Prevention of Hippocampal Neurodegeneration due to Age and Apnea

预防因年龄和呼吸暂停引起的海马神经变性

• 批准号: 8597383
• 负责人: MICHAEL H CHASE
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597383
• 关键词: Adult; Age; Aging; Aging-Related Process; Animals; Apnea; Apoptotic; Area; Behavioral; Brain region; Cavia; Cessation of life; Characteristics; Chronic; Clinical; Cognition; Cognitive deficits; Complement; Data; Development; Disease; Elderly; Electrons; Exhibits; Foundations; GABA Agonists; General Population; Glutamates; Healthcare Systems; Hippocampus (Brain); Hour; Hypoxia; Individual; Knowledge; Learning; Light; Medical; Memory; Microscopic; Mind; Mood Disorders; Moods; Morphology; Nerve Degeneration; Neurocognitive; Neurocognitive Deficit; Neurons; Neuroprotective Agents; Obstructive Sleep Apnea; Older Population; Oxygen; Pathologic Processes; Population; Prevalence; Prevention; Process; Recurrence; Research; Sleep; Sleep Apnea Syndromes; Structure; Symptoms; Synapses; Techniques; Therapeutic Agents; Therapeutic Intervention; Tissues; United States; United States Department of Veterans Affairs; Veterans; age effect; age related; aged; aging hippocampus; base; drug development; extracellular; health administration; insight; mature animal; multidisciplinary; neuronal excitability; neuroprotection; public health relevance; receptor; research study; response; senescence

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.

描述（由申请人提供）： 变老的悲剧不是岁月累积的负担或死亡的迫近，而是一系列衰老的变化，这些变化常常使即使是最英勇、最有能力的人也变得堕落和衰弱。正如哈兹利特在十九世纪指出的那样，在衰老的所有表现形式中，“最糟糕的是心灵的衰老”。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衰弱且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普通人口更快，而且呼吸暂停及其相关认知缺陷的影响不仅在快速增加，但比非退伍军人老年人群体的速度更快。 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，特别是对于老年退伍军人。我们还假设，老年缺氧/呼吸暂停的影响因海马 GABA 能控制的年龄依赖性减少而加剧，从而导致兴奋性毒性过程和神经变性增强。重要的是，我们还建议，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学、形态学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，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。还将确定施用假定的神经保护剂佐匹克隆对成年和老年豚鼠的电生理学、形态学和行为过程的影响。具体来说，前面的实验将得到记忆和学习功能研究的补充，这些研究将与光学和电子显微镜以及免疫细胞化学分析相关。这些数据将建立一个知识基础，为了解老年时氧气减少对海马和其他神经元功能的影响提供重要见解。此外，获得的数据将确定治疗剂开发的目标，这些治疗剂能够消除和/或减少老年人、尤其是患有 OSA 的老年退伍军人群体中缺氧/呼吸暂停的病理后果。 公共卫生相关性： 这项研究的重点是对那些医疗案件由退伍军人管理局负责的个人来说具有特别和独特重要性的领域。重要的是，老年退伍军人有许多特征将他们与一般老年人群区分开来。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，退伍军人的这种情况也更为明显。因此，我们针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）和衰老的联合实验特别独特。这三个区域的交汇反映了对老年退伍军人特别重要的病理过程。此外，我们将探索一种治疗药物，有可能消除或减少海马记忆和学习缺陷，这种缺陷在患有 OSA 的老年退伍军人中尤其突出。