GLUCOCORTICOIDS, STRESS, AND HIPPOCAMPAL AGING

大脑老化最耐人寻味的特征之一是巨大的 功能丧失程度上的可变性。一定的 个体功能敏锐，甚至没有表现出智力上的损失 进入90岁的S。相比之下，其他人显示，早在50多岁的时候 记忆障碍，语言丧失，定向障碍，在极端情况下， 发展为临床痴呆，如阿尔茨海默病。什么是 可能解释如此显著的个体差异的因素 脑部老化？ 我们正在研究下丘脑-垂体-肾上腺(HPA) Axis可能会调节大脑衰老的方式。至少有两种方式可以进入 可能发生这种情况的原因：中国人肾上腺皮质激素暴露增加 老年大鼠可能1)加速或加剧神经元和脑内神经元的丢失 这样做会增加认知功能的损失，或者2)减少 存活细胞补偿神经元丢失的能力，以及这种影响 似乎也涉及到功能的丧失。在这些研究中，我们是 试图将HPA活动的变化与 使用这两种动物模型的晚年海马区病理 “成功”(即没有海马体病理和认知能力 衰退)和“不成功的”衰老。这些实验还涉及长时间- 纵向研究以确定时间关系之间的关系 HPA活性和海马区损伤的变化。在HPA中进行更改 活动预测海马区发生的个体差异 退化？我们也在研究HPA增加之间的关系 海马区晚年活动与其他相关因素的变化 病理(例如，葡萄糖利用率降低，NMDA受体变化 结合素、神经元丢失、胆碱能系统改变等)。有没有 海马区衰退的经验性有效轮廓及其与 HPA活动的变化？最后，我们正在研究是否增加了 老年大鼠糖皮质激素水平损害海马区功能 采用突触可塑性的长时程增强模型。是吗 糖皮质激素水平的升高可能不仅会增强 海马神经元丢失，但功能受损 细胞？

One of the most intriguing features of brain aging is the tremendous variability in the degree to which there is any loss of function. Certain individuals function alertly and show no loss of intellectual ability even into their 90's. In contrast, as early as their mid-5O's, others show memory disorders, language loss, disorientation, and in the extreme form, develop clinical dementias, such as Alzheimer's diseasee. What are the factors that might account for such impressive individual differences in brain aging? We are examining the way in which the hypothalamic-pituitary-adrenal (HPA) axis might regulate how the brain ages. There are at least two ways in which this might occur: Increased exposure to adrenal glucocorticoids in the aged rat might 1) accelerate or potentiate the loss of neurons and in doing so increase the loss of cognitive function, or 2) decrease the capacity of surviving cells to compensate for neuron loss, and this effect also appears to involve a loss of function. In these studies we are attempting relate changes in HPA activity to individual differences in hippocampal pathology in later life using animal models of both "successful"(i.e. the absence of hippocampal pathology and cognitive decline) and "unsuccessful" aging. These experiments also involve long- itudinal studies in order to determine the temporal relationship between changes in HPA activity and hippocampal impairments. Do changes in HPA activity predict individual differences in the occurrence of hippocampal degeneration? We are also examining the relationship between increased HPA activity in later life and changes in other correlates of hippocampal pathology (e.g., decreased glucose utilization, changes in NMDA receptor bindin, neuron loss, changes in cholinergic systems,etc.). Is there an empirically valid profile of hippocampal decline and how is it related to changes in HPA activity? Finall, we are examining whether increased glucocorticoid levels in aged rats compromise function in the hippocampus using the long-term potentiation model of synaptic plasticity. Is it possible that increased glucocorticoid levels might not only potentiate the loss of hippocampal neurons, but also compromise function in remaining cells?