FMRI PILOT STUDY: INTERACTION ESTROGEN -CHOLINERGIC SYSTEM IN POST-MENOPAUSE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。这个试点项目的目标是证明：(1)我们可以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），显示抗毒蕈碱和抗尼古丁药物对老年妇女的特定认知和大脑激活作用，利用我们在UVM/FAHC的新脑功能磁共振成像系统；2)初步探讨雌二醇（E2）是否能减弱fMRI测量的胆碱能拮抗剂药物对脑活化的影响。有相互矛盾的证据表明，性腺类固醇E2可能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。我们提出的首要问题是，这些影响是否可能部分通过与中枢神经系统胆碱能系统的相互作用而介导。我们有初步的证据表明，E2可以显著减弱绝经后妇女（PMW）胆碱能拮抗剂的认知损伤作用。此外，我们最近开始利用功能磁共振成像研究抗胆碱能药物对工作记忆表现时大脑激活的影响。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检查似乎受胆碱能拮抗剂药物和E2存在或不存在影响的大脑回路。如果E2影响对认知功能很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认知能力变化与衰老相关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重要的联系。由于E2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，因此了解神经解剖学回路及其分析对于了解雌激素对绝经后妇女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测试性腺类固醇对神经化学“病变”模型的影响。这种方法通过暂时阻断突触前和突触后的毒蕈碱受体和烟碱胆碱能受体来模拟年龄或疾病相关神经受体和/或神经元损失的影响。该模型可靠地产生轻度和可量化但迅速可逆的认知损伤，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损失有价值。我们已经利用这个模型成功地建立了毒蕈碱和烟碱胆碱能受体在衰老和神经退行性疾病中的作用。我们现在已经扩展了这个模型，以检查雌激素替代对正常衰老中胆碱能功能和认知表现的影响。虽然已有研究利用功能磁共振成像（fMRI）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，这是由血氧水平依赖（BOLD）功能磁共振成像技术测量的。

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.