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

运动引起的压力恢复能力的性别和循环特定决定因素

• 批准号: 10650862
• 负责人: BEN N GREENWOOD
• 金额: $ 54.93万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-21 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650862
• 关键词: Acceleration; Address; Anxiety; Anxiety Disorders; Automobile Driving; Behavior; Behavioral; Brain; Chemosensitization; Chronic; Communication; Corpus striatum structure; Data; Desire for food; Development; Disease; Dopamine; Dopamine D1 Receptor; Exercise; Female; Fluorescent in Situ Hybridization; Future; Genes; Genetic; Goals; Knowledge; Link; Maintenance; Mediating; Mental Depression; Mental Health; Molecular; Mood Disorders; Motivation; Motor; Neurons; Organ; Outcome; Periodicity; Peripheral; Phase; Positioning Attribute; Predisposition; Prefrontal Cortex; Process; Property; Rattus; Resistance; Role; Running; Scanning; Sensorimotor functions; Serotonin; Sex Differences; Signal Transduction; Stimulus; Stress; Substantia nigra structure; System; Testing; Time; Trauma; Woman; behavioral outcome; dorsal raphe nucleus; emotion regulation; experience; experimental study; genetic approach; male; men; neural; neural circuit; novel; optogenetics; prevent; receptor expression; recruit; release factor; resilience; resistance exercise; response; sedentary; sensorimotor system; sex; stress management; stress resilience; treadmill training; treatment strategy

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.

项目摘要 女性比男性更容易受到压力有关的情绪和焦虑症，强调了 确定促进女性压力抵抗力的策略的重要性。运动为 男女的心理健康，但是压力保护程度和潜在机制是否有所不同 在性别之间是未知的。我们最近发现，雌性大鼠对缓冲压力更敏感 运动的影响比男性。它需要自愿行驶（WVR）的一半时间才能防止 雌性大鼠（3周）中不可避免的应激的抑郁和焦虑样影响比男性中的抑郁症（3周）（6周）（6 WK）。女性锻炼的压力得到增强是一种完全未开发的弹性现象。这 该建议的目标是检查多个单元的性别和电路特定的决定因素 分析（分子，细胞，电路，性别和行为）。 VWR防止了IS的行为后遗症 在IS期间，在背侧raphe核（DRN）中限制了5-ht神经元的激活，但是 运动限制DRN 5HT活性的机制尚不清楚。我们的初步数据提供了强大的数据 两性抗压力性的证据来自感觉运动电路（背外侧） 纹状体； DLS）负责维持运动。我们发现DLS定位可抑制DRN 5HT神经元通过直接GABA能投影（DLS-DRN电路）和6周的VWR增强了活动 在IS期间的DLS-DRN电路。重要的是，尽管需要DLS维持两者的VWR行为 性别，DLS在女性（4 d）中比男性（4周）更早地控制VWR。 DLS中的多巴胺（DA）贡献 已知对DLS依赖性行为和女性的行为增强了刺激诱发的多巴胺（DA） 与男性相比的反应。 VWR可能是这种情况，因为只有几次VWR激活D1 女性DLS中表达受体的神经元，而不是男性。 VWR期间DLS的快速招募 在女性中，在约束应力诱导的5HT所需的DLS-DRN电路中可以加速可塑性 活动。实际上，女性3周VWR的应力抗性取决于DLS-DRN电路的活性 在IS。这些数据表明，一旦锻炼由DLS支配，DLS-DRN电路现在 积极回应未来的逆境，从而抑制了DRN并启用压力抗性。我们假设 DLS神经合奏将运动与压力抗性链接链接，并且特别敏感 与男性相比，女性对女性运动的反应提高，女性。交叉遗传 在初次锻炼期间的标签，记录和操纵神经电路活动的方法将是 使用1）确定DLS在运动引起的压力抗性发展中的作用并加速 女性的压力抗性，2）确定DLS在运动诱导的应激表达中的作用 性别的抗性和3）确定DA在驱动VWR加速应力抗性中的作用 女性并确定食欲，感觉运动体验是否具有压力抗性。