Project activities during the current reporting period have included bringing to closure a number of long-term investigations. In one study we evaluated, in aged surgically menopausal rhesus monkeys, the cognitive effects of four hormone therapy (HT) regimens that included progesterone and/or continuous estrogen, mimicking treatments used clinically in women. Whereas our earlier work had demonstrated that intermittent estrogen injection benefits working memory capacities mediated by the prefrontal cortex in aged ovariectormized monkeys, HT in women has often failed to influence cognitive function in clinical studies. The possibility that this discrepancy reflects differences in the formulation and timing of HT regimens, however, has not been tested systematically. Notably, none of the four hormone treatments examined in our experiments produced any beneficial effects on cognition, despite documented efficacy measured by serum hormone levels. A full-length report of these findings was recently accepted for publication pending minor revision at Neurobiology of Aging. The results have significant implications for the development of regimens aimed at promoting successful cognitive aging, and suggest that HT regimens commonly prescribed for women are unlikely to yield cognitive enhancement, at least in relation to capacities mediated by the prefrontal cortex. Consistent with this conclusion, and in stark contrast to our earlier findings for cyclic estrogen administration, quantitative morphometric analysis in the brains of the same animals failed to find any effect of HT on dendritic spine density in the prefrontal cortex (Ohm et al., 2012). Continuing project efforts, in addition to incorporating concurrent in vivo brain imaging (Shamy et al., 2012, Soc. Neurosci. Abstr.) aim to determine whether there is a temporal window of opportunity for protecting cognitive function after ovarian hormone decline, and to document the endurance characteristics of HT and withdrawal.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Institute on Aging
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Snyder, Heather M; Asthana, Sanjay; Bain, Lisa et al. (2016) Sex biology contributions to vulnerability to Alzheimer's disease: A think tank convened by the Women's Alzheimer's Research Initiative. Alzheimers Dement 12:1186-1196
Hara, Yuko; Yuk, Frank; Puri, Rishi et al. (2016) Estrogen Restores Multisynaptic Boutons in the Dorsolateral Prefrontal Cortex while Promoting Working Memory in Aged Rhesus Monkeys. J Neurosci 36:901-10
Crimins, Johanna L; Wang, Athena Ching-Jung; Yuk, Frank et al. (2016) Diverse Synaptic Distributions of G Protein-coupled Estrogen Receptor 1 in Monkey Prefrontal Cortex with Aging and Menopause. Cereb Cortex :
Naugle, Michelle M; Nguyen, Long T; Merceron, Tyler K et al. (2014) G-protein coupled estrogen receptor, estrogen receptor ?, and progesterone receptor immunohistochemistry in the hypothalamus of aging female rhesus macaques given long-term estradiol treatment. J Exp Zool A Ecol Genet Physiol 321:399-414
Young, M E; Ohm, D T; Dumitriu, D et al. (2014) Differential effects of aging on dendritic spines in visual cortex and prefrontal cortex of the rhesus monkey. Neuroscience 274:33-43
Hara, Yuko; Yuk, Frank; Puri, Rishi et al. (2014) Presynaptic mitochondrial morphology in monkey prefrontal cortex correlates with working memory and is improved with estrogen treatment. Proc Natl Acad Sci U S A 111:486-91
Baxter, Mark G; Roberts, Mary T; Gee, Nancy A et al. (2013) Multiple clinically relevant hormone therapy regimens fail to improve cognitive function in aged ovariectomized rhesus monkeys. Neurobiol Aging 34:1882-90
Ohm, Daniel T; Bloss, Erik B; Janssen, William G et al. (2012) Clinically relevant hormone treatments fail to induce spinogenesis in prefrontal cortex of aged female rhesus monkeys. J Neurosci 32:11700-5
Hara, Yuko; Rapp, Peter R; Morrison, John H (2012) Neuronal and morphological bases of cognitive decline in aged rhesus monkeys. Age (Dordr) 34:1051-73
Dumitriu, Dani; Hao, Jiandong; Hara, Yuko et al. (2010) Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment. J Neurosci 30:7507-15

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