Gender-Dependent Effects of Stress During Adolescence on Adult Brain and Behavior

描述(由申请人提供)： 发育过程中的压力暴露与困扰退伍军人的精神疾病有关。精神分裂症目前占所有退伍军人完全残疾病例的19%，与抑郁和焦虑相关的疾病，如创伤后应激障碍，在退伍军人中很常见。抑郁症和精神分裂症在病因学上与产前和青春期发育有关。重要的是，人类青春期的大脑发育持续到20岁出头(有些脑区甚至是24岁)，这与服兵役的时间框架有很大重叠。因此，加强对发育过程中的压力如何影响大脑发育和压力相关疾病的科学理解，对于我们退伍军人的健康是至关重要的。尽管最近在识别精神病高危青少年方面取得了临床进展，但现有模型准确预测精神病转化的能力不到30%，这表明不明因素对个人患精神病的风险有很大影响。一个可能的因素是个体的发展压力史。虽然研究经常在指定“高风险”时考虑青春期压力暴露和/或皮质醇水平，但目前的模型没有包括个体在早期发育时间点经历的压力。从大脑发育的敏感期和个体先前的压力经历的角度来看，可能会改变大脑发育的过程，从而增加风险，甚至增加韧性，以应对后续应激源的影响。尽管已知产前和青春期应激暴露与精神疾病之间的关系，但产前应激暴露是否会增加青春期应激的敏感性尚不清楚。临床前啮齿动物模型在阐明发育过程中应激暴露的时机与脑功能障碍之间的关系方面具有巨大的潜力。因此，目标1将检验这一假设，即产前应激暴露以性别特有的方式规划青春期应激对后续行为功能的影响。这一假设预测：(1)产前和青春期应激对成人行为功能的综合影响将有所不同 从这两个时期的单独应激影响来看，(2)成年期经历的相同应激源不会导致相同程度的行为损害(3)发育应激的行为影响取决于动物的性别。目的2探讨发育应激暴露影响成人行为功能的神经机制。海马尼古丁受体异常存在于抑郁症和精神分裂症等精神疾病中，是记忆功能和焦虑相关行为的重要调节因素。因此，Aim 2将测试这一假设，即应激依赖的行为变化是通过尼古丁受体水平和/或功能的变化来调节的。这一假说预测，尼古丁受体的水平和/或功能将随着产前或青春期经历的压力而变化。最终，这项工作将增进我们对导致精神病理易感性个体差异的发展和环境因素的了解，并使我们能够更好地针对退伍军人进行预防和干预的时间框架。

DESCRIPTION (provided by applicant): Stress exposure during development is associated with mental illnesses that afflict veterans. Schizophrenia currently accounts for a staggering 19% of all veteran full disability cases, and depression and anxiety-related disorders such as post-traumatic stress disorder are common in veterans returning from service. Depressive disorders and schizophrenia have etiological links to both prenatal and adolescent periods of development. Importantly, adolescent brain development in humans extends into the early twenties (even 24 for some brain regions), which overlaps significantly with the time-frame for military service. Thus, increased scientific understanding of how stress during development impacts brain development and stress-related disorders is imperative to the health of our veterans. Despite recent clinical advances in identifying adolescents at high risk for psychosis, the ability of available models to accurately predict psychotic conversion is less than 30%, suggesting that unidentified factors are contributing significantly to an individual's risk for psychosis. One possible factor is the developmental stress history of an individual. While studies often account for adolescent stress exposure and/or cortisol levels when assigning a "high risk" designation, current models have not included stress experienced by individuals at earlier developmental time points. From the standpoint of sensitive periods of brain development, and individual's previous stressful experiences may alter the course of brain development in a manner that confers increased risk, or even resilience, to the impact of subsequent stressors. Despite the known relationships between stress exposure during prenatal and adolescent development and mental illness, whether prenatal stress exposure increases sensitivity to stress during adolescence is not known. Preclinical rodent models have enormous potential for elucidating the relationships between the timing of stress exposure across development and brain dysfunction. Therefore, Aim 1 will test the hypothesis that prenatal stress exposure programs the impact of adolescent stress on subsequent behavioral function in a sex-specific manner. This hypothesis predicts that (1) the combined effects of prenatal and adolescent stress on adult behavioral function will differ from the isolated effects of stress during either time period alone, (2) identical stressors experienced in adulthood will not result in the same magnitude of behavioral impairments (3) the behavioral effects of developmental stress will depend on the sex of the animals. Aim 2 will investigate the neural mechanisms by which developmental stress exposure impacts adult behavioral function. Hippocampal nicotinic receptor abnormalities are present in psychiatric illnesses such as depression and schizophrenia, and are important regulators of memory function and anxiety-related behaviors. Therefore, Aim 2 will test the hypothesis that stress-dependent behavioral changes are mediated by alterations in nicotinic receptor levels and/or function. This hypothesis predicts that levels and/or function of nicotinic receptors will vary as consequence of stress experienced prenatally or during adolescence. Ultimately, this work will advance our knowledge of the developmental and environmental factors contributing to individual differences in vulnerability to psychopathology, and allow for better targeting of the timeframe for prevention and intervention in our veterans.