The primary goal of this proposal is to examine in detail the effects of estrogen, estrogen antagonists, and progesterone on cognitive functions that are affected by cholinergic systems of the brain in postmenopausal women. These systems have critical relevance for the development of age-related cognitive and behavioral changes as well as the symptoms of dementing disorders such as Alzheimer's disease. Changes in estrogen levels after surgical and natural menopause are associated with negative changes in cognitive and behavioral functioning, which are preventable by estrogen administration. Administration of estrogen after menopause is associated with a lower risk of Alzheimer's disease. Specifically, these studies will examine the effects of estrogen and related gonadal steroids on the cholinergic system of the human brain that is thought to be critical for attention, learning, memory, and psychomotor performance. These studies will utilize a well-established method for probing the integrity of central cholinergic mechanisms utilizing cholinergic (muscarinic and nicotinic) antagonists. Preliminary data suggest that short-term administration of estrogen partially protects women from the negative cognitive effects of cholinergic antagonists. This effect could be mediated by trophic effects of estrogen on central cholinergic neurons. Estrogen has a substantial effect on the expression and activity of trophic factors such as Nerve Growth Factor (NGF) and its receptors, thereby directly producing neuroprotective and trophic effects. Estrogen also appears to have signal-transduction modulating properties. These effects are observed particularly in cholinergic neurons of the basal forebrain. However, women are now often taking agents, which may antagonize or modify estrogen effects such as the gonadal steroid progesterone and the anti-estrogen tamoxifen. Studies in this proposal will examine the acute vs. chronic effects of estrogen on anti-cholinergic induced cognitive changes, effects of combined estrogen-progesterone treatment on cholinergic integrity, and the effects of the estrogen antagonist tamoxifen on the cholinergic system. These studies will provide knowledge regarding the magnitude and type of effects of estrogen on cholinergic system integrity and will contribute to an understanding of the potential use of estrogen in late life for maintenance of cognitive functioning during normal aging and the prevention and/or treatment of age-related cognitive disorders such as mild cognitive impairment and Alzheimer's disease. ? ?
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