EARLY EXPERIENCE ALTERS ADULT BEHAVIOR AND THE HPA AXIS

早期经历改变成人行为和 HPA 轴

• 批准号: 6330264
• 负责人: PAUL M PLOTSKY
• 金额: $ 25.05万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6330264
• 关键词: amygdala; animal developmental psychology; antidepressants; arginine vasopressin; behavioral /social science research tag; benzodiazepine receptor; corticotropin releasing factor; early experience; environmental stressor; genetic transcription; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; laboratory rat; microdialysis; mother deprivation; neurochemistry; neuroendocrine system; neuropharmacology; psychological stressor; receptor expression; stress

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.

描述（改编自申请人的摘要）：基础和 流行病学研究表明， 情感障碍的发展 该应激素质模型 部分基于创伤性压力源通常先于 情感发作的开始 不断积累的证据强化了 早期创伤的经历是一个重要的弱点， 这个后遗症的因素。 一个或多个神经系统的功能障碍， 被假定为主要情感障碍的病因学，包括 去甲肾上腺素（NA）系统，肾上腺素（5-HT）系统，和 下丘脑-垂体-肾上腺（HPA）轴。 临床和动物研究 确定了重度抑郁症患者HPA轴的明显失调， 它的实验类似物。 失调包括对 糖皮质激素负反馈， CSF和/或特定神经元细胞中的促肾上腺皮质激素释放因子（CRF） 结构，以及外周和/或中央 糖皮质激素受体密度。 在动物研究中， 外源性CRF不仅激活HPA轴， 与许多抑郁症的症状有关。 鉴于这些新出现的证据 对于CRF在情感性精神障碍发病机制中的主要作用， 由于观察到早期创伤的精神影响， 假设早期的创伤，如母亲剥夺引起的创伤， 或滥用可改变下丘脑和/或下丘脑外CRF神经元， 可能会改变这些CRF神经回路的输入， 神经化学、内分泌和行为对压力的高反应性， 成年人了 他们最近的研究利用新生儿母亲分离， 大鼠不仅证实了存在功能的改变， 中枢CRF系统糖皮质激素受体密度与早期 创伤的经历，但也发现了证据支持， 涉及肾上腺素能、肾上腺素能和GABA能/苯二氮杂卓（BZ） 系统在调解和/或维持这些不适应 改变。 在目前的申请中，研究人员建议 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。 总的来说，这项研究将增加 了解围产期生活经验在发展中的作用 压力反应和识别的个体差异 定义这种脆弱性的神经过程。