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，其特征在于创伤发生时的极端恐惧感，在创伤后数月和数年内具有特征性的重新体验、回避和过度觉醒症状。PTSD的患病率约为6%，但可能发生在经历过严重心理创伤的受试者中高达25%，如退伍军人，难民和袭击受害者。决定那些与那些没有发展PTSD的人相比的差异风险是多因素决定的：1）它部分是遗传的，创伤后PTSD的风险遗传率约为30-40%; 2）它与性别有关，女性在创伤后发展PTSD的风险约为男性的两倍; 3）它部分取决于过去的个人历史，包括成人和儿童创伤以及可能差异介导恐惧和情绪调节的心理因素。我们最近利用会聚遗传学方法鉴定PACAP/PAC 1 R受体通路与PTSD和人类条件性恐惧失调相关1。此外，我们发现，这种关联只在女性中发现，并且主要的多态性位于雌激素反应元件内。此外，我们发现PAC 1 R和PACAP mRNA在啮齿动物模型中被恐惧条件化或雌激素替代诱导。总之，这些数据有力地表明，PACAP/PAC 1 R通路的扰动参与了PTSD的异常恐惧反应，特别是在女性中。我们现在希望通过研究雌激素和遗传多态性差异调节女性恐惧消退的机制来扩展这些数据。这项工作将进一步了解性别依赖的过程可能会特别导致压力相关的生物反应的差异风险。

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.