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

青春期压力对成人大脑和行为的性别依赖性影响

• 批准号: 8512526
• 负责人: KALYNN SCHULZ
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512526
• 关键词: Accounting; Adolescence; Adolescent; Adolescent Development; Adult; Afghanistan; Age; Age-Years; Animals; Anxiety; Attentional deficit; Automobile Driving; Behavior; Behavioral; Brain; Brain region; Cells; Clinical; Depressed mood; Depressive disorder; Development; Disease; Environment; Environmental Risk Factor; Exposure to; Functional disorder; Future; Gender; General Population; Goals; Health; Hippocampus (Brain); Hormones; Human; Hydrocortisone; Individual; Individual Differences; Intervention; Iraq; Knowledge; Life; Link; Major Depressive Disorder; Mediating; Memory; Mental Depression; Mental disorders; Military Personnel; Modeling; Nervous system structure; Neurobiology; Nicotine; Nicotinic Receptors; Outcome; Performance; Perinatal Exposure; Phase; Post-Traumatic Stress Disorders; Pre-Clinical Model; Preventive Intervention; Psychopathology; Psychotic Disorders; Quality of life; Recording of previous events; Regulation; Risk; Rodent Model; Schizophrenia; Services; Shapes; Smoke; Smoking; Soldier; Stress; Symptoms; Testing; Time; Veterans; War; Work; behavior test; behavioral impairment; brain behavior; cognitive function; combat; depressive symptoms; disability; experience; high risk; improved; lifetime risk; nerve injury; neuromechanism; nicotinic receptor beta2; postnatal; pre-clinical; prenatal; prenatal stress; prevent; programs; receptor; relating to nervous system; research study; resilience; sex; stress related disorder; stressor; young adult

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.

描述（由申请人提供）： 在发展过程中的压力暴露与折磨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%，抑郁症和焦虑相关的疾病，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的病因与产前和青春期的发育都有联系。重要的是，人类青少年的大脑发育一直延续到20岁出头（有些大脑区域甚至是24岁），这与服兵役的时间框架有很大的重叠。因此，增加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我们退伍军人的健康至关重要。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%，这表明未识别的因素对个体精神病风险有显著影响。一个可能的因素是个人的发展压力史。虽然研究经常考虑青少年的压力暴露和/或皮质醇水平时，分配一个“高风险”的称号，目前的模型还没有包括个人经历的压力在早期发展的时间点。从大脑发育的敏感期的角度来看，个人以前的压力经历可能会改变大脑发育的过程，从而增加风险，甚至是对后续压力源影响的恢复力。尽管在产前和青春期发育期间的压力暴露与精神疾病之间的关系是已知的，但产前压力暴露是否会增加青春期对压力的敏感性尚不清楚。临床前啮齿类动物模型具有巨大的潜力，可以阐明发育过程中应激暴露的时间与脑功能障碍之间的关系。因此，目的1将测试的假设，产前压力暴露程序的影响，青春期的压力，随后的行为功能，在性别特异性的方式。这一假说预测：（1）产前和青春期压力对成人行为功能的综合影响会有所不同 从单独在任一时间段的应激的孤立影响来看，（2）成年期经历的相同应激源不会导致相同程度的行为损伤（3）发育应激的行为影响将取决于动物的性别。目的二探讨发育应激暴露影响成年人行为功能的神经机制。海马烟碱受体异常存在于精神疾病如抑郁症和精神分裂症中，并且是记忆功能和焦虑相关行为的重要调节剂。因此，目标2将测试这一假设，即压力依赖性行为变化是由烟碱受体水平和/或功能的改变介导的。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，这项工作将促进我们对导致精神病理学脆弱性个体差异的发展和环境因素的了解，并允许更好地针对退伍军人的预防和干预时间表。