A FMRI PILOT STUDY OF ESTROGEN AND CHOLINERGIC SYSTEM IN POST-MENOPAUSE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该试点项目的目标是证明：(1)我们可以利用UVM/FAHC的新脑功能磁共振成像系统，验证和复制我们的初步数据(在达特茅斯-希区柯克的脑成像实验室获得)，这些数据显示抗毒扁豆碱和抗尼古丁药物对老年女性的特定认知和脑激活影响；2)初步检查雌二醇(E2)是否可以钝化胆碱能拮抗剂药物对脑激活的影响。 有相互矛盾的证据表明，性腺类固醇E2可能会减缓或防止认知能力下降，增强认知功能，并可能降低患阿尔茨海默病的风险。我们建议研究的首要问题是，这些效应是否可能部分通过与中枢胆碱能系统的相互作用来调节。我们有初步证据表明，在绝经后妇女(PMW)中，给予E2可以显著减弱胆碱能拮抗剂的认知损害效应。此外，我们最近已经开始利用功能磁共振成像来研究抗胆碱能药物对工作记忆表现中大脑激活的影响。 进一步了解E2对中枢神经系统功能的作用的一个重要方面是研究受胆碱能拮抗剂药物和E2的存在或不存在影响的大脑回路。如果雌二醇影响对认知功能重要的胆碱能系统的完整性、稳定性或活性，那么这种影响可能可以通过功能成像策略检测到。神经化学挑战后大脑功能的直接成像将在与年龄相关的认知表现变化的知识和这些与年龄相关的变化背后的神经解剖结构之间建立至关重要的联系。由于雌激素对中枢神经系统的影响不太可能是一致的，而且可能与特定的认知领域有关，因此了解神经解剖回路及其分析对于理解绝经后雌激素对女性的临床意义和潜在用途至关重要。 我们将使用的基本模型是利用胆碱能拮抗剂药物来测试性腺类固醇对神经化学“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。虽然已经有使用功能磁共振成像研究雌激素对认知过程的影响，但我们相信这将是第一次直接测试E2是否可以通过对中枢胆碱能系统的影响改变与认知过程相关的大脑活动模式，这是通过血氧水平依赖(BOLD)功能磁共振技术测量的。

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 goals of this pilot project are to demonstrate that (1) we can validate and replicate our preliminary data (obtained at the Brain Imaging Laboratory at Dartmouth-Hitchcock) showing specific cognitive and brain activation effects of anti-muscarinic and anti-nicotinic drugs in older women, utilizing our new brain fMRI imaging system here at UVM/FAHC; 2) examine preliminarily whether estradiol (E2) can blunt the effects of cholinergic antagonist drugs on brain activation measured by fMRI. There is contradictory evidence that the gonadal steroid E2 may slow or prevent cognitive decline, enhance cognitive functioning, and may lower the risk of developing Alzheimer's disease. The overarching question we propose to investigate is whether these effects might be mediated in part through interactions with CNS cholinergic systems. We have preliminary evidence that administration of E2 can significantly blunt the cognitive impairing-effects of cholinergic antagonists in postmenopausal women (PMW). In addition, we have recently begun to investigate the effects of anti-cholinergic drugs on brain activation during working memory performance utilizing fMRI. An important aspect of furthering our understanding of the actions of E2 on CNS function is to examine the cerebral circuitry that appears to be influenced by the cholinergic antagonist drugs and the presence or absence of E2. If E2 influences the integrity, stability, or activity of cholinergic systems that are important for cognitive function, then such effects may be detectable by functional imaging strategies. Direct imaging of cerebral function after neurochemical challenge will make a vital connection between knowledge of cognitive performance changes associated with aging and the neuroanatomical structures that underlie these age-related changes. As the effects of E2 on CNS are unlikely to be uniform and perhaps related to particular cognitive domains, knowledge of neuroanatomical circuits and their analysis becomes vital to understanding the clinical implications and potential usefulness of estrogen for women after menopause. The basic model that we will use 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. While there have been investigations of the effects of estrogen on cognitive processes using fMRI, we believe this will be the first investigation directly testing whether E2 can, through effects on central cholinergic systems, alter brain activity patterns associated with cognitive processes as measured by Blood Oxygen Level Dependent (BOLD) fMRI techniques.