ESTROGEN EFFECTS ON CHOLINERGIC FUNCTION IN OLDER WOMEN

雌激素对老年女性胆碱能功能的影响

• 批准号: 8166965
• 负责人: PAUL A. NEWHOUSE
• 金额: $ 6.33万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166965
• 关键词: Aging; Attention; Brain; Cholinergic Antagonists; Cholinergic Receptors; Chronic; Clinical; Cognitive; Computer Retrieval of Information on Scientific Projects Database; Disease; Estrogen Antagonists; Estrogen Replacements; Estrogens; Funding; Goals; Gonadal Steroid Hormones; Grant; Human; Impaired cognition; Institution; Investigation; Learning; Lesion; Mecamylamine; Memory; Modeling; Motor; Muscarinics; Neuraxis; Neurodegenerative Disorders; Performance; Pharmaceutical Preparations; Progesterone; Research; Research Personnel; Resources; Role; Scopolamine; Secondary to; Sensory Receptors; Short-Term Memory; Simulate; Source; Speed; System; Tamoxifen; Testing; United States National Institutes of Health; Verbal Learning; age effect; cholinergic; cognitive function; neurochemistry; neuron loss; normal aging; older women; postsynaptic; presynaptic

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The primary goal of this project is to use clinical and cognitive investigations to establish how estrogen and related compounds influence the functioning of the cholinergic systems of the human brain. The basic model that we will use throughout this proposal is to test the effects of gonadal steroids on a neurochemical "lesion" model utilizing cholinergic antagonist drugs. This approach simulates the effects of age- or disease-related neuroreceptor and/or neuronal loss by temporarily blocking pre- and postsynaptic muscarinic and nicotinic cholinergic receptors. This model reliably produces mild and quantifiable but rapidly reversible cognitive impairment and has proved valuable in understanding the role of the cholinergic system and its loss on human cognitive functioning. We have utilized this model successfully to establish the effects of the loss of muscarinic and nicotinic cholinergic receptors in aging and neurodegenerative disorders. We have now extended this model to examine the effects of estrogen replacement on cholinergic function and cognitive performance in normal aging. Hypotheses: 1. Chronic administration of E2 over three months will produce significantly greater enhancement of cholinergic function (potentially through a trophic mechanism) than acutely administered E2 (e.g. through a pharmacologic mechanism). This will be manifested by blunting the performance-impairing effects of the cholinergic antagonists scopolamine (muscarinic) and mecamylamine (nicotinic) on attention, motor speed, verbal learning and memory. 2. E2 administered alone for 3 months will blunt the negative cognitive and performance effects of muscarinic and nicotinic cholinergic antagonist drugs, to a significantly greater degree than the combination of E2 plus Progesterone (PRO). These effects will be manifested on tasks of visuo-spatial learning and memory, motor speed, and verbal working memory. 3. The estrogen antagonist tamoxifen will enhance the cognition-impairing effects of cholinergic antagonists on tasks of visuo-spatial learning and memory, motor speed, and verbal working memory secondary to negative effects on cholinergic system integrity in the central nervous system.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该项目的主要目标是使用临床和认知研究来确定雌激素和相关化合物如何影响人脑胆碱能系统的功能。我们将在整个建议中使用的基本模型是测试性腺类固醇对利用胆碱能拮抗剂药物的神经化学“病变”模型的影响。 这种方法通过暂时阻断前和突触后毒蕈碱和烟碱胆碱能受体来模拟与年龄或疾病相关的神经感受器和/或神经元丧失的影响。 该模型可靠地产生轻度，可量化但迅速可逆的认知障碍，并证明在理解胆碱能系统的作用及其对人类认知功能的丧失方面非常有价值。 我们成功地利用了该模型来确定毒蕈碱和烟碱胆碱能受体在衰老和神经退行性疾病中的影响。 现在，我们扩展了该模型，以检查雌激素替代对正常衰老中胆碱能功能和认知性能的影响。 假设： 1。在三个月内慢性施用E2将比急性施用E2产生更大的胆碱能功能（可能通过营养机制）的增强（例如，通过药理机制）。 胆碱能拮抗剂scopolamine（毒蕈碱）和美甲基胺（烟碱）对注意力，运动速度，言语学习和记忆力的表现，这将表现出来。 2. E2单独施用3个月，将使毒蕈碱和烟素胆碱能拮抗剂的负面认知和性能效应比E2加孕酮（PRO）的组合的程度明显高得多。这些效果将体现在视觉空间学习和记忆，运动速度和口头工作记忆的任务上。 3。雌激素拮抗剂他莫昔芬将增强胆碱能拮抗剂对视觉空间学习和记忆，运动速度和言语工作记忆的认知影响影响，对中枢神经系统中胆碱能系统的完整性的负面影响。