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，前额叶皮质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大脑发育系统的迹象，这项拟议的研究调查了慢性早期应激对青春期松鼠猴子认知控制、寻求新奇行为、多巴胺神经化学和可卡因敏感性的后续前额叶关联的影响。具体目标1：在先前被证明反映前额叶皮质多巴胺相关功能障碍的测试中，检验早期慢性应激增加持久力倾向并损害对行为的认知控制的假设。具体目标2：检验这样一种假设，即早期慢性应激在不会引起血浆皮质醇或促肾上腺皮质激素水平增加的无压力条件下，会增强自愿寻求新奇的行为。具体目标3：验证这一假说，即早期慢性应激选择性地损害对低剂量而不是高剂量可卡因的敏感性，如位置偏好条件反射所证明的那样。具体目标4：验证早期慢性应激导致基线皮质醇减少并降低脑池脑脊液多巴胺及其代谢物HVA基线水平的假设。具体目标5：确定效果 通过高分辨率磁共振成像在活体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，应激相关组猴子的行为、激素和神经化学指标的差异与青春期前右腹内侧灰质体积的减少相对应，并通过扩散各向异性来衡量白质完整性和连接性的成熟程度降低。为了解决这些假说而收集的数据是根据一些理论进行分析的，这些理论认为精神刺激性药物的使用、冒险和寻求新奇是试图缓解由慢性应激在发育过程中触发的神经适应所产生的唤醒不足。

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.