The role of basal forebrain GABAergic neurons in fear expression and inhibition.

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PROJECT SUMMARY Heightened threat response and dysregulation of emotional learning and memory are key characteristics of fear-related disorders such as post-traumatic stress disorder. The basal forebrain (BF) is considered a crucial structure in the regulation of fear learning and memory through the modulation of arousal, vigilance, and motivation salience. However, the role of specific BF cell types in the expression of conditioned fear behaviors remains unclear. Gamma-Aminobutyric acid (GABA)-containing neurons are one of the most abundant BF cell types, are activated in response to threat-predictive cues, and project broadly throughout the brain. More importantly they project to the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) which are essential brain regions in fear association and expression. In this proposal I will investigate the role of BF GABAergic neurons and their long-range projections in cued fear expression and inhibition. In Aim 1 I investigated the contribution of BF GABAergic activity on expression and extinction of cued fear memory. My research revealed a time-dependent role for this population in cue-evoked freezing, wherein GABAergic activity was required for memory expression at remote but not early time points after learning. For Aim 2 I will examine BF GABAergic projections to the BLA and mPFC during fear expression. For Exp. 2.1 and Exp. 2.2 I will use in vivo calcium imaging and optogenetic approaches to assesses the role basal forebrain projections to mPFC and BLA during cued fear memory expression. To examine the effect of BF GABAergic afferents in mPFC and BLA activity in Exp. 2.3, I will use in vitro electrophysiology. In Aim 3, I delineate plans for postdoctoral research, including the identification of a postdoctoral fellowship mentor and institution, and the use of computational methods to examine neural circuits in risk assessment behavioral assays. The results from this proposal will broaden our understanding on inhibitory circuits that underlie fear expression and provide an insight for how fear memory circuits shift at remote timepoints.