Infralimbic circuit control over a sex-dependent switch in threat responding

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”） 并且预测了改进的消光保持率。更好地理解潜在的性二态性 驱动这种行为的机制可以为治疗更严重的疾病开辟新的途径。 在女性中普遍存在，比如创伤后应激障碍我们建议在这里定义的神经电路，驱动选择的 条件反射与冻结，以及如何与已知的灭绝电路相结合，以促进灭绝 潴留我们的初步数据暗示边缘下皮层（IL）在这一作用中，我们将使用药理学， 化学遗传学和病毒技术来探测IL如何向下投射到背侧和腹侧， 中脑导水管周围灰质（PAG）可能介导主动和被动反应和驱动之间的策略转换 通过杏仁核中假定的侧支来实现长期的行为灵活性。然后我们将使用复杂的 基于机器视觉和机器学习的工具，以定义更广泛的行为库， darting存在，从而确定了一个多方面的表型，可以提供深入了解的机制 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 predictive of improved extinction retention. 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 propose here to define the neural circuitry that drives the selection of conditioned darting vs. freezing, and how that integrates with known extinction circuits to promote extinction retention. Our preliminary data implicate the infralimbic cortex (IL) in this role, and we will use pharmacological, chemogenetic, and viral techniques to probe how descending IL projections to the dorsal and ventral periaqueductal gray (PAG) may mediate a strategic switch between active and passive responding and drive long-term behavioral flexibility through putative collaterals in the amygdala. We will then use sophisticated machine vision and machine learning-based tools to define the broader behavioral repertoires within which darting exists, thereby identifying a multifaceted phenotype that could provide insight into the mechanisms underlying individual differences in stress resilience and vulnerability.