Prevention of Hippocampal Neurodegeneration due to Age and Apnea

描述(由申请人提供)： 变老的悲剧不是岁月积累的负担或死亡的迫近，而是一系列老化的变化，即使是最勇敢和最有能力的人，也经常因此而退化和虚弱。正如哈兹利特在19世纪指出的那样，在衰老的所有表现形式中，“最糟糕的衰老是精神衰老。”在这方面，认知、记忆和学习以及情绪方面的缺陷是衰老过程中最令人虚弱和普遍存在的后遗症之一。在这方面，对退伍军人健康管理局特别重要的是，退伍军人人口的老龄化速度比一般人口快，而且呼吸暂停及其相关认知缺陷的影响不仅在迅速增加，而且比非退伍军人的老年人群体的增长速度更快。支持这项研究的假设是，低氧/呼吸暂停对神经认知和情绪障碍的影响至关重要，特别是在老年退伍军人中。我们还假设，老年时缺氧/呼吸暂停的影响会因海马区GABA能控制的年龄依赖性降低而加剧，这会导致兴奋毒性过程和神经退化的增强。重要的是，我们还提出，GABA激动剂佐匹克隆的应用将提供神经保护，使其免受年龄和呼吸暂停的影响，特别是在海马体记忆和学习功能方面。为了确定我们假设的准确性，我们建议生成与电生理、形态和功能变化相关的基本数据，这些变化是老年缺氧/呼吸暂停导致的神经认知缺陷和情绪障碍的基础。因此，在老年和成年(对照)豚鼠中，海马区突触活性的细胞内和细胞外电生理检查将与药理学和形态学研究相结合。可能的神经保护剂佐匹克隆对成年和老年豚鼠的电生理、形态和行为过程的影响也将被确定。具体地说，前面的实验将得到记忆和学习的功能研究的补充，这些研究将与光学、电子显微镜和免疫细胞化学分析相关联。这些数据将建立一个知识基础，为老年时氧气减少对海马体和其他神经元功能的影响提供关键的见解。此外，将获得的数据将确定开发能够消除和/或减少老年人，特别是患有阻塞性睡眠呼吸暂停的老年退伍军人群体中缺氧/呼吸暂停的病理后果的治疗剂的目标。 公共卫生相关性： 这项研究侧重于对个人具有特殊和独特重要性的领域，这些个人的医疗病例是退伍军人管理局的责任。重要的是，老年退伍军人有许多特点，使他们有别于一般老年人。例如，老年退伍军人患有阻塞性睡眠呼吸暂停，与普通人群中的老年人相比，退伍军人中的阻塞性睡眠呼吸暂停更明显。因此，我们关于阻塞性睡眠呼吸暂停、海马体(包括记忆和学习的功能研究)和衰老的联合实验特别独特。这三个区域的汇合反映了那些对老年退伍军人特别重要的病理过程。此外，我们将探索一种有可能消除或减少海马体记忆和学习障碍的治疗剂，这些缺陷在患有阻塞性睡眠呼吸暂停综合征的老年退伍军人中尤为突出。

DESCRIPTION (provided by applicant): The tragedy of growing old is not the burden of accumulated years or the imminence of death, but rather the host of senescent changes that so often degrade and enfeeble even the most gallant and competent. Of all the various manifestations of senescence, as Hazlitt pointed out in the nineteenth century, "The worst old age is that of the mind." In this regard, deficits in cognition, memory and learning, and mood are among the most debilitating as well as ubiquitous sequelae of the aging process. In this regard, and of particular importance to the Veterans Health Administration is the fact that the population of Veterans is aging faster than the general population, but also that the effects of apnea and its related cognitive deficits are increasing not only at a rapid rate, but faster than that present in groups of elderly individuals who are not Veterans. The hypothesis underlying the proposed research is that the effects of hypoxia/apnea on neurocognitive and mood disorders are of critical importance, especially in elderly Veterans. We also hypothesize that the effects of hypoxia/apnea in old age are exacerbated by an age-dependent reduction in GABAergic control in the hippocampus, which results in enhanced excitotoxic processes and neurodegeneration. Importantly, we also propose that the application of the GABA agonist, zopiclone, will provide neuroprotection from the effects of age and apnea, particularly with respect to hippocampal memory and learning functions. In order to determine the veracity of our hypotheses, we propose to generate basic data relating to the electrophysiological, morphological and functional changes that underlie the neurocognitive deficits and mood disorders that arise as a result of hypoxia/apnea in old age. Accordingly, an intracellular and extracellular electrophysiological examination of synaptic activity of the hippocampus will be combined with pharmacological and morphological studies in aged and adult (control) guinea pigs. The effects of the administration of a putative neuroprotective agent, zopiclone, on electrophysiological, morphological and behavioral processes in adult and aged guinea pigs, will also be determined. Specifically, the preceding experiments will be complemented by functional studies of memory and learning that will be correlated with light and electron microscopic and immunocytochemical analyses. These data will establish a foundation of knowledge that will provide critical insights into the consequences of a decrease in oxygen on the functioning of hippocampal and other neurons that occur in old age. In addition, the data to be obtained will determine targets for the development of therapeutic agents that are capable of eliminating and/or reducing the pathological consequences of hypoxia/apnea in the elderly and especially in populations of elderly Veterans with OSA. PUBLIC HEALTH RELEVANCE: This research focuses on areas that are of particular and unique importance to individuals whose medical case is the responsibility of the Veteran's Administration. Importantly, there are a number of characteristics of aged Veterans that separate them from the general population of aged individuals. For example, aged Veterans suffer from obstructive sleep apnea, which is also more pronounced in Veterans compared with aged individuals in the general population. Thus, our combined experiments dealing with obstructive sleep apnea, the hippocampus (including functional studies of memory and learning), and aging are particularly unique. The confluence of these three areas mirror those pathological processes that are of special importance in aged Veterans. In addition, we will explore a therapeutic agent that has the potential to eliminate or reduce the deficits in hippocampal memory and learning that are especially prominent in aged Veterans with OSA.