The Physiology of Fear: Reconceptualizing the Role of the Central Amygdala in Fear Learning

Abstract

The historically understood role of the central amygdala (CeA) in fear learning is to serve as a passive output station for processing and plasticity that occurs elsewhere in the brain. However, recent research has suggested that the CeA may play a more dynamic role in fear learning. In particular, there is growing evidence that the CeA is a site of plasticity and memory formation, and that its activity is subject to tight regulation. The following review examines the evidence for these three main roles of the CeA as they relate to fear learning. The classical role of the CeA as a routing station to fear effector brain structures like the periaqueductal gray, the lateral hypothalamus, and paraventricular nucleus of the hypothalamus will be briefly reviewed, but specific emphasis is placed on recent literature suggesting that the CeA 1) has an important role in the plasticity underlying fear learning, 2) is involved in regulation of other amygdala subnuclei, and 3) is itself regulated by intra- and extra-amygdalar input. Finally, we discuss the parallels of human and mouse CeA involvement in fear disorders and fear conditioning, respectively.

FIGURE 1.

Subdivisions of the mouse amygdala The basolateral complex (BLA) is composed of the basal (BA) and lateral (LA) nuclei. The central amygdala (CeA) is composed of the centromedial (CEm) and centrolateral (CEl) nuclei. The intercalated cell masses include the dorsal (ITCd), ventral (ITCv), and lateral (ITCl) clusters (87).

FIGURE 2.

Inputs and outputs of the rodent CeA A: intra- and extra-amygdalar CeA inputs. The centrolateral amygdala (CEl) receives direct excitatory input from the auditory cortex (AC), auditory thalamus (AT), pontine parabrachial nucleus (PBN), and lateral nucleus of the amygdala (LA). It also receives indirect excitatory input from the prelimbic cortex (PL) via the posterior paraventricular thalamus (pPVT) as well as indirect inhibitory input from the LA via the dorsal intercalated cell mass (ITCd). The centromedial amygdala (CEm) receives direct excitatory input from the AT and direct inhibitory input from the CEl. It also receives indirect excitatory input from the LA via the BA, as well as indirect inhibitory input from the infralimbic cortex (IL) via the ventral intercalated cell mass (ITCv). B: intra- and extra-amygdalar CeA outputs. The somatostatin-expressing (SOM⁺) cells of the CEl directly inhibit the pPVT, dorsal periaqueductal gray (dPAG), and nucleus tractus solitarius (NTS), as well as the protein kinase C-delta-expressing (PKC-δ⁺) cells of the CEl, which directly inhibit the output neurons of the CEm. The CEm cells directly inhibit the dorsomedial hypothalamus (DMH), rostral ventrolateral medulla (RVLM), and anterior bed nucleus of the stria terminalis (aBNST). Of note, the excitatory projections from the pPVT to the CEl have been shown to preferentially innervate SOM⁺ CEl cells and to release BDNF onto them (107).