ESTROGEN EFFECTS ON CHOLINERGIC FUNCTION IN OLDER WOMEN

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这个项目的主要目标是通过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。我们将在整个提案中使用的基本模型是测试性腺类固醇对使用胆碱能拮抗剂药物的神经化学“损伤”模型的影响。这种方法通过暂时阻断突触前和突触后的M胆碱能和尼古丁胆碱能受体来模拟年龄或疾病相关的神经受体和/或神经元丢失的影响。该模型可靠地产生了轻微的、可量化的、但快速可逆的认知损害，并已被证明对理解胆碱能系统的作用及其对人类认知功能的丧失有价值。我们已经成功地利用这个模型建立了毒碱能和烟碱能胆碱能受体缺失在衰老和神经退行性疾病中的作用。我们现在扩展了这一模型，以检测雌激素替代对正常衰老时胆碱能功能和认知能力的影响。假设：1.长期服用三个月以上的雌激素会显著增强胆碱能功能(潜在地通过营养机制)，而不是急性服用(例如通过药理机制)。这将通过钝化胆碱能拮抗剂东莨菪碱(毒鼠碱)和甲氨基甲胺(烟碱)对注意力、运动速度、语言学习和记忆的影响来表现出来。2.单独应用E_2 3个月后，M胆碱能和尼古丁胆碱能拮抗剂对小鼠认知和表现的负面影响明显大于E_2加黄体酮(PRO)。这些影响将在视觉空间学习和记忆、运动速度和言语工作记忆任务上表现出来。3.雌激素拮抗剂他莫昔芬可增强胆碱能拮抗剂在视觉空间学习记忆、运动速度和言语工作记忆等任务中的认知损害作用，继而对中枢胆碱能系统的完整性产生负面影响。

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