Early Chronic Stress and Prefrontal Development

描述（由申请人提供）： 在人类和非人类灵长类动物中，前额叶皮层的生长和发育从童年一直延伸到成年。基于应激条件改变大鼠发育中的大脑系统的迹象，拟议的研究调查了慢性早期应激对青少年松鼠猴认知控制，新奇寻求行为，多巴胺神经化学和可卡因敏感性的后续前额叶相关性的影响。具体目标1：检验早期慢性压力增加持续性倾向和损害行为的认知控制的假设，这些测试先前显示反映了前额叶皮质多巴胺相关的功能障碍。具体目标二：检验以下假设：早期慢性压力在“无压力”条件下增强了自愿的新奇寻求行为，而这种条件不会引起血浆皮质醇或促肾上腺皮质激素水平的增加。具体目标3：测试假设，早期慢性应激选择性地损害敏感性低，但不是高剂量的可卡因所证明的位置偏好条件。具体目标4：检验早期慢性应激诱导基线皮质醇减少和脑池脑脊液多巴胺及其代谢物HVA的基线水平减弱的假设。具体目标5：确定效果 通过高分辨率磁共振成像在体内纵向评估早期慢性应激对前额叶生长和发育的影响。我们的假设预测，猴子的行为，激素和神经化学措施的压力相关的组差异对应于减少青春期周围减少右腹内侧灰质体积，减少成熟的白色物质的完整性和连接性，通过扩散各向异性测量。收集到的数据来解决这些假设进行了分析，考虑精神兴奋剂药物的使用，冒险，和新奇的寻求，试图减轻由神经适应触发在发展中的慢性压力引起的觉醒不足的理论。

DESCRIPTION (provided by applicant): Growth and development of prefrontal cortex extends across childhood into adulthood in humans and nonhuman primates. Based on indications that stressful conditions alter developing brain systems in rats, the proposed research investigates chronic early stress effects on subsequent prefrontal correlates of cognitive control, novelty-seeking behavior, dopamine neurochemistry, and sensitivity to cocaine in adolescent squirrel monkeys. Specific Aim 1: Test the hypothesis that early chronic stress increases perseverative tendencies and impairs cognitive control of behavior on tests previously shown to reflect prefrontal cortical dopamine related dysfunctions. Specific Aim 2: Test the hypothesis that early chronic stress enhances voluntary novelty seeking behavior in "stress-free" conditions that do not elicit increases in plasma levels of cortisol or adrenocorticotropic hormone. Specific Aim 3: Test the hypothesis that early chronic stress selectively impairs sensitivity to low but not high doses of cocaine as demonstrated by place preference conditioning. Specific Aim 4: Test the hypothesis that early chronic stress induces baseline hypocortisolism and attenuates baseline levels of cisternal cerebrospinal fluid dopamine and its metabolite HVA. Specific Aim 5: Determine the effects of early chronic stress on prefrontal growth and development assessed longitudinally in vivo by high resolution magnetic resonance imaging. Our hypotheses predict that stress-related group differences in behavioral, hormonal, and neurochemical measures in monkeys correspond with diminished peri-pubertal reductions in right ventromedial gray matter volumes, and diminished maturation of white matter integrity and connectivity as measured by diffusion anisotropy. The data collected to address these hypotheses are analyzed with respect to theories that consider psychostimulant drug-use, risk-taking, and novelty seeking as attempts to alleviate underarousal produced by neuroadaptations trigger in development by chronic stress.