Factors mediating effects of pubertal stressors on adult response to hormones

描述(由申请人提供)：在青春期应激源对成年后精神障碍发展的影响的理解上存在差距。最近发现，雌性小鼠青春期的特定应激源会导致对卵巢激素的行为反应发生持久的变化，包括与抑郁和焦虑有关的行为。由于这一发育阶段在与心理健康有关的成人行为中的重要性，由卵巢激素调节，因此将测试特定青春期应激源对成年后对卵巢激素的行为反应产生或不影响的急性生理效应。该项目的长期目标是通过动物模型发现在狭窄的青春期特定应激源改变成人对卵巢激素的行为反应的机制。中心假设是，在明确定义的青春期期间，特定的应激源会引发急性的生理变化，然后导致对卵巢激素的行为反应的改变，包括对雌激素对抑郁和焦虑样行为的反应。这一预测的基础是，在狭义的青春期，特定的青春期应激源极大地改变了卵巢激素对各种行为的影响，在这些时间段，动物对这些应激源的急性生理反应肯定是不同的。我们观察到，在青春期暴露于特定应激源的雌性小鼠，对雌二醇的行为反应发生了消除或改变。这与其他人的工作一致，即青春期是成人对卵巢激素行为反应发展的关键时期，但这一发现是新颖的，即此时的短暂应激源可以对卵巢激素的行为反应产生永久性影响。在这个特定的目标中，将测试与成年期荷尔蒙反应改变有关的细胞过程的假说。具体地说，将评估免疫挑战诱导的疾病行为、体温调节反应以及血浆和脑细胞因子的变化与卵巢激素改变的行为反应的关系。这些实验将导致对持续到成年的卵巢激素行为反应改变的机制进行直接测试。这项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以及这些影响的机制来推动行为神经内分泌学领域的发展。这项研究具有创新性，因为它调查了在明确定义的青春期发育阶段，应激源对行为反应产生持久影响的原因，特别是对卵巢激素的反应。这项工作意义重大，因为它将作为研究其他心理健康相关终点的模型，这些终点受到雌二醇的影响，包括成瘾和其他人格和精神障碍。 公共卫生相关性：拟议的研究与心理健康相关，因为青春期/青春期的特定应激源会减少成年后卵巢激素对心理健康相关行为的反应。这项研究与NIMH的使命有关，因为它将提供一些青春期应激源影响成人对卵巢激素的行为反应的机制。

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.