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）： 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充分残疾病例的惊人，抑郁症和焦虑症相关的疾病（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与产前和青少年发育时期都有病因。重要的是，人类的青春期大脑发育扩展到二十多岁（某些大脑区域的24个），这与兵役时间大相径庭。因此，对发展过程中压力如何影响大脑发育和与压力有关的疾病的科学了解对我们的退伍军人的健康至关重要。尽管最近在识别有精神病高风险的青少年方面的临床进展，但可用模型准确预测精神病转化的能力却小于30％，这表明身份不明的因素对个人的精神病风险产生了重大贡献。一个可能的因素是个人的发展压力史。虽然研究通常会说明“高风险”名称时的青春期压力暴露和/或皮质醇水平，但当前模型并未包括个人在较早发育时间点上经历的压力。从敏感的大脑发育时期的角度来看，个人以前的压力经历可能会改变大脑发育的过程，以使风险增加甚至弹性的方式对随后的压力源的影响。尽管在产前和青少年发育期间的压力暴露与精神疾病之间存在已知的关系，但未知产前压力暴露会增加对青春期压力的敏感性。临床前啮齿动物模型具有巨大的潜力，可以阐明在发育和大脑功能障碍之间的压力时间暴露时间之间的关系。因此，AIM 1将检验以下假设：产前压力暴露计划以性别特定方式对青少年应力对随后的行为功能的影响。该假设预测（1）产前压力和青少年对成人行为功能的综合作用将有所不同 （2）成年中所经历的相同的压力源从两个时期的孤立作用中，不会导致相同的行为障碍（3）发育应力的行为效应将取决于动物的性别。 AIM 2将研究发育压力暴露会影响成人行为功能的神经机制。海马烟碱受体异常存在于抑郁症和精神分裂症等精神疾病中，并且是记忆功能和与焦虑相关的行为的重要调节剂。因此，AIM 2将检验以下假设：烟碱受体水平和/或功能的改变介导了依赖压力的行为变化。该假设预测，烟碱受体的水平和/或功能会因产前或青春期经历的压力而变化。最终，这项工作将提高我们对导致精神病理脆弱性个体差异的发展和环境因素的了解，并允许更好地针对预防和干预退伍军人的时间表。