Cognition in Rhesus Macaques in Relation to Age and Endocrine Status

描述(由申请人提供)：在男性和雄性猕猴中，睾酮(T)和脱氢表雄酮(DHEA，一种肾上腺雄激素前体)在循环中显示出典型的24小时模式，两者都显示出与年龄相关的显著下降。尽管这些激素变化的确切生理后果尚不清楚，但T和DHEA都被认为是大脑中合成雌二醇(E2)的内分泌底物。因此，它们与年龄相关的下降可能直接通过雄激素受体和/或间接通过雌激素受体对大脑功能产生负面影响。使用恒河猴作为翻译动物模型，我们建议检验这一假说，即与年龄相关的循环T和DHEA水平的下降对中枢调节的生理过程产生负面影响，包括昼夜睡眠-觉醒周期和认知。此外，我们预测，生理性睾酮补充，旨在模拟幼年动物循环的24小时T模式，将改善这些与年龄相关的疾病。特定目标1将使用一系列认知测试来评估年轻和老年雄性恒河猴之间的差异，以及接受长期治疗的老年动物之间的差异，这些差异是由年轻的T或安慰剂的生理水平决定的。认知评估将包括：1)空间工作记忆的延迟反应测试，这对衰老和前额叶皮质功能障碍特别敏感；2)延迟不匹配样本，这是一项主要探测基于颞叶的记忆的任务；3)视觉注意的视觉空间线索测试，对雌激素敏感；以及4)在新迷宫中的表现，以评估空间学习和记忆。此外，将使用Actiwatch连续监测睡眠-觉醒周期，同时将通过磁共振成像(MRI)检查目标大脑区域的形态和生化差异。特定目的2将使用一系列生化和组织化学方法来阐明男性衰老过程中中枢神经系统(CNS)内发生的可塑性，并在补充恒河猴特异基因芯片和定量实时PCR后，将用于鉴定年轻男性、未经治疗的老年男性和接受T治疗的老年男性中枢神经系统中差异表达的基因。这种整合系统的方法应该有助于识别神经递质系统和突触的可塑性，并阐明潜在的调控机制。将使用原位杂交、免疫组织化学、酶学和激素测量来进一步证实这一结果。我们目前的国立卫生研究院拨款(AG-029612)类似地研究了围绝经期雌性恒河猴卵巢-肾上腺相互作用的相互影响。因此，正在进行的女性研究的数据，与拟议的男性研究的数据相结合，将揭示基于性别的重要差异，并有助于阐明其潜在机制。

DESCRIPTION (provided by applicant): In men and male rhesus macaques testosterone (T) and dehydroepiandrosterone (DHEA, an adrenal androgen precursor) show characteristic 24-hour patterns in the circulation, and both show significant age-related decreases. Although the exact physiological consequence of these hormonal changes is unclear, both T and DHEA are thought to act as intracrine substrates for estradiol (E2) synthesis in the brain. Therefore, it is plausible that their age-related decline negatively impacts brain function, either directly through androgen receptors and/or indirectly through estrogen receptors. Using the rhesus macaque as a translational animal model, we propose to test the hypothesis that age-related attenuation of circulating T and DHEA levels negatively impacts centrally-mediated physiological processes, including the circadian sleep-wake cycle and cognition. Moreover, we predict that physiological testosterone supplementation, designed to mimic the circulating 24-hour T pattern of young animals, will ameliorate these age-associated disorders. Specific Aim 1 will use a battery of cognitive tests to assess differences between young and old male rhesus macaques, and between old animals receiving extended treatment with "young" physiological levels of T or placebo. Cognitive assessments will include: 1) the delayed response test of spatial working memory, which is particularly sensitive to aging and prefrontal cortex dysfunction; 2) delayed non-matching-to-sample, a task probing primarily temporal lobe-based memory; 3) a visuospatial cueing test of visual attention that is estrogen-sensitive, and 4) performance in a novel maze to assess spatial learning and memory. In addition, sleep-wake cycles will be continuously monitored using Actiwatches, while morphological and biochemical differences will be examined in targeted brain areas by magnetic resonance imaging (MRI). Specific Aim 2 will use a series of biochemical and histochemical methodologies to elucidate the plasticity that occurs within the central nervous system (CNS) during male aging and after supplementation with T. Rhesus-specific gene microarrays and quantitative real-time PCR will be used to identify genes that are differentially expressed in the CNS among young males, untreated old and the T-treated old males. This integrative systems approach should help to identify plasticity in neurotransmitter systems and synapses and shed light on potential regulatory mechanisms. In situ hybridization, immunohistochemistry, enzymology, and hormone measurements will be used to further corroborate the results. Our current NIH grant (AG-029612) similarly examines the interacting impact of ovarian-adrenal interactions in perimenopausal female rhesus macaques. Consequently, data from the ongoing female study, combined with data from the proposed male study, will disclose important gender-based differences and help to elucidate their underlying mechanisms.