GLUCOCORTICOIDS, STRESS, AND HIPPOCAMPAL AGING

长期暴露于升高的血浆糖皮质激素水平， 生命促进海马神经元的丧失， 电生理学，并有助于认知缺陷。老年大鼠 (and可能在人类中）糖皮质激素水平长期升高 源自下丘脑-垂体-肾上腺（HPA）功能障碍 轴，特别是从低效的皮质类固醇负反馈 调控这种情况导致促肾上腺皮质激素释放增加 激素（CRH）的合成在下丘脑神经元，调节 垂体灰分释放。老年大鼠选择性增加HPA活性 与海马病理学有关，两者都不是不可避免的 老化的后果。在这个建议的第一部分是 研究这种个体差异的神经生物学机制 在以后的生活中的HPA活动。我们的研究重点是：1）下丘脑CRH基因 表达和2）老年人糖皮质激素负反馈敏感性。 受损与老年未受损大鼠。在建议的第二部分，我们 正在研究各种抗抑郁药物治疗对 老年大鼠HPA功能的研究这些研究来自于早期的研究， 年轻的动物和我们最初的研究表明， 老年认知受损大鼠的功能障碍用慢性 地昔帕明治疗我们打算检验一下这个观点， 抗抑郁药物治疗可能有助于1）增加皮质类固醇 通过增加皮质类固醇受体的负反馈效率 在某些已知调节HPA的关键脑区中的生物合成 活性，2）减少下丘脑CRH的合成和释放，3）因此 降低老年大鼠HPA过度活动，4）减弱海马 晚年的病理学本节的研究将探讨 抗抑郁药物治疗对下丘脑CRH mRNA的影响 皮质类固醇激素受体mRNA和结合水平， 大脑区域和垂体，以及糖皮质激素反馈敏感性。 进一步的研究旨在研究短期和长期 衰老时海马功能降低HPA活性的后果 动物，包括可以被认为是 “高风险”的发展与年龄有关的海马病理。 越来越明显的是，与年龄有关的各种形式的 神经病理学的出现是对一些事件的反应， 毫无疑问与基因组有关，其他的起源于表观遗传。 是否这些表观遗传因素，如内分泌对压力的反应 有助于阿尔茨海默病（或其他形式的 临床痴呆症）仍有待确定。然而据我们所知 疾病过程和最受影响的脑结构（例如， 海马体），这似乎是无限合理的，慢性暴露于 “压力荷尔蒙”，如糖皮质激素，可以影响70岁以下的人， 症状和疾病的发展。根据我们的 最近的调查结果，我们认为1）我们有一个非常相关的目标， 治疗干预（神经糖皮质激素受体系统和 反馈灵敏度）和2）潜在的非常有用的工具 （抗抑郁药），研究其潜在的有效性 干预（无论是某种形式的抗抑郁药或其他治疗）。 虽然这里的重点是神经老化，慢性增加 糖皮质激素水平也可导致糖尿病的发作， 高血压，两者都在老年人中普遍存在。因此， 这项研究的范围超出了大脑老化的范围。

Prolonged exposure to increased plasma glucocorticoid levels in later life promotes the loss of hippocampal neurons, disrupts hippocampal electrophysiology, and contributes to cognitive deficits. In the aged rat (and probably in humans) chronically elevated glucocorticoid levels derive from dysfunction within the hypothalamic-pituitary-adrenal (HPA) axis, notably from inefficient corticosteroid negative feedback regulation. This condition results in increased corticotropin-releasing hormone (CRH) synthesis in the hypothalamic neurons which regulate pituitary ASH release. In aged rats increased HPA activity selectively associated with hippocampal pathology, and neither are an inevitable consequence of aging. In the first part of this proposal were are examining the neurobiological mechanisms for such individual differences in HPA activity in later life. Our focus is on 1) hypothalamic CRH gene expression and 2) glucocorticoid negative feedback sensitivity in aged- impaired vs. aged-unimpaired rats. In the second part of the proposal we are examining the effects of various antidepressant drugs treatments on HPA function in aged rats. These studies derive from earlier research in young animals and our initial studies where we showed that HPA dysfunction in the aged, cognitive-impaired rat is reversed with chronic desipramine treatment. We propose to test the idea that longterm antidepressant drug treatment might serve to 1) increase corticosteroid negative-feedback efficiency by increasing corticosteroid receptor biosynthesis in certain critical brain regions known to regulate HPA activity, 2) to reduce hypothalamic CRH synthesis and release, 3) thus to reduce HPA hyperactivity in aged rats, and 4) to attenuate hippocampal pathology in later life. The studies in this section will examine the effects of antidepressant drug treatment on hypothalamic CRH mRNA expression, corticosteroid receptor mRNA and binding levels in various brain regions and pituitary, and glucocorticoid feedback sensitivity. Further studies are designed to examine both the short term and long-term consequences for hippocampal function of reducing HPA activity in aging animals, including a populations of animals that can be considered at "high risk" for the development of age-related hippocampal pathology. It is becoming increasingly apparent that age-related forms of neuropathology emerge in response to a number of events, some unquestionably associated with the genome, others epigenetic in origin. Whether such epigenetic factors, such as endocrine responses to stress contribute to the development of Alzheimer's disease (or other forms of clinical dementia) remains to be determined. However, from what we know of the disease process and the brain structures most affected (e.g., hippocampus), it seems infinitely reasonable that chronic exposure to "stress hormones" such as the glucocorticoids can influence the seventy of symptoms and the progression of the disorder. On the basis of our recent findings, we feel that 1) we have a very relevant target for therapeutic intervention (the neural glucocorticoid receptor system and feedback sensitivity) and 2) a potentially very useful tool (antidepressant drugs) with which to study potentially effective interventions (be they some form of antidepressant or other treatments). Although the focus here is on neurological aging, chronically increased glucocorticoid levels can also contribute to the onset of diabetes and hypertension, both prevalent amongst the elderly. Thus the saliency of this research extends beyond that of brain aging.