Genetic dissection of an amygdala CRF circuit for fear and anxiety
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Fear and anxiety are ethological responses to threats and danger in the environment. The central amygdala (CeA) is a brain structure important for fear responses to discrete cues that predict threat. Recent findings indicate that the CeA also contributes to states of sustained apprehension in the absence of discrete cues that characterize anxiety, although less is known about the neural circuitry involved. The stress neuropeptide corticotropin releasing factor (CRF) is anxiogenic and produced by subpopulations of neurons in the CeA and the dorsolateral bed nucleus of the stria terminalis (dlBNST), a structure with strong connections to the CeA. Early models of the neurobiology of fear and anxiety proposed that the CeA promotes fear behaviors but not anxiety behaviors, and the BNST mediates anxiety but not fear. Furthermore, these models also hypothesized that a CRF pathway from the CeA to the dlBNST could be important for anxiety behavior, but this prediction remained untested. Here, the function of CeA CRF (CeA [superscript CRF]) neurons in fear and anxiety was investigated using Cre-dependent viral-genetic tools and male rats that express Cre recombinase from a Crh promoter. CeA [superscript CRF] neurons mediated both stress-induced anxiety and fear behaviors, both of which were dependent on CRF signaling. Additionally, the neuropeptide dynorphin, but not neurotensin, produced by CeA [superscript CRF] neurons was critical for fear and anxiety behaviors. Neurotensin release had no effect on anxiety but dampened fear learning. GABA release from these neurons played a major role in setting the level of anxiety in the basal state. Finally, the CeA [superscript CRF] pathway to the dlBNST was tested for its role in anxiety and was found to be critical for these behaviors. This pathway also recruited CRF signaling and local CRF neurons in the dlBNST to engage anxiety-like behaviors. Collectively, these findings suggest that CeA [superscript CRF] neurons promote both fear and anxiety via the release of GABA and different neuropeptides and a projection to the dlBNST. The data presented here refine early neuroanatomical models of fear and anxiety and provide mechanistic support for recent human primate data suggesting that the CeA and BNST act together to generate negative emotional states.