The primary goal of this Program Project is to investigate interactions between the aging brain and female reproductive senescence. Early studies in young female rats demonstrated clearly that changes in circulating estrogen (E) levels affect cellular and molecular attributes of hypothalamic circuits as well as hippocampus, implicating E in modulating both reproductive neuroendocrine circuits and cognition. However, we now know that the aged brain reacts to E differently than the young brain, and we also know that the estrogen/aging interactions differ in important ways between rodents and nonhuman primates. The key to the next five years is to use both animal models to their best advantage to provide a neurobiological framework for the complex clinical issues surrounding the neurobiology of menopause and post-menopausal cognitive impairment. We will pursue a full spectrum analysis of the key issues;from signaling mechanisms of estrogen to an in-depth structural and functional assessment of the effects of estrogen on the circuits regulating reproductive function (hypothalamus), and cognition (hippocampus and prefrontal cortex). We will continue to reveal the neuronal signaling pathways activated by circulating E, as well as the molecular and synaptic basis for age related decline in E-induced synaptic plasticity. The rodent studies are particularly informative with respect to molecular mechanisms, and they have revealed several new targets of investigation for E signaling in hypothalamus, hippocampus and prefrontal cortex. The nonhuman primate studies reveal the neurobiological underpinnings of E-induced cognitive enhancement in aged monkeys, as well as the synaptic basis of cognitive resilience in the absence of E in young female monkeys. In addition, the nonhuman primate studies have highlighted the importance of prefrontal cortex and related cognitive functions as a target for E. Current studies in both the rat and nonhuman primate models are investigating the cognitive and neurobiological effects of different hormone treatment regimens. Proposed studies will investigate the "window of opportunity" hypothesis and the duration of beneficial effects after cessation of treatment. These results will provide critically important information on brain aging and will aid in the design of hormone treatments that provide maximal neurological benefits for post-menopausal women.

Public Health Relevance

Currently American women can expect to live nearly half of their adult life post-menopause. Given the importance of the brain as a target organ for estrogen, it is not surprising that many of the complaints that prompt women to seek treatment at menopause are neurological in origin. The proposed studies will lead to more successful hormone treatments for menopausal women that maximize beneficial effects to the brain and minimize potential risks. REVIEW OF INDIVIDUAL COMPONENTS OF THE PROGRAM PROJECT CORE A: THE NONHUMAN PRIMATE CORE;Dr. Bill Lasley, Core Leader (CL) DESCRIPTION (provided by applicant): The Animal Core is essential for the extension of the concepts that have been developed during the previous funding periods. In this application the Animal Core continues to provide the unique nonhuman primate (NHP) animal model, a trained staff in NHP research as well as specific methodologies and services that are required to make appropriate and efficient use of this limited resource. Studies involving monkeys currently in protocol will be completed in early 2011 and additional aged female rhesus monkeys will enter protocols and be studied over the five-year funding period. Our current data demonstrate the importance of estrogen treatment (ET) for the maintenance of higher brain function and structure in the absence of normal ovarian function in aged female primates. However, these previous studies have not conclusively identified which modality of ET or combined hormone treatment (HT) regimens are most effective and specifically which effective modalities would be best for clinical applications. The monkeys currently in protocol are committed to these studies. The monkeys that will enter protocols over this funding period will be used to investigate the structural and functional repercussions of altering the time of onset and duration of treatment following ovariectomy (OVX). These studies will investigate two critically important clinical issues;1) Is there a window of opportunity following cessation of ovarian function after which the brain is less responsive to ET/HT, and 2) Do the cognitive benefits of ET/HT started soon after the loss of circulating sex steroids persist after treatment is halted? Resources provided by the Animal Core include clinical care, trained animal care staff, therapeutic support, surgery/necropsy services and endocrine services. In addition, the California National Primate Center (CNPRC) behavior and endocrine staff scientists have participated in the design of the experiments and will be involved in the execution of the total research plan. Appropriately, the current application addresses specific questions that cannot be ethically approached in clinical studies but are effectively addressed in a NHP model. These studies will provide new and important information and insights for designing critical studies in the future. In addition, the results from all of the experiments will have direct and important implications for improved therapies to insure healthy aging in women. Both the use of the NHP model and a Primate Center setting and staff are required in order to effectively conduct such experiments and guarantee the delivery of interpretable data.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG016765-14
Application #
8645547
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9 (01))
Program Officer
Wise, Bradley C
Project Start
1999-04-21
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
14
Fiscal Year
2014
Total Cost
$1,740,280
Indirect Cost
$265,699
Name
Icahn School of Medicine at Mount Sinai
Department
Neurosciences
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Marques-Lopes, Jose; Van Kempen, Tracey; Waters, Elizabeth M et al. (2014) Slow-pressor angiotensin II hypertension and concomitant dendritic NMDA receptor trafficking in estrogen receptor ?-containing neurons of the mouse hypothalamic paraventricular nucleus are sex and age dependent. J Comp Neurol 522:3075-90
McEwen, B S (2014) Sex, stress and the brain: interactive actions of hormones on the developing and adult brain. Climacteric 17 Suppl 2:18-25
Almey, Anne; Cannell, Elizabeth; Bertram, Kyla et al. (2014) Medial prefrontal cortical estradiol rapidly alters memory system bias in female rats: ultrastructural analysis reveals membrane-associated estrogen receptors as potential mediators. Endocrinology 155:4422-32
Picard, Martin; McEwen, Bruce S (2014) Mitochondria impact brain function and cognition. Proc Natl Acad Sci U S A 111:7-8
Morrison, John H; Baxter, Mark G (2014) Synaptic health. JAMA Psychiatry 71:835-7
Wu, Melody V; Shamy, Jul Lea; Bedi, Gillinder et al. (2014) Impact of social status and antidepressant treatment on neurogenesis in the baboon hippocampus. Neuropsychopharmacology 39:1861-71
Kermath, Bailey A; Riha, Penny D; Woller, Michael J et al. (2014) Hypothalamic molecular changes underlying natural reproductive senescence in the female rat. Endocrinology 155:3597-609
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
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
Naugle, Michelle M; Gore, Andrea C (2014) GnRH neurons of young and aged female rhesus monkeys co-express GPER but are unaffected by long-term hormone replacement. Neuroendocrinology 100:334-46

Showing the most recent 10 out of 102 publications