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的积累或死亡的迫近，而是衰老的变化，即使是最勇敢和有能力的人也经常退化和衰弱。正如黑兹利特在世纪指出的，在衰老的各种表现中，“最糟糕的老年是心智的老年。“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衰弱和普遍存在的后遗症。在这方面，对退伍军人健康管理局特别重要的是，退伍军人的人口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迅速增加，而且比非退伍军人的老年人群体更快。 这项研究的假设是，缺氧/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，海马中GABA能控制的年龄依赖性减少会加剧老年缺氧/呼吸暂停的影响，从而导致兴奋性毒性过程和神经退行性变增强。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，免受年龄和呼吸暂停的影响，特别是在海马记忆和学习功能方面。 为了确定我们的假设的准确性，我们建议生成基本数据的电生理，形态学和功能的变化，神经认知缺陷和情绪障碍，出现由于缺氧/呼吸暂停在老年。因此，海马突触活动的细胞内和细胞外电生理检查将与老年和成年（对照）豚鼠的药理学和形态学研究相结合。还将确定一种假定的神经保护剂佐匹克隆给药对成年和老年豚鼠电生理、形态和行为过程的影响。具体来说，前面的实验将补充记忆和学习的功能研究，将与光和电子显微镜和免疫细胞化学分析。这些数据将建立一个知识的基础，将提供关键的洞察力的后果，减少氧气对海马和其他神经元的功能，发生在老年。此外，待获得的数据将确定用于开发能够消除和/或减少老年人，特别是患有OSA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靶点。 公共卫生相关性： 这项研究的重点是领域是特别和独特的重要性，个人的医疗案件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征将他们与老年人的一般人群分开。例如，老年退伍军人患有阻塞性睡眠呼吸暂停，与一般人群中的老年人相比，这在退伍军人中也更明显。因此，我们对阻塞性睡眠呼吸暂停、海马体（包括记忆和学习的功能研究）和衰老的综合实验是特别独特的。这三个领域的汇合反映了那些病理过程，这是特别重要的老年退伍军人。此外，我们将探索一种治疗剂，有可能消除或减少海马记忆和学习的缺陷，这在患有OSA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.