Sex Specific Neuroanatomical Markers Of Vulnerability In Animal Model Of PTSD

描述（由申请人提供）：大多数美国人在一生中都会受到创伤，但只有10%的人会因此患上创伤后应激障碍（PTSD）。然而，女性在创伤后患PTSD的可能性是男性的两倍。确定导致女性PTSD易感性和恢复力的神经生物学因素对于开发更有效的治疗方法至关重要，但对这个问题的基础科学研究普遍缺乏。创伤后应激障碍的特征在于创伤与其相关线索之间的强烈关联，这是一种行为表型，可能是内侧前额叶皮质（mPFC）和杏仁核之间连接中断的结果。在动物模型中，这条通路被证明可以介导条件性恐惧的消退，而未能消退的动物可能是PTSD脆弱性的良好模型。这项提议将探索雄性和雌性大鼠脆弱性和弹性的神经解剖学标志。将在经典的线索恐惧条件反射和消退方案中对动物进行行为表征，确定这些行为测试中变异性的性别差异。使用逆行示踪剂和离子电渗荧光显微注射的组合，mPFC神经元的树突形态，项目杏仁核将在动物中进行分析，表现出高（脆弱）和低（恢复）水平的冻结后灭绝。这些实验将建立恐惧行为变异性的基线性别差异，这将有助于解释未来的性别差异研究。此外，形态学分析将提供一个全面的神经解剖学的脆弱性和弹性在男性和女性的个人资料，从而确定的领域，标志着独特的女性脆弱性。

DESCRIPTION (provided by applicant): A majority of Americans will be exposed to a trauma in their lifetimes, but only 10% of those people will develop Post-Traumatic Stress Disorder (PTSD) as a result. Women, however, are twice as likely as men to develop PTSD after a trauma. Identification of the neurobiological factors that contribute to PTSD susceptibility and resilience in women is critical to developing more effective treatments, but basic science research into this problem is generally lacking. PTSD is characterized by a strong association between the trauma and its associated cues, a behavioral phenotype that may be the result of disrupted connectivity between the medial prefrontal cortex (mPFC) and amygdala. This pathway has been shown in animal models to mediate extinction from conditioned fear, and animals that fail to extinguish may be a good model of PTSD vulnerability. This proposal will explore neuroanatomical markers of vulnerability and resilience in male and female rats. Animals will be behaviorally characterized in classic cued fear conditioning and extinction protocols, identifying sex differences in variability in these behavioral tests. Using a combinatio of retrograde tracer and iontophoretic fluorescent microinjections, the dendritic morphology of mPFC neurons that project to the amygdala will be analyzed in animals that show high (vulnerable) and low (resilient) levels of freezing after extinction. These experiments will establish baseline sex differences in variability in fear behavior, which will be useful for interpreting future sex differences studies. Moreover, morphology analysis will provide a comprehensive neuroanatomical profile of vulnerability and resilience in both males and females, thus identifying areas that signify vulnerability uniquely in females.