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

边缘下电路控制威胁响应中的性别依赖性开关

• 批准号: 10033671
• 负责人: REBECCA M SHANSKY
• 金额: $ 50.33万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10033671
• 关键词: Amygdaloid structure; Anatomy; Animal Experimentation; Aversive Stimulus; Behavior; Behavioral; Clinical; Complex; Conditioned Reflex; Crete; Data; Development; Disease; Disease susceptibility; Dorsal; Equilibrium; Exhibits; Extinction (Psychology); FOS gene; Female; Freezing; Fright; Goals; Immunofluorescence Immunologic; Individual Differences; Investigation; Learning; Link; Machine Learning; Measures; Mediating; Mediator of activation protein; Mental disorders; Modeling; Neurobiology; Odors; Outcome; Outcome Measure; Pain; Pattern; Performance; Pharmacology; Phenotype; Post-Traumatic Stress Disorders; Pre-Clinical Model; Prevalence; Rattus; Risk Factors; Risk Marker; Role; Sex Differences; Shock; Stimulus; Stress; Structure; Synapses; Techniques; Testing; Time; Viral; Woman; Work; base; behavioral outcome; behavioral response; cohort; conditioned fear; conditioning; coping; disorder risk; flexibility; improved; insight; machine vision; male; men; midbrain central gray substance; neural circuit; neurobiological mechanism; novel; pre-clinical; predictive marker; prevent; recruit; relating to nervous system; resilience; response; selective expression; sex; sexual dimorphism; stress resilience; success; tool; translational neuroscience; trauma exposure

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.

项目概要 精神疾病的发展和患病率存在​​广泛的性别差异，这表明 促进疾病风险和恢复力的因素在男性和女性中可能不同。神经生物学 然而，人们对这种可能性背后的机制知之甚少，因为绝大多数预 已在雄性身上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僵硬的行为上。我们最近确定 老鼠身上出现一种活跃的、类似逃避的条件性恐惧反应（“飞镖”），几乎只发生在雌性老鼠身上 并预测了消光保留的改善。更好地理解潜在的性别二态性 驱动这种行为的机制可能会为治疗更严重的疾病开辟新途径。 常见于女性，如创伤后应激障碍（PTSD）。我们在这里建议定义驱动选择的神经回路 条件性飞镖与冻结，以及如何与已知的灭绝回路相结合以促进灭绝 保留。我们的初步数据表明边缘下皮层 (IL) 发挥着这一作用，我们将使用药理学、 化学遗传学和病毒技术来探究 IL 如何向下投射到背侧和腹侧 导水管周围灰质（PAG）可能介导主动和被动响应和驱动之间的策略切换 通过杏仁核中假定的抵押品实现长期行为灵活性。然后我们将使用复杂的 基于机器视觉和机器学习的工具来定义更广泛的行为库，其中 飞镖的存在，从而确定了多方面的表型，可以提供对机制的深入了解 压力恢复能力和脆弱性的潜在个体差异。