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

总结 女性在创伤后患创伤后应激障碍（PTSD）的可能性是男性的两倍，但 这种差异的神经生物学基础知之甚少。创伤后应激障碍的一个标志性症状是 在安全的情况下经历创伤，这是一种“泛化”现象，可以使用 临床前啮齿动物模型，如巴甫洛夫恐惧条件反射。因为女性和雌性啮齿动物都表现出 更倾向于在安全的环境中概括恐惧，更好地洞察潜在的性别依赖因素， 破坏厌恶性的背景处理可能会导致创伤后应激障碍的新疗法的发展。初步 我们实验室的数据指出，内源性大麻素系统在赋予性别特异性 对情境恐惧泛化的易感性。具体来说，我们观察到TRPV1介导的增加， 女性的情境恐惧泛化，但男性则不然。对这一挑衅性发现的深入调查 可能为PTSD女性患者的治疗开发开辟新的途径。但是为了确定关键区域 和机制的目标操纵，我们必须首先进行探索性研究，以帮助指导 大规模审讯的方向。我们在这里提出的工作将首先确定我们的行为是否 效应选择性地由背侧或腹侧海马介导（Aim 1），然后检查 eCB和恐惧条件相关突触可塑性机制的潜在性别差异（目的2）。我们 将使用行为药理学，荧光显微镜， 生物化学和高分辨率神经元结构分析。总之，这些实验将确定 我们的行为效应的潜在中介，开放我们的模型，更集中的审讯， 提供对基本学习和记忆过程的性别特异性机制的深入了解。

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.