The goal of this project is to examine functional changes in the GnRH neuron with aging that may contribute to reproductive senescence. Reproduction in mammals is critically dependent upon the appropriate neurosecretion of gonadotropin-releasing hormone (GnRH). The pulsatile release of GnRH, resulting in the pulsatile release of gonadotropic hormones from the anterior pituitary, is necessary for the maintenance of normal reproductive function in both males and females. Before and during menopause, a number of changes occur at the level of the hypothalamus, including changes in GnRH activity. The studies outlined in this proposal are designed to determine if changes are seen in intrinsic episodic activity and/or excitatory amino acid receptor expression in GnRH neurons with age and reproductive status. Until recently, functional studies of the GnRH system have been extremely difficult, due to the scattered distribution and homogeneous appearance of cells. However, the development of a transgenic mouse that expresses enhanced green fluorescent protein (EGFP) in GnRH neurons is providing a promising new model for the study of GnRH function. Whole cell voltage-clamp and current clamp electrophysiology will be performed on isolated GnRH-EGFP neurons from young adult, middle-aged, and old female transgenic mice. All animals will be ovariectomized; half will be estrogen replaced. Functional studies will examine changes in spontaneous and evoked activity, ion channels, and excitatory amino acid receptor expression in these groups. Changes at the level of the GnRH neuron during aging would significantly influence reproductive function. The transition to menopause has a significant physical and emotional impact on aging women. Thus, it has become increasingly important to understand factors that contribute to reproductive aging and the transition to reproductive senescence. ? ? ? ? ?

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Monjan, Andrew A
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University of Missouri-Columbia
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Wang, Yong; Kuehl-Kovarik, M Cathleen (2012) Estradiol directly attenuates sodium currents and depolarizing afterpotentials in isolated gonadotropin-releasing hormone neurons. Brain Res 1436:81-91
Wang, Yong; Garro, Mona; Kuehl-Kovarik, M Cathleen (2010) Estradiol attenuates multiple tetrodotoxin-sensitive sodium currents in isolated gonadotropin-releasing hormone neurons. Brain Res 1345:137-45
Wang, Yong; Kuehl-Kovarik, M Cathleen (2010) Flufenamic acid modulates multiple currents in gonadotropin-releasing hormone neurons. Brain Res 1353:94-105
Wang, Yong; Garro, Mona; Dantzler, Heather A et al. (2008) Age affects spontaneous activity and depolarizing afterpotentials in isolated gonadotropin-releasing hormone neurons. Endocrinology 149:4938-47
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