Development of Defensive Behavior and Social Stress Consequences

项目摘要/摘要 社会压力对一生的身心健康都有不利影响，其影响可能 在青春期尤其重要，因为这是一个实质性增长和重组的时期 大脑回路。与男性相比，社会压力对女性的影响也不同，尽管大多数 研究主要集中在男性身上。建议的研究使用了社会压力的居民入侵者模型。 我们精炼地理解了个体如何应对反复的社会压力，以及这是如何决定的 反复社会压力对与抑郁和受损相关的行为的个体后果 认知功能。我们的研究重点是蓝斑(LC)去甲肾上腺素系统，它是一种主要的 压力反应系统，调节觉醒和认知对压力的反应。工作假说 这项研究的框架是，压力脆弱性的个体差异是由于 在应激状态下调节LC活动的回路。具体地说，LC的兴奋性调节由 促肾上腺皮质激素释放因子(CRF)和食欲素能传入被认为是被动应对的基础 以过度唤醒为特征的压力相关障碍的风格和脆弱性。相比之下， LC的抑制性脑啡肽输入是逆调节的，并与更积极的应对有关 战略和减少对这些疾病的脆弱性。我们假设激活LC的输入和LC- 抑制输入在发育过程中和性别之间的变化是不同的。这一假设在3年内得到了检验。 使用技术方法的特定目标，包括细胞测量受体表达和 运输，行为大鼠的体内电生理学，电路的化学发生操纵 DREADDS和认知功能和行为的评估。目标1将确定应力诱导的可塑性 在调节LC活动的电路中，以及这如何依赖于年龄和性别。AIM 2将使用DREADS 和神经药理学技术直接测试LC活性及其CRF、食欲素A和 脑啡肽参与应对社会压力的应对策略。目标3将测试LC和其 社会失败的病理后果的传入，包括快感缺乏、吗啡条件化 在注意定势转移测验中放置偏好和认知功能。因为应对策略是一种 作为压力恢复力的重要决定因素，拟议研究的结果将显著增加我们的 了解应对策略如何优化LC-NE唤醒系统的活动。结果将会是 告知旨在修改应对策略以努力提高复原力的治疗方法，以及这些 治疗方法应该根据年龄和性别的不同而不同。

Project Summary/Abstract Social stress has adverse consequences for physical and mental health throughout life and its impact may be particularly relevant during adolescence as this is a time of substantial growth and reorganization of brain circuits. Social stress also has a differential impact in females compared to males though most research has focused on males. The proposed research uses the resident intruder model of social stress that we refined to understand how individuals cope during repeated social stress and how this determines individual consequences of repeated social stress for behaviors associated with depression and impaired cognitive function. Our research focuses on the locus coeruleus (LC) norepinephrine system, a major stress response system that mediates arousal and cognition in response to stress. The working hypothesis that frames this research is that individual differences in stress vulnerability result from differences in the circuitry that is engaged to regulate LC activity during stress. Specifically, excitatory regulation of the LC by corticotropin-releasing factor (CRF) and orexinergic afferents is hypothesized to underlie a passive coping style and vulnerability to stress-related disorders that are characterized by hyperarousal. In contrast, inhibitory enkephalin inputs to the LC are counterregulatory and are associated with a more active coping strategy and decreased vulnerability to those disorders. We hypothesize that LC-activating inputs and LC- inhibiting inputs are differentially altered in development and between sexes. This hypothesis is tested in 3 specific aims using technical approaches that include cellular measurements of receptor expression and trafficking, in vivo electrophysiology in behaving rats, chemogenetic manipulation of circuits using DREADDs and assessment of cognitive function and behavior. Aim 1 will identify stress-induced plasticity in circuits that regulate LC activity and how this is dependent on age and sex. Aim 2 will use DREADDs and neuropharmacological techniques to directly test the role of LC activity and its CRF, orexin A and enkephalin afferents in coping strategy in response to social stress. Aim 3 will test the role of the LC and its afferents on the pathological consequences of social defeat, including anhedonia, morphine conditioned place preference and cognitive function in the attention set-shifting test. Because coping strategy is an important determinant of stress resilience, the results of the proposed studies will significantly increase our understanding of how coping strategy can optimize activity of the LC-NE arousal system. The results will inform therapies designed to modify coping strategy in an effort to promote resilience and whether these therapies should be different depending on age and on sex.