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 Our unpublished data using pathway-specific optogenetic circuit analyses have revealed that two parallel pathways from caudal and rostral prelimbic (cPL and rPL) cortex,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适应压力的一个关键方面涉及选择适当的应对方式 应答积极应对反应集允许维持较低水平的糖皮质激素应激 激素和交感神经活动，部分原因是由于实际或感知的机构对厌恶刺激，当 主动反应受到限制，例如在被动应对设置中，行为被动性增加，HPA和 同情的反应被夸大了。在这方面，HPA和自主系统的升高是由 过度偏向于被动应对有助于精神和系统性疾病的发病机制。我们 使用通路特异性光遗传学电路分析的未发表数据显示， 从尾侧和吻侧前边缘（cPL和rPL）皮质，支配背外侧和腹外侧亚部的 中脑导水管周围灰质（dlPAG和vlPAG），分别促进主动和防止被动行为， 急性应激反应。根据这些初步数据，我们将检验其中一个或两个假设 需要这些途径来促进积极的应对设置，而在慢性 压力条件使动物偏向于被动的应对方式。第一个目标将决定活动如何变化 在PAG投射神经元中PL与慢性应激后的主动和被动应对行为相关 与之前没有接触过的大鼠相比。目的2和3将利用途径特异性光遗传学操作 评价在急性应激条件下cPL-dlPAG或rPL-vlPAG通路的失活是否 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 在慢性应激的大鼠中，增加这些通路中的任何一个的活性是否可以挽救积极的应对 包括增加的主动行为和减弱的HPA和交感神经输出。第四个目标，我们将 解决每个电路功能之间的互补关系（即，cPL-dlPAG通路促进了 主动应对设置; rPL-vlPAG途径防止被动应对设置），因为这些数据涉及 一个电路优于另一个电路。在这里，我们将利用顺行跨突触病毒策略， 光遗传学测试cPL-dlPAG途径是否接合vlPAG作为下游介体用于抑制细胞凋亡。 被动行为和防止CVS条件下过度的HPA和交感神经激活。这些 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， 压力相关的精神疾病-通过阐明一种新的电路和活动模式的反应， 急性和慢性疾病，以及易感性和恢复力概念的扩展， 行为、内分泌和生理特征。