GLUCOCORTICOIDS, STRESS, AND HIPPOCAMPAL AGING

大脑老化最有趣的特征之一是 功能丧失程度的可变性。某些 个人的功能警觉，并显示没有损失的智力，甚至 进入90年代。 相比之下，早在50岁左右，其他人就表现出 记忆障碍，语言丧失，定向障碍，极端的情况下， 发展成临床痴呆症，如阿尔茨海默氏病。有哪些 这些因素可能会解释这种令人印象深刻的个体差异， 大脑老化？ 我们正在研究下丘脑-垂体-肾上腺（HPA） 轴可能调节大脑的衰老。 至少有两条路可以进去 这可能发生：增加暴露于肾上腺糖皮质激素， 老年大鼠可能1）加速或加强神经元的损失， 这样做会增加认知功能的丧失，或者2）减少 存活细胞补偿神经元损失的能力， 似乎还包括功能丧失 在这些研究中，我们 试图将HPA活性的变化与个体差异联系起来， 海马病理学在以后的生活中使用的动物模型， “成功”（即没有海马病理和认知功能障碍） 衰退）和“不成功”的老化。 这些实验也涉及到长期的- 研究，以确定时间之间的关系 HPA活性和海马损伤的变化。 HPA的变化 活动预测海马发生的个体差异 退化？我们还在研究HPA增加与 活动在以后的生活和变化的其他相关的海马 病理学（例如，葡萄糖利用率降低，NMDA受体变化 结合蛋白、神经元损失、胆碱能系统的变化等）。 是否有 海马下降的经验有效的概况，以及它如何与 HPA活性的变化？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功能 使用突触可塑性的长时程增强模型。吗 糖皮质激素水平的增加可能不仅会增强 海马神经元的损失，但也损害了剩余的功能， 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?