Sex-dependent pain processing circuitry in classical Pavlovian fear conditioning

项目摘要 在精神疾病的发展和流行方面，性别差异很普遍，这表明， 促进疾病风险和复原力的因素在男子和妇女中可能不同。的神经生物学 然而，这种可能性背后的机制却知之甚少，因为绝大多数的前 在雄性动物中进行了临床动物研究。此外，行为结果测量用于 了解习得性恐惧主要集中在被动或冻结行为上。我们最近发现 大鼠中几乎仅在雌性中发生的一种活跃的、类似逃跑的条件性恐惧反应（“快速移动”） 并且与对足部电击无条件刺激的增强反应相关。更好的 了解驱动这种行为的潜在性二态性机制可能会开辟新的途径 用于治疗女性更常见的疾病，如创伤后应激障碍。我们已经收集了初步数据 暗示前扣带回（ACC）到中脑导水管周围灰质腹外侧的神经投射 （vlPAG）作为一种潜在的新颖的、性别依赖的回路，其将感觉疼痛信息整合到条件反射中。 和无条件的恐惧反应我们建议在这里探讨性别差异，在这两个电路 结构和功能水平。首先，我们将使用逆行示踪剂进行ACC的定量映射- vlPAG投射，那么我们将使用trans-vlPAG来表征ACC传入的突触后vlPAG靶。 突触病毒方法结合荧光免疫组织化学。接下来，我们将记录ACC-vlPAG 使用纤维光度测定法将活动与刺激呈现相关联， 行为反应，最后测试因果关系的作用，这个电路在驱动飞镖使用特定的电路 化学遗传学技术总之，这些研究可以提供对性别依赖性回路机制的深入了解 潜在的压力恢复力和脆弱性的个体差异。

Project Summary Sex differences in the development and prevalence of mental illnesses are widespread, suggesting that the factors that promote disease risk and resilience may be distinct in men and women. The neurobiological mechanisms underlying this possibility are poorly understood, however, because the vast majority of pre- clinical animal research has been conducted in males. In addition, the behavioral outcome measures used to understand learned fear have focused predominantly on passive, or freezing behavior. We recently identified an active, escape-like conditioned fear response in rats (“darting”) that occurred almost exclusively in females and was associated with an augmented response to the foot shock unconditioned stimulus. A better understanding of potentially sexually dimorphic mechanisms that drive this behavior could open new avenues for treatment of disorders that are more prevalent in women, like PTSD. We have collected preliminary data implicating the neural projections from the anterior cingulate (ACC) to ventrolateral periaqueductal gray (vlPAG) as a potentially novel, sex-dependent circuit that integrates sensory pain information into conditioned and unconditioned fear responses. We propose here to explore sex differences in this circuit at both the structural and functional level. First, we will use a retrograde tracer to perform a quantitative mapping of ACC- vlPAG projections, then we will characterize the post-synaptic vlPAG targets of ACC afferents using trans- synaptic viral approaches combined with fluorescent immunohistochemistry. Next, we will record ACC-vlPAG activity during fear conditioning using fiber photometry to correlate activity to stimulus presentation and behavioral responses, and finally test the causal role this circuit plays in driving darting using circuit-specific chemogenetic techniques. Together, these studies can provide insight into sex-dependent circuit mechanisms underlying individual differences in stress resilience and vulnerability.