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.

项目总结/摘要 社会压力对人的一生的身心健康都有不利影响，其影响可能 在青少年时期尤其重要，因为这是一个大幅度增长和重组的时期。 大脑回路与男性相比，社会压力对女性的影响也有所不同，尽管大多数人都认为， 研究集中在男性身上。拟议的研究使用社会压力的居民入侵者模型 我们改进了它，以了解个体如何科普反复的社会压力，以及这如何决定 重复的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集中在蓝斑（LC）去甲肾上腺素系统，一个主要的 应激反应系统，调节对应激的唤醒和认知。工作假设 这一研究的框架是，压力脆弱性的个体差异是由不同的 在压力期间参与调节LC活动的电路。具体而言，LC的兴奋性调节， 促肾上腺皮质激素释放因子（CRF）和食欲素能传入被假设为被动应对的基础 风格和易受压力相关疾病的影响，这些疾病的特征是过度觉醒。与此相反， 对LC的抑制性脑啡肽输入是反调节的，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LC激活输入和LC- 抑制性输入在发育过程中和性别之间发生不同的变化。这一假设在3 使用技术方法的具体目标，包括受体表达的细胞测量， 贩运，在行为大鼠体内电生理学，使用化学遗传操纵电路 DREADDs和认知功能和行为的评估。目标1将确定应力诱导塑性 在调节LC活动的电路中，以及这如何取决于年龄和性别。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策略中的作用目标3将检验立法会的作用及其 传入对社会失败的病理后果，包括快感缺乏，吗啡条件 注意力转移测试中的位置偏好和认知功能。因为应对策略是 压力弹性的重要决定因素，拟议研究的结果将显着增加我们的 了解应对策略如何优化LC-NE唤醒系统的活动。结果将 旨在修改应对策略以促进恢复力知情疗法，以及这些疗法是否 治疗应根据年龄和性别而有所不同。