STRESS, ADRENAL STEROIDS AND THE BRAIN

我们研究的目的是阐明 肾上腺皮质的糖皮质激素（GC）介导适应性和 压力对大脑的适应不良影响。 垂体-肾上腺轴是 对于适应压力至关重要，因为，没有它，动物 非常容易受到各种压力的影响;然而，这个轴也是 破坏作用的介质，如免疫抑制和丧失 脆弱的大脑结构如海马体中的神经元。 1968年，我们 发现海马体含有肾上腺素的受体部位， 类固醇. 随后的研究表明，有两种类型的 大脑中的受体，一个集中在海马体，另一个集中在海马体。 更广泛。 越来越多的证据表明海马体 参与控制垂体肾上腺功能，我们最近的研究表明， 研究集中于循环GC的应激升高， 与正在进行神经活动协同作用以改变脑形态， 神经化学 GC对大脑的影响有两种类型：1）影响 从而抵消并缓冲初级神经反应， 应激，如去甲肾上腺素能、肾上腺素能和苯二氮卓类 2）导致神经组织损伤和破坏的影响， 特别是通过与兴奋性氨基酸及其 受体。 我们计划研究的目标是清楚地建立 并描述GC的神经化学、分子和形态学效应 在海马体和相关的大脑区域，然后建立时间 在这一过程中，它们介导了大脑的变化， 以及可控的应力。 我们也将开始评估 这些GC所依赖的神经系统的发育决定因素 通过检查产前压力的影响， 产后“处理”。 我们还将研究压力的影响， 海马对室旁核神经元的输入 下丘脑产生促肾上腺皮质激素释放激素和加压素 调节脑垂体促肾上腺皮质激素分泌的细胞 这项工作特别 相关，因为压力是诱发抑郁症的可能因素 疾病，以及增加对肿瘤和感染的脆弱性， 改变影响免疫系统的神经和内分泌输出。 我们 工作假设是，抑郁症代表了失败的， 正常的适应机制运作，GC是身体自己的 抗抑郁药-或至少其中之一。 我们认为， 了解压力的正常适应机制 大脑中的生化和形态变化，我们会更好地 准备好在适应失败时认识到问题所在。 除了 与抑郁症有关，GC对生存的影响， 神经元的破坏，特别是海马体， 老年痴呆症和其他神经退行性疾病 压力可能会加速疾病的发生。 更好地理解 GC对神经元的作用的有益和破坏方面 生存率可能有助于制定治疗策略，以减缓 神经退行性疾病的进展。

The goal of our research is to elucidate mechanisms by which glucocorticoids (GC's) of the adrenal cortex mediate adaptive and maladaptive effects of stress on the brain. The pituitary-adrenal axis is essential for the adaptation to stress, because, without it, animals are extremely vulnerable to a variety of stressors; and yet this axis is also the mediator of damaging effects, such as immunosuppression and loss of neurons in vulnerable brain structures like the hippocampus. In 1968, we discovered that the hippocampus contains receptor sites for adrenal steroids. Subsequent studies have shown that there are two types of receptors in the brain, one concentrated in the hippocampus and the other more widespread. Accumulating evidence indicates that the hippocampus participates in control of pituitary-adrenal function, and our recent studies have focused on the stress-elevation of circulating GC's which synergize with ongoing neural activity to alter brain morphology and neurochemistry. GC effects on the brain are of two types: 1) Effects which counteract and thereby buffer against the primary neural reactions to stress, as in the case of noradrenergic, serotonergic and benzodiazepine systems; 2) Effects which lead to damage and destruction of neural tissue, particularly via interactions with excitatory amino acids and their receptors. The goals of our projected research are to clearly establish and characterize neurochemical, molecular and morphological effects of GC's in the hippocampus and related brain regions and then to establish the time course over which they mediate brain changes resulting from uncontrollable as well as controllable stress. We shall also begin to assess developmental determinants of the neural systems upon which these GC actions take place, by examining the effects of prenatal stress and postnatal "handling". We will also examine the influence of stress and hippocampal input on neurons of the paraventricular nuclei of the hypothalamus which produce corticotrophin releasing hormone and vasopressin that regulate ACTH secretion from the pituitary. This work is particularly relevant because stress is a likely factor in precipitating depressive illness, as well as in increasing vulnerability to tumors and infections by altering neural and endocrine outputs that affect the immune system. Our working hypothesis is that depressive illness represents a failure of normal adaptive mechanisms to operate, and that GC's are the body's own antidepressant agent - or at least one of them. We feel that by understanding the normal adaptive mechanisms to stress in terms of biochemical and morphological changes in the brain, we will be better prepared to recognize what goes wrong when adaptation fails. Besides relating to depressive illness, the effects of GC's on the survival and destruction of neurons, particularly in hippocampus, raises the possibility that the course of Alzheimer's disease and other neural degenerative diseases may be accelerated by stress. Better understanding of the beneficial as well as destructive aspects of GC actions on neuronal survival may aid in developing treatment strategies to slow the rate of progress of neural degenerative diseases.