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

项目摘要 精神疾病的发展和流行的性别差异是普遍存在的，这表明 在男性和女性中，促进疾病风险和韧性的因素可能是不同的。神经生物学 然而，人们对这种可能性背后的机制知之甚少，因为绝大多数前 已经在雄性身上进行了临床动物研究。此外，行为结果衡量标准用于 了解习得性恐惧主要集中在被动或僵硬的行为上。我们最近确认了 一种几乎只发生在雌性大鼠身上的主动的、逃逸样的条件性恐惧反应(“跳跃”) 并预示着灭绝保持能力的提高。更好地理解潜在的性二相性 驱动这种行为的机制可能会为治疗更严重的疾病开辟新的途径 流行于女性，如创伤后应激障碍。我们建议在这里定义驱动选择的神经电路 条件性飞镖与冰冻，以及它如何与已知的灭绝电路相结合来促进灭绝 留存。我们的初步数据表明，下缘皮质(IL)参与了这一作用，我们将使用药理学、 化学发生和病毒技术探索IL如何向背侧和腹侧投射下降 中脑导水管周围灰质(PAG)可能在主动和被动反应和驱动之间调节一种策略性转换 通过杏仁核中推定的侧支的长期行为灵活性。然后我们将使用复杂的 机器视觉和基于机器学习的工具，用于定义更广泛的行为曲目，其中 DARTING的存在，从而确定了一个多方面的表型，可以提供对机制的洞察 在压力韧性和脆弱性方面存在潜在的个体差异。

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.