Interacting Impact of Adrenal and Ovarian Aging on the CNS

肾上腺和卵巢衰老对中枢神经系统的相互作用影响

• 批准号: 7600787
• 负责人: HENRYK F URBANSKI
• 金额: $ 14.43万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7600787
• 关键词: 21 year old; Acetylcholine; Activity Cycles; Adrenal Glands; Adult; Age; Age-associated memory impairment; Aging; Amygdaloid structure; Animal Model; Animals; Area; Attention; Autopsy; Award; Behavior; Behavior assessment; Behavioral; Biochemical; Blood Circulation; Brain; Brain region; Characteristics; Circadian Rhythms; Cognition; Cognitive; Cues; Data; Development; Dopamine; Elderly; Endocrine; Enzymatic Biochemistry; Enzymes; Estradiol; Estrogens; Event; Experimental Designs; Female; Functional disorder; Future; Genes; Glutamates; Gonadal Steroid Hormones; Grant; Health; Hippocampus (Brain); Histocytochemistry; Hormone replacement therapy; Hormones; Human; Immunoassay; Immunohistochemistry; Impaired cognition; In Situ Hybridization; Inherited; Inorganic Sulfates; Laboratories; Learning; Macaca mulatta; Magnetic Resonance Imaging; Memory; Menopause; Methodology; Monitor; Neuraxis; Neurosecretory Systems; Neurotransmitters; Norepinephrine; Oregon; Output; Ovarian; Ovarian Tissue; Ovary; Parents; Perimenopause; Physiological; Physiological Processes; Physiology; Plasma; Play; Postmenopause; Prefrontal Cortex; Premenopause; Primates; Procedures; Production; Progesterone; Receptor Gene; Replacement Therapy; Research; Resources; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Sampling; Series; Short-Term Memory; Sleep; Sleep Wake Cycle; Solid; Source; Steroid Receptors; Steroids; System; Testing; Time; Tissues; Training; Unspecified or Sulfate Ion Sulfates; Visual attention; Visuospatial; Woman; age related; attenuation; base; behavior test; brain morphology; circadian pacemaker; cognitive change; cognitive function; cost; dehydroepiandrosterone; design; effective therapy; falls; gamma-Aminobutyric Acid; in vivo Model; inhibin B; nonhuman primate; parent grant; protective effect; public health relevance; response; stem; young adult

DESCRIPTION (provided by applicant): A characteristic feature of the menopause is a marked attenuation in the production and release of ovarian steroids, such as estradiol and progesterone. However, the impact of these changes on human physiology, especially within the central nervous system (CNS), is far from being clear. We have already shown that female rhesus macaques, like women, undergo menopause, and that a change in plasma FSH and inhibin B levels represents the first endocrine manifestation of this event. We have also shown that plasma levels of the adrenal steroid, dehydroepiandrosterone (DHEA), fall markedly around this time. DHEA is one of the most abundant steroids in the circulation; it is released into the circulation in a circadian manner and is readily converted to estradiol in many tissues. The overall aim of the parent R01 grant (AG-029612) is to examine the interacting impact of adrenal and ovarian aging on the CNS of primates. Using the female rhesus macaque as a pragmatic animal model, we propose to test the hypothesis that the aging-related attenuation of DHEA release exacerbates the perimenopausal decline in estradiol, and thereby negatively impacts central physiological processes such as cognition, learning, and attention, and leads to perturbation of the circadian sleep-wake cycle. Specific Aim 1 will use a battery of behavioral tests to assess differences between young adults, and old regularly-cycling and irregularly-cycling adults; the old animals will be tested both as untreated controls and also after extended treatment with "young" physiological levels of DHEA. Cognitive and behavioral assessments will include: 1) 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 hippocampus-based memory; 3) a visuospatial cueing test of visual attention that is estrogen-sensitive; and 4) a test of behavioral reactivity sensitive to amygdala damage. In addition, sleep-wake cycles will be continuously monitored using Actiwatch recorders, and MRI will be performed before and after DHEA replacement to monitor morphological and biochemical changes in the key brain regions. Specific Aim 2 will use a series of biochemical and histochemical methodologies to elucidate the plasticity that occurs within the CNS during adrenal-ovarian aging. Gene microarrays and RT-PCR will be used to identify genes that are differentially expressed in the CNS between young and old animals, regular and irregular old cyclers, and DHEA-treated and untreated old animals. The focus will be on genes encoding enzymes involved in the conversion of DHEA to estradiol, steroid receptors, and genes associated with key neurotransmitters systems and circadian clocks. Immunohistochemistry, in situ hybridization histochemistry, RIA and biochemical enzymology will be used to corroborate the results. Aim of Supplement: At the end of 2008, our pilot R21 grant (AG-026472) will be releasing 20 ovariectomized rhesus macaques, which have already been cognitively tested using the same procedures described in Specific Aim 1. More importantly, some of these animals have been (and still are) continuously exposed to hormone replacement therapy (HRT), involving combinations of estradiol and progesterone. We thus have a unique opportunity to integrate these additional animals into the parent DHEA-replacement study, with very little additional expense. This integration of old ovariectomized, estradiol-treated and estradiol/progesterone-treated animals represents a major strengthening of the original experimental design, because it will enable us to compare and contrast the efficacy of DHEA replacement therapy to that of more conventional HRT. PUBLIC HEALTH RELEVANCE: A characteristic feature of the menopause is a marked attenuation in the production and release of ovarian steroids, such as estradiol and progesterone. However, plasma levels of the adrenal steroid, dehydroepiandrosterone (DHEA), also fall markedly around this time. DHEA is one of the most abundant steroids in the circulation; it is released into the circulation in a circadian manner and is readily converted to estradiol in many tissues. The overall aim this research is to examine the interacting impact of adrenal and ovarian aging on the central nervous system of primates. Using the female rhesus macaque as a pragmatic animal model, we propose to test the hypothesis that the aging-related attenuation of DHEA release exacerbates the perimenopausal decline in estradiol, and thereby negatively impacts central physiological processes such as cognition, learning, and attention, and leads to perturbation of the circadian sleep-wake cycle.

描述（由申请人提供）：更年期的一个特征是卵巢类固醇（例如雌二醇和黄体酮）的产生和释放显着减弱。然而，这些变化对人类生理学的影响，特别是对中枢神经系统（CNS）的影响，目前还不清楚。我们已经证明，雌性恒河猴与女性一样，都会经历更年期，血浆 FSH 和抑制素 B 水平的变化代表了这一事件的第一个内分泌表现。我们还发现，肾上腺类固醇脱氢表雄酮 (DHEA) 的血浆水平在此时显着下降。 DHEA 是循环系统中最丰富的类固醇之一；它以昼夜节律的方式释放到循环中，并且很容易在许多组织中转化为雌二醇。母公司 R01 资助 (AG-029612) 的总体目标是研究肾上腺和卵巢衰老对灵长类动物中枢神经系统的相互作用影响。使用雌性恒河猴作为实用动物模型，我们建议检验以下假设：与衰老相关的 DHEA 释放减弱会加剧围绝经期雌二醇的下降，从而对认知、学习和注意力等中枢生理过程产生负面影响。导致昼夜节律睡眠-觉醒周期的扰动。具体目标 1 将使用一系列行为测试来评估年轻人、定期骑车和不定期骑车的老年人之间的差异；年老的动物将作为未经治疗的对照以及经过“年轻”生理水平的 DHEA 长期治疗后进行测试。认知和行为评估将包括：1）空间工作记忆的延迟反应测试，该测试对衰老和前额皮质功能障碍特别敏感； 2）延迟非匹配样本，这是一项主要探测基于海马体的记忆的任务； 3）雌激素敏感的视觉注意力视觉空间提示测试； 4) 对杏仁核损伤敏感的行为反应性测试。此外，将使用 Actiwatch 记录仪持续监测睡眠-觉醒周期，并在 DHEA 替代前后进行 MRI，以监测关键大脑区域的形态和生化变化。具体目标 2 将使用一系列生化和组织化学方法来阐明肾上腺-卵巢衰老过程中中枢神经系统内发生的可塑性。基因微阵列和 RT-PCR 将用于识别年轻和年老动物、规则和不规则的老年循环者以及 DHEA 处理和未处理的老年动物之间中枢神经系统中差异表达的基因。重点是编码参与 DHEA 转化为雌二醇、类固醇受体的酶的基因，以及与关键神经递质系统和生物钟相关的基因。免疫组织化学、原位杂交组织化学、RIA和生化酶学将用于证实结果。补充目标： 2008 年底，我们的 R21 试点拨款 (AG-026472) 将释放 20 只切除卵巢的恒河猴，这些猕猴已经使用特定目标 1 中描述的相同程序进行了认知测试。更重要的是，其中一些动物已经（并且仍然）持续接受激素替代疗法（HRT），包括雌二醇和黄体酮的组合。因此，我们有一个独特的机会将这些额外的动物整合到亲本 DHEA 替代研究中，而无需额外费用。这种对旧卵巢切除、雌二醇治疗和雌二醇/黄体酮治疗动物的整合代表了对原始实验设计的重大加强，因为它将使我们能够比较和对比 DHEA 替代疗法与更传统的 HRT 的疗效。公共健康相关性：更年期的一个特征是卵巢类固醇（例如雌二醇和黄体酮）的产生和释放显着减弱。然而，肾上腺类固醇脱氢表雄酮（DHEA）的血浆水平也在此时显着下降。 DHEA 是循环中最丰富的类固醇之一；它以昼夜节律的方式释放到循环中，并且很容易在许多组织中转化为雌二醇。这项研究的总体目标是研究肾上腺和卵巢衰老对灵长类动物中枢神经系统的相互作用影响。使用雌性恒河猴作为实用动物模型，我们建议检验以下假设：与衰老相关的 DHEA 释放减弱会加剧围绝经期雌二醇的下降，从而对认知、学习和注意力等中枢生理过程产生负面影响。导致昼夜节律睡眠-觉醒周期的扰动。