Sex and circuit-specific determinants of exercise-induced stress resilience

项目摘要 女性比男性更容易患上与压力相关的情绪和焦虑症，这突显了 确定促进妇女抵抗压力的战略的重要性。锻炼对以下方面有广泛的好处 两性的心理健康，但压力保护的程度和潜在的机制是否不同 性别之间的差异是未知的。我们最近发现雌性大鼠对压力缓冲的反应更强 运动的效果要好于男性。自愿车轮运行(WVR)需要一半的时间才能实现对 不可逃避的压力(IS)对雌性大鼠(3周)的抑郁和焦虑样影响(6)比雄性大鼠(6 Wk)。增强女性对运动的压力保护是一种完全未经探索的弹性现象。这个 这项建议的目标是检查性别和电路特定的决定因素的过程中的多个单位 分析(分子、细胞、电路、性和行为)。VWR通过以下方式预防IS的行为后遗症 抑制IS时中缝背核(DRN)5-羟色胺(5-HT)能神经元的激活 运动抑制DRN-5HT活性的机制尚不清楚。我们的初步数据提供了强有力的 两性的应激抵抗是由于感觉运动回路(背侧)的参与而产生的 纹状体(DLS)负责维持运动。我们发现DLS被定位为抑制DRN 通过直接GABA能投射的5HT神经元(DLS-DRN回路)和6wk的VWR增强活动 在IS期间的DLS-DRN电路。重要的是，尽管DLS被要求在这两个环境中维持VWR行为 在性别上，DLS对VWR的控制在雌性(4d)早于雄性(4wk)。DLS中的多巴胺(DA)对 对DLS依赖的行为，女性刺激诱发的多巴胺(DA)已知增加 与男性的反应相比较。这很可能是VWR的情况，因为仅仅几轮VWR就会激活D1 雌性DLS内有受体表达的神经元，而雄性则没有。VWR期间DLS的快速招募 雌性可以加速DLS-DRN回路的可塑性，这是抑制应激诱导的5HT所必需的 活动。事实上，雌性动物对3wk vwr应激的抵抗力取决于DLS-DRN回路的活性 在IS期间。这些数据表明，一旦运动由DLS控制，现在DLS-DRN回路 积极应对未来的逆境，从而抑制DRN，从而增强抗逆性。我们假设 DLS神经集合将运动与应激抵抗联系起来，并且对运动特别敏感 女性，因为与男性相比，女性对运动的DA反应更强。区段遗传 在最初的锻炼和以后的压力中标记、记录和操纵神经回路活动的方法将是 用于1)确定DLS在运动诱导的应激抵抗和加速发展中的作用 女性的应激抵抗，2)确定DLS在运动应激表达中的作用 两性抗性，以及3)确定DA在驱动VWR对VWR的加速应激抵抗中的作用 在决定一种有食欲的感觉运动体验是否能够抵抗压力方面，女性也是如此。

Project Summary Women are more susceptible than are men to stress-related mood and anxiety disorders, underscoring the importance of identifying strategies to promote stress resistance in women. Exercise affords broad benefits to mental health in both sexes, but whether the degree of stress protection and underlying mechanisms differ between sexes is unknown. We recently discovered that female rats are more responsive to the stress-buffering effects of exercise than males. It takes voluntary wheel running (WVR) half the time to enable protection against the depression- and anxiety-like effects of inescapable stress (IS) in female rats (3 wk) than it does in males (6 wk). Enhanced stress protection from exercise in females is an entirely unexplored resilience phenomenon. The goal of this proposal is to examine the sex- and circuit-specific determinants of this process across multiple units of analysis (molecular, cellular, circuits, sex, and behavior). VWR prevents the behavioral sequelae of IS by constraining activation of serotoninergic (5HT) neurons in the dorsal raphe nucleus (DRN) during IS, but the mechanism by which exercise constrains DRN 5HT activity is unknown. Our preliminary data provide strong evidence that stress resistance in both sexes arises from engagement of sensorimotor circuits (dorsolateral striatum; DLS) responsible for maintaining exercise. We have found that the DLS is positioned to inhibit DRN 5HT neurons through a direct GABAergic projection (DLS-DRN circuit), and 6 wk of VWR potentiates the activity of the DLS-DRN circuit during IS. Importantly, although the DLS is required to maintain VWR behavior in both sexes, the DLS governs VWR earlier in females (4 d) than in males (4 wk). Dopamine (DA) in the DLS contributes to DLS-dependent behavior and females are known to have heightened stimulus-evoked dopamine (DA) responses compared to males. This is likely the case with VWR, as just a few bouts of VWR activates D1 receptor-expressing neurons in the DLS of females, but not males. The rapid recruitment of the DLS during VWR in females could accelerate plasticity in the DLS-DRN circuit required for constraining stress-induced 5HT activity. Indeed, stress resistance from 3 wk of VWR in females depends on activity of the DLS-DRN circuit during IS. These data suggest that once exercise becomes governed by the DLS, the DLS-DRN circuit now responds actively to future adversity, thereby inhibiting the DRN & enabling stress resistance. We hypothesize that DLS neural ensembles link exercise to stress resistance and are particularly responsive to exercise in females, due to heightened DA responses to exercise in females compared to males. Intersectional genetic approaches that tag, record, and manipulate neural circuit activity during initial exercise and later stress will be used to 1) identify the role of the DLS in the development of exercise-induced stress resistance and accelerated stress resistance in females, 2) determine the role of the DLS in the expression of exercise-induced stress resistance in both sexes, and 3) identify the role of DA in driving accelerated stress resistance from VWR in females and in determining whether an appetitive, sensorimotor experience enables stress resistance.