The Impact of Estrogen and PAC1R Genotype on Fear Extinction in Women with PTSD

描述（由申请人提供）：创伤后应激障碍（PTSD）是一种适应不良和使人衰弱的精神障碍，其特征是在创伤发生时极度恐惧，在创伤发生后的几个月和几年内出现特征性的再体验、逃避和过度觉醒症状。PTSD的患病率约为6%，但在经历过严重心理创伤的受试者中，如退伍军人、难民和袭击受害者中，可发生高达25%的PTSD。PTSD患者与非PTSD患者的差异风险是多重决定的：1)部分是遗传的，创伤后PTSD的遗传风险约为30-40%；2)与性别有关，女性在创伤后患PTSD的风险大约是男性的两倍；3)部分依赖于过去的个人历史，包括成人和童年创伤和心理因素，这些因素可能会对恐惧和情绪调节产生差异。我们最近利用趋同遗传方法确定PACAP/PAC1R受体通路与创伤后应激障碍和人类条件恐惧失调有关1。此外，我们发现这种关联仅在女性中发现，并且主要多态性位于雌激素反应元件中。此外，我们发现在啮齿类动物模型中，恐惧条件或雌激素替代会诱导PAC1R和PACAP mRNA的表达。综上所述，这些数据有力地表明，PACAP/PAC1R通路的扰动与PTSD潜在的异常恐惧反应有关，尤其是在女性中。我们现在希望通过研究雌激素和基因多态性对女性恐惧消退的不同调节机制来扩展这些数据。这项工作将进一步加深我们对性别依赖过程如何具体导致与压力相关的生物反应的不同风险的理解。

DESCRIPTION (provided by applicant): Post-traumatic stress disorder (PTSD) is a maladaptive and debilitating psychiatric disorder characterized by an extreme sense of fear at the time of trauma occurrence, with characteristic re-experiencing, avoidance, and hyperarousal symptoms in the months and years following the trauma. PTSD has a prevalence of approximately 6%, but can occur in up to 25% of subjects who have experienced severe psychological trauma, such as combat veterans, refugees, and assault victims. The differential risk determining those who do vs. those who do not develop PTSD is multi-determined: 1) it is in part genetic, with approximately a 30-40% risk heritability for PTSD following trauma; 2) it in par depends on sex, with women having approximately twice the risk as men to develop PTSD following trauma; and 3) it in part depends on past personal history, including adult and childhood trauma and psychological factors which may differentially mediate fear and emotion regulation. We have recently utilized convergent genetic approaches to identify the PACAP/PAC1R receptor pathway as being associated with PTSD and with dysregulation of conditioned fear in humans1. Further, we found that this association was only found in females, and that the primary polymorphism lay within an Estrogen Response Element. Additionally, we found that PAC1R and PACAP mRNA are induced with fear conditioning or estrogen replacement in rodent models. Together, these data strongly suggest that perturbations in the PACAP/PAC1R pathway are involved in abnormal fear responses underlying PTSD, particularly in females. We now wish to extend these data by examining the mechanisms by which estrogen and genetic polymorphisms differentially modulate fear extinction in women. This work will further our understanding of how sex-dependent processes may specifically lead to differential risk for stress-related biological responses.