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遭受创伤，但只有10%的人会因此患上创伤后应激障碍(PTSD)。然而，女性在创伤后患创伤后应激障碍的可能性是男性的两倍。确定导致女性创伤后应激障碍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，但对这一问题的基础科学研究普遍缺乏。创伤后应激障碍的特征是创伤与其相关线索之间的强烈关联，这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。这一途径已经在动物模型中显示出来，可以调节条件性恐惧的消亡，而未能消退的动物可能是创伤后应激障碍脆弱性的一个很好的模型。这项提议将探索雄性和雌性大鼠的脆弱性和韧性的神经解剖学标记。动物将在经典的线索恐惧条件反射和消退方案中表现出行为特征，在这些行为测试中识别变异性的性别差异。使用逆行示踪剂和离子导入荧光显微注射相结合的方法，将分析在灭绝后表现出高(脆弱)和低(弹性)冰冻水平的动物中投射到杏仁核的mPFC神经元的树突形态。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，形态分析将提供男性和女性脆弱性和复原力的全面神经解剖学概况，从而确定女性特有的脆弱性区域。

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.