The amygdaloid region of the brain (i.e. the amygdala) is a complex structure involved in a wide range of normal behavioral functions and psychiatric conditions. Not so long ago it was an obscure region of the brain that attracted relatively little scientific interest. Today it is one of the most heavily studied brain areas, and practically a household word. This article will summarize the anatomical organization of the amygdala and its functions.
The existence of the amygdala was first formally recognized in the early 19th century. The name, derived from the Greek, was meant to denote the almond-like shape of this region in the medial temporal lobe. Much debate has since ensued, and continues today, about how the amygdala should be subdivided. Also controversial is how the subdivisions relate to other major regions of the brain.
One long-standing idea is that the amygdala consists of an evolutionarily primitive division associated with the olfactory system (cortical, medial and central nuclei) and an evolutionarily newer division associated with the neocortex (lateral, basal, and accessory basal nuclei). The areas of the older division are sometimes grouped as the cortico-medial 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 basolateral region rather than the whole structure now considered to be the amygdala.
In recent years, there have been a number of attempts to reclassify the amygdala and its relation to other areas. For example, Heimer and colleagues have argued for the concept of an extended amygdala. In this view, the central and medial amygdala form continuous structures with the lateral and medial divisions of the bed nucleus of the stria terminalis. 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. Instead, they argue that the amygdala consist 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 associated with the olfactory system. While this scheme has some merit, the present review focuses on the organization and function of nuclei and subnuclei that, while traditionally said to be part of the amygdala, nevertheless perform their functions regardless of whether the amygdala itself exists, or whether it is extended.
It is easy to be confused by the terminology used to describe the amygdala nuclei, as different sets of terms are used. This problem is especially acute with regards to the basolateral region of the amygdala. One popular scheme refers to the basolateral region as consisting of the lateral, basal and accessory basal nuclei. Another scheme uses the terms basolateral and basomedial nuclei to refer to the regions named as the basal and accessory basal nuclei in the first scheme. 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. The major nuclei of the amygdala are shown in sections from the rat brain in Figure 2.
The amygdala has a wide range of connections with other brain regions, allowing it to participate in a wide variety of behavioral functions. Some of the major connections are shown above in Figure 3.
Different nuclei of the amygdala have unique connections (Figure 4, Figure 5, and Figure 6), which is why each nucleus makes unique contributions to functions. A thorough discussion of all the connections is beyond the present scope. Therefore, a few key examples will be given. The lateral amygdala is a major site receiving inputs from visual, auditory, somatosensory (including pain) systems, the medial nucleus of the amygdala is strongly connected with the olfactory system, and the central nucleus connects with brainstem areas that control the expression of innate behaviors and associated physiological responses. In many instances, the subnuclei of a given nucleus also have distinct connections. The lateral nucleus, for example, includes dorsal, medial, and ventrolateral subnuclei, while the central nucleus contains lateral, capsular, and medial subnuclei. The dorsal subnucleus of the lateral nucleus receives much of the direct sensory flow to the amygdala, while the medial division of the central nucleus is the part that connects with response control regions.
Most of the inputs to the amygdala involve excitatory pathways that use glutamate as a transmitter. These inputs form synaptic connections on the dendrites of excitatory principal neurons that transit signals to other regions or subregions of the amygdala or to extrinsic regions. Principal neurons are thus also called projection neurons since the project out. However, axons of principal neurons also give rise to local connections to inhibitory interneurons that then provide feedback inhibition to the principal neurons. 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.
The scheme of connections just described applies to the neurons of the basolateral complex more so than to neurons within the centro-medial group. For example, while the projection neurons of the basolateral group are excitatory, the projection neurons in the central nucleus tend to be inhibitory in nature. Thus, excitation of neurons in the central nucleus leads to inhibition of target neurons, while inhibition of these projection neurons gives rise to increased output of the target neurons. Whether central amygdala cells are activated by excitatory projection neurons or by way of connections from projection neurons to local interneurons thus influences the ultimate output state of the central amygdala. These connections are consistent with the notion described above that the basolateral group is closely associated with the cerebral cortex and the cortico-medial group with the basal ganglia.
The flow of information through amygdala circuits is modulated by a variety of neurotransmitter systems. Thus, norepinephrine, dopamine, serotonin, and acetylcholine released in the amygdala influences how excitatory and inhibitory neurons interact. Receptors for these various neuromodulators are differentially distributed in the various amygdala nuclei. Also differentially distributed are receptors for various hormones, including glucocorticoid and estrogen. Numerous peptides receptors are also present in the amygdala, including receptors for opioid peptides, oxytocin, vasopressin, corticotropin releasing factor, and neuropeptide Y, to name a few.
In the late 1930s, researchers observed that damage to the temporal lobe resulted in profound changes in fear reactivity, feeding, and sexual behavior. Around mid century, it was determined that damage to the amygdala accounted for these changes in emotional processing. 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 and subnuclear organization of the amygdala, which was not fully appreciated, and partly because the functions measured by behavioral tasks were not well understood.
The early studies of fear used avoidance conditioning tasks. These measure fear in terms of how well an animal leans to avoid shock. However, avoidance is a two stage process in which Pavlovian 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. In the 1980s, researchers began to use tasks that isolated the Pavlovian from the instrumental components of the task to study the brain mechanisms of fear. This strategy allowed a focus on the fear reaction conditioned by the shock rather than on behaviors that avoid the shock.
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 (Figure 7). Studies in rodents have mapped the inputs to and outputs of amygdala nuclei and subnuclei that mediate fear conditioning. 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. 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 (Figure 8). Much has been learned about the cellular and molecular mechanisms within lateral amygdala cells that underlie the plastic changes. In brief, convergence of the strong US inputs to cells that also receive CS inputs results in an elevation of intracellular calcium, and event that triggers a host of molecular responses leading to protein synthesis (Figure 9). The proteins then help strengthen stabilize the CS input synapses, allowing them to respond more strongly to the CS after conditioning. As a result, the CS flows through the amygdala circuits to elicit the fear responses controlled by the central nucleus. Amygdala areas, together with the prefrontal cortex and hippocampus, is involved in the reduction of learned fear through extinction and cognitive regulatory processes.
Although fear is the emotion best understood in terms of brain mechanisms, the amygdala has also been implicated in a variety of other emotional functions. 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. As with aversive conditioning, the lateral, basal, and central amygdala have been implicated in different aspects of reward learning and motivation, though the involvement of these nuclei differs somewhat from their role in fear. The amygdala has also been implicated in emotional states associated with aggressive, maternal, sexual, and ingestive (eating and drinking) behaviors. Less is known about the detailed circuitry involved in these emotional states than is known about fear.
Because the amygdala learns and stores information about emotional events, it is said to participate in emotional memory. Emotional memory is viewed as an implicit or unconscious form of memory and contrasts with explicit or declarative memory mediated by the hippocampus.
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. It is generally thought that these cognitive functions are modulated by the amygdala's processing of the emotional significance of external stimuli. Outputs of the amygdala then lead to the release of hormones and/or neuromodulators in the brain that then alter cognitive processing in cortical areas. For example, via amygdala outputs that ultimately affect the hippocampus, explicit memories about emotional situations are enhanced. For example, glucocorticoid hormone released into the blood stream via amygdala activity travels to the brain and then binds to neurons in the basal amygdala. The latter then connects to the hippocampus to enhance explicit memory. There is also evidence that the amygdala can, through direct neural connections, modulate the function of cortical areas.
Over the past decade, interest in the human amygdala has grown considerably, spurred on by the progress in animal studies and by the development of functional imaging techniques. 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. Further, exposure to emotional faces potently activates the human amygdala. 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. Studies of humans and non-human primates also implicate the amygdala in social behavior. Findings regarding the human amygdala are mainly at the level of the whole region rather than nuclei.
Structural and/or functional changes in the amygdala are associated with a wide variety of psychiatric conditions in humans. Included are various anxiety disorders (PTSD, phobia, and panic), depression, schizophrenia, and autism, to name a few. This does not mean that amygdala causes 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.
The rise in popularity of the amygdala as a research topic should not overshadow the fact that much remains to be learned. Especially important for the future will be studies that attempt to understand whether the importance of the amygdala in fear reflects the importance of fear to the amygdala or whether fear is just the function that has been studied most.
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