EARLY EXPERIENCE ALTERS ADULT BEHAVIOR AND THE HPA AXIS

描述(改编自申请人的摘要)：基本情况和 流行病学研究涉及心理社会压力源和生活事件 情感性精神障碍的发展。这个压力素质模型是 部分是基于创伤应激源通常先于 情感发作的开始。不断积累的证据强化了这一概念 早期创伤的经历是一个重要的脆弱性 考虑到这一后遗症。一个或多个神经系统的功能障碍 在主要情感障碍的病因学中被假设，包括 去甲肾上腺素(NA)系统、5-羟色胺(5-HT)系统和 下丘脑-垂体-肾上腺(HPA)轴。临床和动物研究表明 发现重度抑郁症患者HPA轴明显失调 它的实验类比。调节失调包括抵抗 糖皮质激素负反馈，浓度升高 脑脊液和/或特定神经元中促肾上腺皮质激素释放因子 外周和/或中央的结构和改变 糖皮质激素受体密度。在动物研究中给药 外源性促肾上腺皮质激素释放激素不仅激活HPA轴，而且 与许多抑郁症状有关。鉴于这一迅速增长的证据 CRF在情感性精神障碍发病机制中的重要作用 根据观察到的早期创伤的精神影响，调查人员 假设早期的创伤，如母亲被剥夺所造成的创伤 或滥用可改变下丘脑和/或下丘脑外CRF神经元和 可能会改变这些CRF神经回路的输入，从而产生 应激源的神经化学、内分泌和行为高反应性 成年人。他们最近的研究利用新生儿母体分离在 大鼠不仅证实了脑细胞功能的改变 糖皮质激素受体密度的中枢CRF系统与早期 创伤经历，但也发现了支持 肾上腺素能、5-羟色胺能和GABA能/苯二氮平(BZ)的参与 系统在调解和/或维持这些不适应 改装。在目前的申请中，调查人员提议 进一步描述这些变化，以阐明潜在的机制 这些变化并评估药物干预的潜力 来扭转这些功能障碍。总体而言，这项研究将增强 对围产期生活经验在儿童发育中的作用的认识 应激反应和认同感的个体差异 定义了这种脆弱性的神经过程。

DESCRIPTION (adapted from applicant's abstract): Both basic and epidemiological studies implicate psychosocial stressors and life events in the development of affective disorders. This stress diathesis model is partially based on the findings that a traumatic stressor often precedes the onset of affective episodes. Accumulating evidence strengthens the concept that the experience of early trauma serves as an important vulnerability factor in this sequelae. Dysfunction of one or more neuronal systems has been postulated in the etiology of major affective disorders, including the noradrenergic (NA) system, the serotonergic (5-HT) system, and the hypothalamic-pituitary-adrenal (HPA) axis. Clinical and animal studies have identified apparent dysregulation of the HPA axis in major depression and its experimental analogs. Dysregulation includes resistance to glucocorticoid negative feedback, elevated concentrations of corticotropin-releasing factor (CRF) in the CSF and/or in specific neuronal structures, and alterations in either peripheral and/or central glucocorticoid receptor density. In animals studies administration of exogenous CRF not only produces activation of the HPA axis, but is associated with many symptoms of depression. Given this burgeoning evidence for a major role for CRF in the pathogenesis of affective disorders coupled with the observed psychiatric impact of early trauma, the investigators hypothesize that early trauma such as that induced by maternal deprivation or abuse may modify hypothalamic and/or extrahypothalamic CRF neurons and may alter inputs to these CRF neurocircuits in such a way as to produce neurochemical, endocrine, and behavioral hyperresponsivity to stressors in adults. Their recent research utilizing neonatal maternal separation in rats has not only verified the existence of alterations in the function of central CRF systems of glucocorticoid receptor density associated with early traumatic experience, but has also uncovered evidence supporting the involvement of adrenergic, serotonergic and GABAergic/benzodiazapine (BZ) systems in either mediating and/or maintaining these maladaptive alterations. In the current application, the investigators propose to further characterize these changes, to elucidate the mechanisms underlying these changes and to evaluate the potential of pharmacological interventions to reverse these dysfunctions. Overall, this research will augment understanding of the role of perinatal life expereince in the development of individual differences in stress responsiveness as well as in identification of neural processes that define this vulnerability.