Cognitive aging in women is closely related to age-related changes in neuroendocrine systems, particulariy the loss of circulating ovarian steroid hormones that occurs in menopause. Surprising findings from the Women's Health Initiative Memory Study showed that hormone treatment (HT) begun long after the onset of menopause failed to improve cognition and may have been harmful. This contrasts with other studies indicating beneficial cognitive effects of HT begun soon after the onset of menopause. To reconcile these findings a 'window of opportunity'hypothesis has been proposed, such that there is a limited period of fime after menopause during which HT may improve cognifion. Because of other health risks associated with long-term HT including cardiovascular disease and cancer, current advice is for women to take a short course of HT at the onset of menopause and then disconfinue it. We will test, in a well-characterized animal model, whether beneficial cognitive effects of HT (on spatiotemporal working memory, visual recognition memory, and vulnerability to distraction) persist after discontinuation of HT, and whether they are sfill observed when HT is begun after a long delay post-menopause. In vivo neuroimaging analyses conducted concurrently with behavioral tesfing will measure neurobiological changes in parallel with cognitive ability. This study will test the 'window of opportunity'hypothesis explicitly, as well as whether cognitiye benefits can be maintained after withdrawal of HT. These studies will provide critical translational insights into how HT can improve cognitive outcomes of aging.

Public Health Relevance

Hormone replacement therapy in women after menopause can improve brain funcfion, including memory. We will test, in an animal model, how the fiming of hormone therapy after menopause affects its ability to improve brain function, both in terms of whether therapy must begin soon after menopause to be effective, and whether its beneficial effects persist after therapy is discontinued. These studies will help us maintain best brain and memory function in women as they age.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG016765-12
Application #
8376633
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9)
Project Start
Project End
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
12
Fiscal Year
2012
Total Cost
$496,969
Indirect Cost
$69,990
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
McEwen, Bruce S; Milner, Teresa A (2017) Understanding the broad influence of sex hormones and sex differences in the brain. J Neurosci Res 95:24-39
Nutsch, Victoria L; Will, Ryan G; Tobiansky, Daniel J et al. (2017) Age-related changes in sexual function and steroid-hormone receptors in the medial preoptic area of male rats. Horm Behav 96:4-12
Nutsch, Victoria L; Bell, Margaret R; Will, Ryan G et al. (2017) Aging and estradiol effects on gene expression in the medial preoptic area, bed nucleus of the stria terminalis, and posterodorsal medial amygdala of male rats. Mol Cell Endocrinol 442:153-164
Marques-Lopes, Jose; Tesfaye, Ephrath; Israilov, Sigal et al. (2017) Redistribution of NMDA Receptors in Estrogen-Receptor-?-Containing Paraventricular Hypothalamic Neurons following Slow-Pressor Angiotensin II Hypertension in Female Mice with Accelerated Ovarian Failure. Neuroendocrinology 104:239-256
Garcia, Alexandra N; Bezner, Kelsey; Depena, Christina et al. (2017) The effects of long-term estradiol treatment on social behavior and gene expression in adult female rats. Horm Behav 87:145-154
Almey, Anne; Milner, Teresa A; Brake, Wayne G (2016) Estrogen receptor ? and G-protein coupled estrogen receptor 1 are localized to GABAergic neurons in the dorsal striatum. Neurosci Lett 622:118-23
Mazid, Sanoara; Hall, Baila S; Odell, Shannon C et al. (2016) Sex differences in subcellular distribution of delta opioid receptors in the rat hippocampus in response to acute and chronic stress. Neurobiol Stress 5:37-53
Naugle, Michelle M; Lozano, Sateria A; Guarraci, Fay A et al. (2016) Age and Long-Term Hormone Treatment Effects on the Ultrastructural Morphology of the Median Eminence of Female Rhesus Macaques. Neuroendocrinology 103:650-64
Garcia, Alexandra N; Depena, Christina K; Yin, Weiling et al. (2016) Testing the critical window of estradiol replacement on gene expression of vasopressin, oxytocin, and their receptors, in the hypothalamus of aging female rats. Mol Cell Endocrinol 419:102-12
Marques-Lopes, Jose; Lynch, Mary-Katherine; Van Kempen, Tracey A et al. (2015) Female protection from slow-pressor effects of angiotensin II involves prevention of ROS production independent of NMDA receptor trafficking in hypothalamic neurons expressing angiotensin 1A receptors. Synapse 69:148-65

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