Factors mediating effects of pubertal stressors on adult response to hormones

描述（由申请人提供）：对青春期压力源对成年后精神障碍发展的影响的理解存在空白。最近发现，雌性小鼠在发育期的特定压力源会导致对卵巢激素的行为反应发生持久的改变，包括与抑郁和焦虑相关的行为。由于这一发育阶段在与卵巢激素调节的心理健康相关的成人行为中的重要性，因此将测试特定的青春期应激源是否影响成年期对卵巢激素的行为反应的急性生理效应。该项目的长期目标是利用动物模型，发现特定的应激源在一个狭窄的青春期改变成人对卵巢激素的行为反应的机制。核心假设是，特定的压力源在一个明确的青春期引起急性的生理变化，然后导致对卵巢激素的行为反应的改变，包括对雌二醇对抑郁和焦虑样行为的反应。这一预测的基本原理是，特定的青春期压力源在一个狭窄的时期内显著地改变了卵巢激素对各种行为的影响，并且在这些时间内动物对这些压力源的急性生理反应一定是不同的。我们已经观察到雌性小鼠在青春期暴露于特定压力源时对雌二醇的行为反应的消除或改变。这与其他人的研究一致，即青春期是成人对卵巢激素的行为反应发展的关键时期，但这一时期的短暂压力源可以对卵巢激素的行为反应产生永久性影响的发现是新颖的。在特定的目的，假设有关的细胞过程，负责在成年激素反应的改变将被测试。具体来说，免疫挑战引起的疾病行为、体温调节反应、血浆和脑细胞因子的变化与卵巢激素行为反应的改变之间的关系将被评估。这些实验将导致对持续到成年的卵巢激素改变的行为反应机制的直接测试。本研究将通过确定青春期对成人对卵巢激素的行为反应的影响及其影响机制，推动行为神经内分泌学领域的发展。这项研究是创新的，因为它调查了在一个明确的青春期发育阶段，压力源对行为反应的持久影响的原因，特别是对卵巢激素的影响。这项工作意义重大，因为它将作为一个模型，用于研究受雌二醇影响的其他与心理健康相关的终点，包括成瘾和其他人格和精神疾病。

DESCRIPTION (provided by applicant): There are gaps in understanding of the influences of stressors during puberty on the later development of psychiatric disorders in adulthood. It has recently been discovered that particular stressors during the pubertal period in female mice result in an enduring alteration in behavioral response to ovarian hormones, including behaviors related to depression and anxiety. Because of the importance of this developmental stage in adult behaviors related to mental health that are regulated by the ovarian hormones, the acute physiological effects of particular pubertal stressors that do or do not influence behavioral response to ovarian hormones in adulthood will be tested. The long-term goal of this project is to discover the mechanisms by which particular stressors during a narrow, pubertal period alter adult, behavioral responses to ovarian hormones using animal models. The central hypothesis is that particular stressors during a well-defined, pubertal period induce acute, physiological changes that then result in an alteration in behavioral responses to ovarian hormones, including the response to estradiol on depression- and anxiety-like behaviors. The rationale for this prediction is that particular pubertal stressors during a narrowly defined period dramatically alter the effects of ovarian hormones on a variety of behaviors, and there must be differences in the acute physiological responses of the animals to these stressors at these times. We have observed elimination of, or alteration in, behavioral responses to estradiol in female mice exposed to particular stressors during puberty. This is consistent with work by others that the pubertal period is a critical time in the development of adult behavioral response to ovarian hormones, but the finding that a transient stressor at this time can have permanent effects on behavioral response to ovarian hormones is novel. In the specific aim, hypotheses concerning the cellular processes that are responsible for the alteration in hormonal response in adulthood will be tested. Specifically the relationship of immune challenge-induced sickness behavior, thermoregulatory responses, and changes in plasma and brain cytokines to the altered behavioral response to ovarian hormones will be assessed. These experiments will lead to direct tests of the mechanisms responsible for the altered behavioral response to ovarian hormones that endures into adulthood. This research will advance the field of Behavioral Neuroendocrinology by identifying influences during the pubertal period on adult behavioral response to ovarian hormones and the mechanisms of these influences. The research is innovative, because it investigates the causes of enduring influences of stressors during a well-defined, pubertal stage of development on behavioral response specifically to ovarian hormones. This work is significant, because it will serve as a model for studies of other mental health-related endpoints that are influenced by estradiol, including addiction and other personality and psychiatric disorders. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to mental health, because particular stressors during the pubertal/adolescent period decrease response to ovarian hormones on mental health-related behaviors in adulthood. The research is relevant to the mission of NIMH, because it will provide understanding of the mechanisms by which some pubertal stressors influence adult behavioral response to ovarian hormones.