Neural circuits and mechanisms underlying active and passive stress coping

项目摘要 在人类和其他哺乳动物中，应激源适应的一个关键方面涉及选择适当的应对方式 回应。积极的应对反应集允许维持较低水平的糖皮质激素应激 荷尔蒙和交感神经活动，部分是由于实际的或感觉到的对厌恶刺激的作用，以及何时 主动反应受到限制，如在被动应对集中，行为被动性增加，HPA和 同情的反应被夸大了。在这方面，HPA和自主系统的海拔高度是由 过度偏向消极应对导致精神疾病和系统性疾病的发生。我们的 使用特定路径的光遗传电路分析的未发表数据揭示了两条平行的路径 从尾侧和吻侧的前额叶(Cpl和Rpl)皮质，支配大鼠的背外侧和腹外侧区 中脑导水管周围灰质(dlPAG和vlPAG)，分别促进主动行为和防止被动行为，在 对急性压力源的反应。基于这些初步数据，我们将检验以下假设 在这些途径中，需要促进积极的应对，而在慢性疾病中，它们的影响会减弱 应激条件使动物偏向于被动应对。第一个目标将决定活动如何变化 PAG内PL投射神经元与慢性应激后主动和被动应对行为的关系 与之前没有接触过的老鼠相比。AIMS 2和AIMS 3将利用路径特定的光遗传操作 评估急性应激条件下Cpl-dlPAG或Rpl-vlPAG通路是否失活 增加被动行为和夸张的HPA和交感神经激活。相反，我们将评估 在慢性应激大鼠中增加上述两种途径中的任何一种的活动是否可以挽救主动应对 SET增加了主动行为，减弱了HPA和交感神经输出。第四个目标是，我们将 解决每个电路功能之间的互补关系(即，Cpl-dlPAG途径促进 主动应对集；RPL-vlPAG通路防止被动应对集)，因为这些数据暗示 一条赛道比另一条赛道占优势。在这里，我们将利用顺行跨突触病毒策略来 光遗传学检测cpl-dlPAG通路是否参与vlPAG作为下游抑制因子 在CVS条件下，被动行为和防止夸大的HPA和交感神经激活。这些 研究将为理解压力应对的神经调节提供一个新的框架 应激相关的精神疾病-通过阐明一种新的回路和活动模式的反应 急性和慢性病，以及易感性和复原力概念的扩展，以涵盖 行为、内分泌和生理特征。

Project Summary A key aspect of stressor adaptation in humans and other mammals involves the selection of appropriate coping responses. The active coping response set allows for the maintenance of lower levels of glucocorticoid stress hormones and sympathetic activity, due in part to the actual or perceived agency over aversive stimuli, and when active responses are restricted, such as in the passive coping set, behavioral passivity increases and HPA and sympathetic responses are exaggerated. In this regard, elevations in HPA and autonomic systems resulting from over-biasing toward passive coping contribute to psychiatric and systemic disease pathogenesis. Our unpublished data using pathway-specific optogenetic circuit analyses have revealed that two parallel pathways from caudal and rostral prelimbic (cPL and rPL) cortex, innervating dorsolateral and ventrolateral subdivisions of periaqueductal gray (dlPAG and vlPAG), that promote active and prevent passive behaviors, respectively, in response to acute stressors. Based on these preliminary data, we will examine the hypotheses that one or both of these pathways are required to promote an active coping set, whereas their diminished influence under chronic stress conditions biases the animal toward a passive coping set. The first aim will determine how activity changes in PAG projector neurons in PL correlate with active and passive coping behavior following chronic stress compared to rats with no previous exposure. Aims 2 and 3 will utilize pathway specific optogenetic manipulations to evaluate whether inactivation of either cPL–dlPAG or rPL–vlPAG pathways under acute stress conditions increases passive behavior and exaggerated HPA and sympathetic activation. Conversely, we will evaluate whether increasing activity in either of these pathways in chronically stressed rats can rescue an active coping set involving increased active behavior, and attenuated HPA and sympathetic output. In the fourth aim, we will address the complementary relationship between each circuit’s function (i.e., cPL–dlPAG pathway promotes an active coping set; rPL–vlPAG pathway prevents a passive coping set), since these data implicate the predominance of one circuit over the other. Here, we will utilize an anterograde transsynaptic viral strategy to optogenetically test whether the cPL–dlPAG pathway engages vlPAG as a downstream mediator for restraining passive behavior and preventing exaggerated HPA and sympathetic activation under CVS conditions. These studies will advance a new framework for understanding the neural regulation of stress coping for translation to stress-related psychiatric diseases— by elucidating a novel circuitry and activity patterns of responses under acute and chronic conditions, and the expansion of the concepts of susceptibility and resilience to encompass behavioral, endocrine and physiological features.