TRPV1 signaling as a sex-specific mechanism of contextual fear generalization

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Summary Women are twice as likely as men to develop Post-Traumatic Stress Disorder (PTSD) after a trauma, but the neurobiological basis for this discrepancy is poorly understood. One hallmark symptom of PTSD is a re- experiencing of the trauma in safe situations, a “generalization” phenomenon that can be studied using preclinical rodent models like Pavlovian fear conditioning. Because both women and female rodents exhibit a greater tendency to generalize fear in safe contexts, better insight into potential sex-dependent factors that disrupt aversive context processing could lead to the development of novel treatments for PTSD. Preliminary data from our lab points to a novel role for the endocannabinoid system in conferring a sex-specific susceptibility to contextual fear generalization. Specifically, we observe a TRPV1-mediated increase in contextual fear generalization in females, but not males. A deeper investigation into this provocative finding may open new avenues for therapeutic development for women with PTSD. But in order to identify key areas and mechanisms to target for manipulation, we must first conduct exploratory studies to help guide the direction of larger-scale interrogations. The work we propose here will first determine whether our behavioral effects are selectively mediated by either the dorsal or ventral hippocampus (Aim 1), and then examine potential sex differences in mechanisms of eCB- and fear conditioning-related synaptic plasticity (Aim 2). We will carry out these Aims using a combination of behavioral pharmacology, fluorescent microscopy, biochemistry, and high resolution neuronal structural analysis. Together, these experiments will identify potential mediators of our behavioral effects, opening up our model for more focused interrogation and providing insight into sex-specific mechanisms of fundamental learning and memory processes.