DESCRIPTION (provided by applicant): The amygdala is critical for fear processing and fear regulation. The central amygdala (CeA), once viewed as a passive relay between the amygdala complex and downstream fear effectors, has emerged as an active participant in fear learning. In particular, neurons in the lateral subdivision of the CeA (CeL), which tonically inhibits the medial subdivision of CeA (CeM) and thereby gates fear expression, are thought to encode learned fear. However, the mechanisms by which CeL contributes to fear learning remain unknown. In addition, the link between the role of CeL in fear learning and its known role in fear expression is also unclear. The objective of the proposed project is to elucidate the mechanisms by which the central amygdala contributes to fear learning and orchestrates fear expression in Pavlovian fear conditioning. We will focus on distinct classes of inhibitory neurons in the CeL. Our central hypothesis is that fear conditioning induces cell type-specific synaptic modifications in CeL circuits that serve as fear memory traces. We further propose that these memory traces act to promote the inhibition of CeL output during fear memory recall, thereby disinhibiting CeM and releasing fear expression. We designed an integrated approach, combining molecular genetic tools, in vitro and in vivo electrophysiology, and optogenetic and chemical-genetic techniques, to test our hypotheses in the following Specific Aims: 1) to delineate the functional organization of the CeA inhibitory circuits; 2) to determine the mechanisms of the fear conditioning-induced synaptic plasticity in CeL; and 3) to determine the role of specific CeL inhibitory circuits in fear conditioning. Findings from this project will have important clinical implications, as dysfunction of fear regulation mechanisms is implicated in a number of psychiatric conditions, including generalized anxiety disorder and post-traumatic stress disorder.

PUBLIC HEALTH RELEVANCE: The neural mechanisms of fear processing and fear regulation remain unclear. In the proposed research program, we will determine the synaptic and circuit mechanisms by which the central amygdala mediates fear learning and fear expression in auditory Pavlovian fear conditioning. Findings from this project will have important clinical implications, as impairments in fear processing and fear regulation are core features of several anxiety disorders, including post-traumatic stress disorder (PTSD).