand specific brain functions.
Emotional Functions In the late 1930s, researchers observed that damage to the temporal lobe resulted in profound changes in fear reactivity, feeding, and sexual behavior [35]. These behavioral changes came to be called the Kluver-Bucy Syndrome. Just under 20 years later, it was determined that damage to the amygdala accounted for these changes in emotional behavior [36]. Numerous studies subsequently attempted to understand the role of the amygdala in emotional functions, especially fear. The result was a large and confusing body of knowledge about the functions of the amygdala because much of the research ignored the nuclear organization of the amygdala, which was not fully appreciated, and partly because the functions measured by behavioral tasks were not well understood [37].
Most studies of the brain mechanisms of fear have used tasks in which animals learn to express fear responses to stimuli or situations that were not previously threatening. Early studies tended to use avoidance conditioning tasks for this purpose [38]. Such tasks measure fear in terms of how well an animal leans to avoid shock. However, avoidance is a two stage process in which Pavolvian conditioning establishes fear responses to stimuli that predict the occurrence of the shock, and then new behaviors that allow escape from or avoidance of the shock, and thus that reduce the fear elicited by the stimuli, are learned [39]. By the 1980s, researchers had turned to the use of tasks that isolated the Pavlovian from the instrumental components of the task to study the brain mechanisms of fear [40].
In Pavlovian fear conditioning a neutral conditioned stimulus (CS) that is paired with a painful shock unconditioned stimulus (US) comes to elicit fear responses such as freezing behavior and related physiological changes [41]. Studies in rodents have mapped the inputs to and outputs of amygdala nuclei and subnuclei that mediate fear conditioning [42]. In particular, it is widely accepted that convergence of the CS and US leads to synaptic plasticity in the dorsal subregion of the lateral amygdala [43]. When the CS then occurs alone later, it flows through these potentiated synapses to the other amygdala targets and ultimately to the medial part of the central nucleus, outputs of which control conditioned fear responses [44]. Much has been learned about the cellular and molecular mechanisms within lateral amygdala cells that underlie the plastic changes during learning and in the consolidation and maintenance of long-term memory of the CS-US association [45]. Indeed, once the CS-US assoication is formed, the CS has to capacity to elicit fear responses indefinitely [46]. Pavlovian fear responses can be weakened by extinction, repeated exposure to the CS without the US [47]. Extinction involves a form of active learning rather than passive forgetting or erasure [48]. The lateral, basal, and central nuclei are involved in extinction [49], as is the medial prefrontal cortex [49] and hippocampus [50].
Aggressive behavior also involves the amygdala [51]. While the inputs to the amygdala have not been studied in relation to aggression in much detail, the output connections involved have been studied extensively [52].
The amygdala is also involved in learning about the toxicity of food. In so-called taste aversive learning, novel foods that produce nausea are subsequently avoided [53]. This type of learning involves both the lateral, basal and central amygdala as well as the insular cortex [54]. The molecular mechanisms involved have been elucidated as well [55].
Fear, aggression, and taste aversion are not the only emotional states that the amygdala contributes to. A relatively large body of research has focused on the role of the amygdala in processing of rewards and the use of rewards to motivate and reinforce behavior [56]. As with aversive conditioning, the lateral, basal, and central amygdala have been implicated in different aspects of reward learning and motivation [49]. However, the circuitry may differ from aversive learning [57]. The amygdala has also been implicated in emotional states associated with maternal [58], sexual [59], and ingestive (eating and drinking) [60] behaviors.
Over the past decade, interest in the human amygdala in emotional processing has grown considerably, spurred on by the progress in animal studies and by the development of functional imaging techniques [61]. As in the animal brain, damage to the human amygdala interferes with fear conditioning and functional activity changes in the human amygdala in response to fear conditioning [62]. Further, exposure to emotional faces potently activates the human amygdala [63] and detection of emotion in the face of others is impaired in people with amygdala damage [64]. Both conditioned stimuli and emotional faces produce strong amygdala activation when presented unconsciously, emphasizing the importance of the amygdala as an implicit information processor and its role in unconscious memory [65]. Findings regarding the human amygdala are mainly at the level of the whole region rather than nuclei.
Cognitive-Emotional Interactions In addition to its role in emotion and unconscious emotional memory, the amygdala is also involved in the regulation or modulation of a variety of cognitive functions, such as attention, perception, and explicit memory.
Implicit or unconscious emotional memory mediated by the amygdala contrasts with explicit or declarative memory mediated by the hippocampus and related areas of the medial temporal lobe (MTL) memory system [66]. Included in the MTL memory system are the hippocampus and the entrorhinal, perihrinal, and parahippocampal cortical areas. Early studies suggested that the amygdala, which is located in the MTL, might be part of the MTL declarative or explicit memory system [67] but this turned out to not be the case [68]. In an emotional situation, both the amygdala and the MTL system participate in the storage of information. The MTL memories can be said to be cognitive memories about emotion as opposed to emotional memories per se [69].
Memories about emotion are often modulated by the co-occurence of emotional arousal [70]. Damage to the amygdala in humans interferes which the emotional enhancement of memory [71]. Animal studies have shown that one way emotional arousal impacts memory is via the release of hormones [72]. For example, amygdala activity causes the hypothalamus trigger the secretion of ACTH from the pituitary gland and this results in glucocorticoid release from the adrenal cortex into the blood stream. The hormone then travels in the circulation to the brain where it binds to receptors in a number of areas, including the basal amygdala which then, via anatomical connections, enhances explicit memory formation in the hippocampus [73]. However, under conditions of intense or prolonged stress, glucorticoid hormone directly impairs the ability of the hippocampus to form and retain memories [74] and can lead to an amnesia for a traumatic event [75].
Emotional arousal also biases cognitive processing towards stimuli that are eliciting emotional arousal [76]. These biases involve interactions between the amygdala and cortical circuits involved in sensory processing and attention.
Cognitive systems can also exert top-down influences on emotional processing by the amygdala, allowing self regulation of emotion [77]. These top-down influences involve interactions between the prefrontal cortex and the amygdala. While there are few direct connections from the lateral areas of prefrontal cortex to the amygdala [78], medial prefrontal areas connect with the amygdala [79].
Psychopathology Structural and/or functional changes in the amygdala are associated with a wide variety of psychiatric conditions in humans. Persons suffering from anxiety disorders, such as PTSD [80], phobia [81], and panic disorder [82], show exaggerated amygdala responses to threatening stimuli, as measured by fMRI or PET imaging. It has been proposed that alterations in fear processing circuits may contribute to these disorders [83], and indeed imaging studies show increased amygdala responses to conditioned fear stimuli in patients with anxiety disorders [84].
Patients with depression [85], schizophrenia [86], and autism [87] also show altered amygdala activity as compared to controls in response to emotional stimulation (including emotional faces or words). Changes in amygdala structure (volume) have also been found in depression [88], schizophrenia [89], and autism [90]. These findings do not mean that changes in the amygdala cause these disorders. It simply means that in people who have these disorders alterations occur in the amygdala. Because each of these disorders involves fear and anxiety to some extent, the involvement of the amygdala in some of these disorders may be related to the increased anxiety in these patients.
