This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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 system.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
General Clinical Research Centers Program (M01)
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University of Vermont & St Agric College
Schools of Medicine
United States
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Scagnelli, Connor N; Howard, Diantha B; Bromberg, Mark B et al. (2018) Hydration measured by doubly labeled water in ALS and its effects on survival. Amyotroph Lateral Scler Frontotemporal Degener 19:220-231
Horne, Hisani N; Sherman, Mark E; Pfeiffer, Ruth M et al. (2016) Circulating insulin-like growth factor-I, insulin-like growth factor binding protein-3 and terminal duct lobular unit involution of the breast: a cross-sectional study of women with benign breast disease. Breast Cancer Res 18:24
Kien, C Lawrence; Matthews, Dwight E; Poynter, Matthew E et al. (2015) Increased palmitate intake: higher acylcarnitine concentrations without impaired progression of ?-oxidation. J Lipid Res 56:1795-807
Gierach, Gretchen L; Patel, Deesha A; Falk, Roni T et al. (2015) Relationship of serum estrogens and metabolites with area and volume mammographic densities. Horm Cancer 6:107-19
Albert, Kimberly; Pruessner, Jens; Newhouse, Paul (2015) Estradiol levels modulate brain activity and negative responses to psychosocial stress across the menstrual cycle. Psychoneuroendocrinology 59:14-24
Bodelon, Clara; Heaphy, Christopher M; Meeker, Alan K et al. (2015) Leukocyte telomere length and its association with mammographic density and proliferative diagnosis among women undergoing diagnostic image-guided breast biopsy. BMC Cancer 15:823
Morris, Erin A; Hale, Sarah A; Badger, Gary J et al. (2015) Pregnancy induces persistent changes in vascular compliance in primiparous women. Am J Obstet Gynecol 212:633.e1-6
Miller, Mark S; Bedrin, Nicholas G; Ades, Philip A et al. (2015) Molecular determinants of force production in human skeletal muscle fibers: effects of myosin isoform expression and cross-sectional area. Am J Physiol Cell Physiol 308:C473-84
Kien, C Lawrence; Bunn, Janice Y; Fukagawa, Naomi K et al. (2015) Lipidomic evidence that lowering the typical dietary palmitate to oleate ratio in humans decreases the leukocyte production of proinflammatory cytokines and muscle expression of redox-sensitive genes. J Nutr Biochem 26:1599-606
Fox, James R; Gray, Weili; Koptiuch, Cathryn et al. (2014) Anisotropic tissue motion induced by acupuncture needling along intermuscular connective tissue planes. J Altern Complement Med 20:290-4

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