Cognition in Rhesus Macaques in Relation to Age and Endocrine Status

恒河猴的认知与年龄和内分泌状况相关

• 批准号: 8106930
• 负责人: HENRYK F URBANSKI
• 金额: $ 68.93万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8106930
• 关键词: 20 year old; Adrenal Glands; Affect; Age; Aging; Amygdaloid structure; Androgen Receptor; Androgen Therapy; Androgens; Animal Model; Animals; Area; Autopsy; Biochemical; Blood Circulation; Brain; Candidate Disease Gene; Characteristics; Circadian Rhythms; Clinical Research; Cognition; Cognitive; Cues; Data; Disease; Endocrine; Enzymatic Biochemistry; Enzymes; Estradiol; Estrogen Receptors; Estrogens; Female; Foundations; Functional disorder; Funding; Gender; Genes; Gonadal Steroid Hormones; Grant; Hippocampus (Brain); Hormonal Change; Hormones; Hour; Human; Hypothalamic structure; Image; Immunohistochemistry; In Situ Hybridization; Learning; Light; Macaca mulatta; Magnetic Resonance Imaging; Measurement; Mediating; Memory; Menopause; Methodology; Molecular Analysis; Monitor; Monkeys; Motor; Neuraxis; Neurotransmitters; Output; Ovarian; Pattern; Performance; Perimenopause; Periodicity; Physiological; Physiological Processes; Physiology; Placebos; Play; Prefrontal Cortex; Primates; Research; Resources; Rest; Rodent; Role; Sampling; Scientist; Series; Short-Term Memory; Sleep Wake Cycle; Solid; Steroids; Supplementation; Synapses; System; Temporal Lobe; Testing; Testis; Testosterone; Time; United States National Institutes of Health; Visual attention; Visuospatial; Woman; age related; attenuation; base; brain morphology; cognitive function; dehydroepiandrosterone; design; improved; inflammatory marker; interdisciplinary approach; juvenile animal; male; men; middle age; multidisciplinary; neuromechanism; nonhuman primate; novel; response

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. PUBLIC HEALTH RELEVANCE: The overall aim of this research is to examine the impact of aging-related endocrine changes on the central nervous system of male primates. Using the rhesus macaque as a pragmatic animal model, we propose to test the hypothesis that aging-related attenuation of testosterone levels in the brain negatively impacts centrally-mediated physiological processes, including the circadian sleep-wake cycle and cognition. Moreover, we predict that a physiological testosterone replacement paradigm will ameliorate many of these disorders.

描述（由申请人提供）：在男性和雄性恒河猴中，睾酮(T)和脱氢表雄酮（DHEA，一种肾上腺雄激素前体）在循环中表现出典型的24小时模式，两者都表现出明显的年龄相关下降。虽然这些激素变化的确切生理后果尚不清楚，但人们认为T和脱氢表雄酮（DHEA）都是大脑中雌二醇（E2）合成的分泌底物。因此，他们的年龄相关的下降可能会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，我们提出验证与年龄相关的循环T和DHEA水平衰减对中枢介导的生理过程（包括昼夜睡眠-觉醒周期和认知）产生负面影响的假设。此外，我们预测生理睾酮补充，旨在模仿年轻动物的循环24小时T模式，将改善这些年龄相关的疾病。Specific Aim 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“年轻”生理水平T或安慰剂长期治疗的老年动物之间的差异。认知评估将包括：1)空间工作记忆延迟反应测试，该测试对年龄和前额皮质功能障碍特别敏感；2)延迟非样本匹配，一种主要探测基于颞叶记忆的任务；3)雌激素敏感的视觉注意视觉空间线索测试；4)在新型迷宫中的表现评估空间学习和记忆。此外，将使用actiwatch持续监测睡眠-觉醒周期，同时通过磁共振成像（MRI）检查目标大脑区域的形态和生化差异。Specific Aim 2将使用一系列生化和组织化学方法来阐明雄性衰老期间和补充t后中枢神经系统（CNS）内发生的可塑性，恒河猴特异性基因微阵列和定量实时PCR将用于鉴定年轻雄性、未治疗老年雄性和t治疗老年雄性中枢神经系统中差异表达的基因。这种综合系统方法应该有助于识别神经递质系统和突触的可塑性，并阐明潜在的调节机制。原位杂交、免疫组织化学、酶学和激素测量将用于进一步证实结果。我们目前的NIH拨款（AG-029612）类似地检查了卵巢-肾上腺相互作用对围绝经期雌性恒河猴的相互作用影响。因此，来自正在进行的女性研究的数据，结合来自拟议的男性研究的数据，将揭示重要的性别差异，并有助于阐明其潜在机制。