Neural circuits and mechanisms underlying active and passive stress coping

主动和被动压力应对的神经回路和机制

• 批准号: 10681051
• 负责人: RYAN T LALUMIERE
• 金额: $ 67.13万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681051
• 关键词: Acute; Animals; Attenuated; Aversive Stimulus; Behavior; Behavioral; Chronic; Chronic stress; Coping Behavior; Data; Development; Disease; Disease susceptibility; Endocrine; Exposure to; Freezing; Functional disorder; Future; Glucocorticoids; Hormones; Human; Immobilization; Intervention; Link; Maintenance; Mammals; Maps; Measures; Medial; Mediating; Mediator; Mental disorders; Nature; Neural Pathways; Neurobiology; Neurons; Neurosecretory Systems; Output; Pathogenesis; Pathway interactions; Pattern; Physiological; Positioning Attribute; Predisposition; Prefrontal Cortex; Rattus; Recording of previous events; Rodent; Role; Shock; Stress; Stress and Coping; Synapses; System; Systemic disease; Testing; Translations; Viral; acute stress; base; coping; midbrain central gray substance; neural; neural circuit; neuromechanism; neuroregulation; novel; optogenetics; pressure; prevent; resilience; response; restraint; stress resilience; stressor

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 Our unpublished data using pathway-specific optogenetic circuit analyses have revealed that two parallel pathways from caudal and rostral prelimbic (cPL and rPL) cortex,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.

项目摘要 人类和其他哺乳动物压力源适应的关键方面涉及选择适当的应对 回答。主动应对响应集可以维持较低水平的糖皮质激素应力 骑马和同情活动，部分是由于对厌恶刺激的实际或感知的代理 主动响应受到限制，例如在被动应对集中，行为被动性提高，HPA和HPA和 同情反应被夸大了。在这方面，HPA和自主系统的高程是由 对被动应对的过度偏见有助于精神病和全身性疾病发病机理。我们的 使用途径特异性的光遗传电路分析的未发表的数据表明，两个平行途径 从尾骨和鼻鼻序（CPL和RPL）皮质中，支配双层和腹外侧细分 分别在 对急性应激源的反应。基于这些初步数据，我们将研究一个或两个的假设 这些途径需要促进主动应对集，而它们在慢性下的影响减弱 压力状况使动物偏向被动应对集。第一个目标将决定活动的变化 在PL中的PAG投影剂神经元中，与慢性应激后的主动和被动应对行为相关 与以前没有暴露的大鼠相比。目标2和3将利用途径特定的光遗传操作 评估在急性应力条件下CPL -DLPAG还是RPL -VLPAG途径的失活是 增加被动行为，夸张的HPA和交感神经激活。相反，我们将评估 在慢性压力大鼠中，这两种途径中的两种途径中的活动是否增加可以挽救主动应对 设置涉及增加的主动行为，并减弱HPA和交感神经输出。在第四个目标中，我们将 解决每个电路功能之间的完整关系（即CPL – DLPAG途径促进 主动应对集； RPL – VLPAG途径可防止被动应对集），因为这些数据暗示 一个电路优于另一个电路。在这里，我们将利用顺行的透射性病毒策略 通过光源测试CPL – DLPAG途径是否将VLPAG作为下游介体与限制 在CVS条件下，被动行为并防止夸张的HPA和交感神经激活。这些 研究将推进一个新的框架，以理解压力应对的神经调节以翻译为 与压力有关的精神病 - 通过阐明新的电路和反应的活性模式 急性和慢性条件，以及易感性和弹性概念包含的概念的扩展 行为，内分泌和物理特征。