It is becoming increasingly clear that the mechanisms for reproductive aging involve a complex interaction of the three levels of the hypothalamic-pituitary-gonadal (HPG) axis. In rats and other rodents, reproductive cycles become irregular at middle age and acyclicity ensues shortly thereafter, although the ovaries still contain functional follicles. These observations support the role of the hypothalamus and/or pituitary in the transition to acyclicity. My laboratory has been studying a role in reproductive senescence for GnRH neurons, the primary cells controlling reproductive function. Recent evidence suggests that a major mechanism for compromised HPG function during aging is due to age-related alterations in regulatory inputs to GnRH cells. Here, I will investigate the neuroendocrine mechanisms that underlie the transition to acyclicity at middle age, focusing on how the NMDA receptor (NMDAR), which mediates effects of the neurotransmitter glutamate, interacts with GnRH cells at their perikarya in the preoptic area (POA) and neuroterminals in the median eminence (ME), and the consequences of these effects on reproductive decline. My model is young (regular estrous cycles) and middle-aged (regular or irregular cycles, or acyclic) Sprague-Dawley rats;therefore, my analyses will take both age (young vs. middle-aged) and reproductive status (cyclic, irregularly cycling, or acyclic) into consideration as independent variables.
Three Specific Aims are proposed to test our hypotheses.
Aim 1 will investigate effects of age-related changes in NMDARs in POA, on GnRH cells specifically and in POA nuclei in general.
Aim 2 will examine similar relationships in the ME.
Aim 3 will study how NMDARs and estrogen receptors (ERs) may be expressed in the same target cells in POA and ME, including GnRH cells, and how these change during reproductive aging. Together, these studies will link GnRH neurons, NMDARs, and ERs, to elucidate how these systems act coordinately to result in the transition to acyclicity at middle age, and to provide insight into their mechanisms. My three Specific Aims form the basis for a model of the perimenopausal transition in women, an area relevant to improving healthy aging, and will provide fundamental and functional insights into the role of the hypothalamus in reproductive senescence. These experiments have clinical implications for postmenopausal hormone replacement therapy, for identifying non- hormonal approaches to treating menopausal symptoms, and for potentially expanding the reproductive lifespan, which is becoming more important as women continue to postpone childbearing until later in life.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG028051-05
Application #
8032449
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Mackiewicz, Miroslaw
Project Start
2007-02-01
Project End
2013-01-31
Budget Start
2011-02-15
Budget End
2013-01-31
Support Year
5
Fiscal Year
2011
Total Cost
$291,007
Indirect Cost
Name
University of Texas Austin
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
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
Kermath, B A; Riha, P D; Sajjad, A et al. (2013) Effects of chronic NMDA-NR2b inhibition in the median eminence of the reproductive senescent female rat. J Neuroendocrinol 25:887-97
Kermath, Bailey A; Gore, Andrea C (2012) Neuroendocrine control of the transition to reproductive senescence: lessons learned from the female rodent model. Neuroendocrinology 96:1-12
Williams, Tanya J; Mitterling, Katherine L; Thompson, Louisa I et al. (2011) Age- and hormone-regulation of opioid peptides and synaptic proteins in the rat dorsal hippocampal formation. Brain Res 1379:71-85
Wu, Di; Gore, Andrea C (2010) Changes in androgen receptor, estrogen receptor alpha, and sexual behavior with aging and testosterone in male rats. Horm Behav 58:306-16
Yin, Weiling; Gore, Andrea C (2010) The hypothalamic median eminence and its role in reproductive aging. Ann N Y Acad Sci 1204:113-22
Yin, Weiling; Mendenhall, John M; Monita, Monique et al. (2009) Three-dimensional properties of GnRH neuroterminals in the median eminence of young and old rats. J Comp Neurol 517:284-95
Yin, Weiling; Wu, Di; Noel, Megan L et al. (2009) Gonadotropin-releasing hormone neuroterminals and their microenvironment in the median eminence: effects of aging and estradiol treatment. Endocrinology 150:5498-508
Maffucci, Jacqueline A; Gore, Andrea C (2009) Chapter 2: hypothalamic neural systems controlling the female reproductive life cycle gonadotropin-releasing hormone, glutamate, and GABA. Int Rev Cell Mol Biol 274:69-127
Maffucci, J A; Noel, M L; Gillette, R et al. (2009) Age- and hormone-regulation of N-methyl-D-aspartate receptor subunit NR2b in the anteroventral periventricular nucleus of the female rat: implications for reproductive senescence. J Neuroendocrinol 21:506-17

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