Development of Defensive Behavior and Social Stress Consequences

防御行为的发展和社会压力后果

• 批准号: 9313932
• 负责人: SEEMA BHATNAGAR
• 金额: $ 50.8万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9313932
• 关键词: Adolescence; Adolescent; Adult; Age; Anatomy; Anhedonia; Arousal; Attention; Behavior; Behavioral; Brain; Cognition; Corticotropin-Releasing Hormone; Development; Disease; Electrophysiology (science); Endocrine; Enkephalins; FOS gene; Female; Female Adolescents; Goals; Growth; Human; Immunoelectron Microscopy; Impaired cognition; In Situ Hybridization; Individual; Individual Differences; Injection of therapeutic agent; Life; Male Adolescents; Measurement; Measures; Medial; Mediating; Mental Depression; Mental Health; Mental disorders; Messenger RNA; Modeling; Morphine; Neurons; Neuropeptides; Norepinephrine; Opioid; Pathologic; Performance; Plant Roots; Posture; Prefrontal Cortex; RNA; Rattus; Regulation; Research; Rewards; Rodent; Role; Sex Characteristics; Shapes; Stress; Stress and Coping; Sucrose; System; Techniques; Technology; Testing; Time; Western Blotting; adverse outcome; age difference; age related; biological adaptation to stress; brain dysfunction; cognitive function; cognitive task; coping; designer receptors exclusively activated by designer drugs; experimental study; hypocretin; immunoreactivity; in vivo; locus ceruleus structure; male; neural circuit; neurobiological mechanism; norepinephrine system; novel; orexin A; physical conditioning; preference; receptor; receptor expression; resilience; response; sex; social; social stress; stress related disorder; stress resilience; stressor; therapy design; trafficking

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.

项目概要/摘要 社会压力会对一生的身心健康产生不利影响，其影响可能 在青春期尤其重要，因为这是一个实质性成长和重组的时期 脑回路。与男性相比，社会压力对女性也有不同的影响，尽管大多数 研究主要集中在男性。拟议的研究使用社会压力的居民入侵者模型 我们进行了改进，以了解个人在反复的社会压力下如何应对以及这如何决定 反复的社会压力对抑郁和受损行为的个体后果 认知功能。我们的研究重点是蓝斑 (LC) 去甲肾上腺素系统，这是一个主要的 压力反应系统，调节对压力的反应的唤醒和认知。工作假设 这项研究的框架是，压力脆弱性的个体差异是由 负责在压力期间调节 LC 活动的电路。具体来说，LC 的兴奋性调节 假设促肾上腺皮质激素释放因子（CRF）和食欲素能传入是被动应对的基础 风格和易受以过度警觉为特征的压力相关疾病的影响。相比之下， LC 的抑制性脑啡肽输入具有反调节作用，与更积极的应对相关 战略并降低对这些疾病的脆弱性。我们假设 LC 激活输入和 LC- 抑制输入在发育过程中和性别之间存在差异。这个假设在 3 中得到检验 使用技术方法的具体目标，包括受体表达的细胞测量和 贩运、行为大鼠的体内电生理学、使用电路的化学遗传学操作 DREADD 以及认知功能和行为的评估。目标 1 将识别应力引起的塑性 调节 LC 活性的电路以及这如何依赖于年龄和性别。目标 2 将使用 DREADD 和神经药理学技术直接测试 LC 活性及其 CRF、食欲素 A 和 脑啡肽传入在应对社会压力的策略中。目标 3 将测试 LC 的作用及其 社会失败的病理后果的传入，包括快感缺失、吗啡条件反射 在注意力转移测试中放置偏好和认知功能。因为应对策略是 压力恢复能力的重要决定因素，拟议研究的结果将显着提高我们的 了解应对策略如何优化 LC-NE 唤醒系统的活动。结果将 告知旨在修改应对策略以努力提高复原力的疗法，以及这些疗法是否 治疗方法应根据年龄和性别而有所不同。