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.
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