Development of Defensive Behavior and Social Stress Consequences

描述(申请人提供)：社会压力对一生的身心健康有不利影响，其影响在青春期可能特别相关，因为这是一个大脑回路大幅增长和重组的时期。到目前为止，关于社会压力的行为和生理后果的大多数基础研究都集中在成年雄性啮齿动物身上。这项拟议的研究使用了一种大鼠社交应激模型--居民-入侵者模型，以表征与成年相比，青春期不同发展阶段的社交应激的神经行为反应和后果。这项研究还承担了一项重要的挑战，即调查性别差异对社会压力或其后果的反应。这里提出的研究计划是基于初步数据，表明对攻击性同种的防御性从属反应在整个青春期到成年期都会发展。在时间上与此相关的是，为了应对随后的挑战，从积极的应对战略转向。这些与年龄相关的行为差异与蓝斑(LC)神经元活动的明显变化有关。因此，这一提议检验了中心假设，即青春期早期的社会压力扰乱了特定神经通路的个体发育，这些通路对于调节从属防御行为的发展至关重要，而且这种扰乱对青春期的行为和认知产生影响，并持续到成年。这一假设将在三个具体目标上得到检验。目标1将使用功能神经解剖学方法，并检测与社会行为和压力相关的肽系统的变化，识别和比较青春期和成年期不同阶段的社会应激所涉及的神经回路。目的2描述和比较青春期和成年期LC神经元对社会应激的反应。目标3将检查青春期社会压力的特定行为和认知后果，并评估这些影响的耐受性。由于AIM 1和AIM 2中正在研究的一些神经底物与AIM 3中正在测试的行为终点有关，因此这些研究旨在揭示在发育的特定时期参与对社会压力的初始反应(防御行为)的神经底物和神经回路如何在决定随后的社会应激的急性和长期后果中发挥作用。总之，拟议的研究将提供有关防御行为和社会压力后果中的发育和性别差异的关键信息。鉴于社会压力对精神健康的影响，这些研究将促进我们对人类精神障碍的发展以及这些疾病发病和病因性别差异的神经生物学基础的理解。)

DESCRIPTION (provided by applicant): 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. To date, most basic research into the behavioral and physiological consequences of social stress has focused on adult male rodents. The proposed research uses a model of rat social stress, "the resident- intruder model", to characterize the neurobehavioral responses to, and consequences of, social stress at different stages of adolescent development compared to adulthood. This research also takes on the important challenge of investigating sex differences in the response to social stress or its consequences. The research program proposed here is based on preliminary data indicating that the defensive subordinate response to an aggressive conspecific develops throughout adolescence into adulthood. Temporally correlated to this is a shift away from active coping strategies in response to subsequent challenges. These age-related behavioral differences are associated with distinct changes in locus coeruleus (LC) neuronal activity. Therefore, this proposal tests the central hypothesis that social stress in early adolescence disrupts the ontogeny of specific neural pathways important for regulating the development of subordinate defensive behaviors and that this disruption has effects on behavior and cognition in adolescence that endure into adulthood. This hypothesis will be tested in three specific Aims. Aim 1 will identify and compare neural circuits engaged by social stress at different stages of adolescence and in adulthood using a functional neuroanatomy approach and examining changes in peptide systems related to social behavior and stress. Aim 2 will characterize and compare responses of LC neurons to the social stress at different stages of adolescence and in adulthood. Aim 3 will examine specific behavioral and cognitive consequences of social stress during adolescence and evaluate the endurance of these effects. Because some of the neural substrates being investigated in Aims 1 and 2 have been implicated in the behavioral endpoints being tested in AIM 3, the studies are organized to reveal how the neural substrates and circuits involved in the initial response to social stress (the defensive behaviors) at a particularly time in development play a role in determining the subsequent acute and long-term consequences of social stress. Together, the proposed studies will provide critical information about developmental and sex differences in defensive behaviors and in the consequences of social stress. Given the impact of social stress on mental health these studies will advance our understanding of the development of psychiatric disorders in humans and on the neurobiological basis for gender differences in the onset and etiology of these diseases.)