Invited reviewInterneurons in the basolateral amygdala
Research highlights
► The amygdala is well known to play a key role in emotional processing. ► Dysfunction of the amygdala plays a central role in many anxiety disorders. ► Here we review the inhibitory micro-circuitry of the basolateral amygdala. ► We point out that there are significant differences between the amygdala and cortical inhibitory circuitry. ► Understanding this circuitry may provide novel targets for the treatment of anxiety disorders.
Introduction
The amygdala is a collection of associated nuclei located in the temporal lobe that is the center of emotion processing in the mammalian brain. Recent interest in the amygdala largely arises from its central role in a simple form of learning known as fear conditioning (Davis and Whalen, 2001, Fanselow and Poulos, 2005, LeDoux, 2003). This is a Pavlovian conditioning procedure in which an emotionally neutral stimulus (the conditioned stimulus, CS), such as a tone or light is contingently paired with an aversive one, typically a mild foot shock. After a small number of pairings subjects learn to associate the two stimuli and now respond with fear to the initially neutral CS. This learnt response, the conditioned response (CR), is rapidly acquired and long lasting (Davis, 1992, LeDoux, 2000). As such, the CR results from subjects learning the association between two sensory stimuli, storing this association and subsequent retrieval of the memory in response to sensing the CS. Once a fear memory has been established, it is generally stable for long periods of time, sometimes a lifetime. However, subsequent repeated presentation of the CS gradually reduces the CR, a process known as extinction (Myers and Davis, 2007, Quirk and Mueller, 2008). In extinction, rather than forgetting the initial learning, subjects form new associations that inform them that the previously conditioned CS is no longer threatening. This therefore represents the learning and storage of new memory such that the original CS is no longer perceived as fearful, and the response to the CS is inhibited (Maren and Quirk, 2004, Pape and Pare, 2010, Quirk and Mueller, 2008).
A large body of data has shown that the amygdala is critically involved in the learning, storage and retrieval of both conditioned fear and extinction (Herry et al., 2008, LeDoux, 1995, Pape and Pare, 2010, Sah et al., 2003). Thus, understanding the function of the amygdala, its intrinsic neural circuits, and the molecular mechanisms that underlie fear conditioning will firstly provide insight into the physiological mechanisms of learning and memory formation in the mammalian brain. Secondly, as there are clear similarities between learnt fear and anxiety in humans, it is believed that understanding the mechanisms that underlie fear conditioning and its dysfunction, may provide a window into the cellular mechanisms that underlie the genesis of disorders such as generalized anxiety, depression and post-traumatic stress (Davis and Whalen, 2001, Quirk and Gehlert, 2003). Moreover, treatments like exposure therapy that are used for a variety of anxiety disorders are largely based on extinction protocols (McNally, 2007). Thus, understanding the cellular mechanisms that underlie extinction inform us about the mechanisms that underpin the treatment of anxiety disorders, and suggest possible targets for the development of new therapies.
The nuclei of the amygdaloid complex can be grouped in to three functionally relevant subdivisions: the centromedial, cortical and basolateral groups. These subdivisions can be identified based on their unique connectivity, immunohistochemical and cytoarchitectural profiles. The anatomy and physiology of the amygdala has been reviewed in detail previously (Alheid et al., 1995, McDonald, 1998, Sah et al., 2003, Swanson and Petrovich, 1998). A converging body of data has established that sensory information from both cortical and subcortical regions enters the amygdala at the level of the basolateral nucleus (BLA). This information is processed within the BLA and transmitted to the central nucleus (CeA). Projections from the CeA target hypothalamic and brainstem structures that evoke the conditioned response (Davis and Whalen, 2001, LeDoux, 2000). These two regions, the BLA and the CeA, and their connections play a central role in the formation and recall of memory traces during fear conditioning and extinction (Maren and Quirk, 2004, Pape and Pare, 2010, Pare et al., 2004). Learning and memory formation in the mammalian brain are generally thought to result from synaptic plasticity at glutamatergic synapses (Bliss and Collingridge, 1993). In agreement with this, both fear conditioning and extinction are accompanied by changes at glutamatergic synapses in the amygdala (Pape and Pare, 2010, Sah et al., 2008). However, emerging evidence indicates that GABAergic synapses within the amygdala also play key roles in both fear conditioning and extinction (Ehrlich et al., 2009). For example, enhancers of GABAergic inhibition in the BLA interfere with learning and expression of conditioned fear (Davis, 1979, Harris and Westbrook, 1998) whereas reduction in GABAergic inhibition has the opposite effect (Tang et al., 2007). Moreover, pharmacological agents that modulate anxiety levels are thought to produce their anxiolytic actions by acting at γ-aminobutyric-acid (GABA) receptors within the amygdala (Rudolph and Mohler, 2006).
Section snippets
GABAergic neurons in the amygdala
The amygdaloid complex (Fig. 1) can be described as an interface of cortical and striatal cell lineages (Swanson and Petrovich, 1998, Waclaw et al., 2010). This feature makes a general discussion of GABAergic neurons in the amygdala a tale of two halves. Both developmentally (Waclaw et al., 2010), and structurally (McDonald, 1992), the BLA is a cortical like structure. As with other cortical regions, it contains two main types of neuron: glutamatergic principal neurons and GABAergic
Conclusions
The amygdala is a temporal lobe structure that is involved in emotional processing. In particular it plays a key role in fear learning and extinction. The BLA is the main route by which sensory information enters the amygdala and much of the plasticity that underlies fear learning is thought to occur at synapses in the BLA. The BLA is a cortical like structure that contains glutamatergic principal neurons and local circuit interneurons; however, the local circuitry of the BLA is just beginning
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Present address: Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 1050 Arastradero Road, Palo Alto, CA 94304-5543, USA.