Dr. Genevieve Neal-Perry

Our lab is interested in identifying the neural mechanisms that drive reproductive aging in females. We are testing the hypothesis that altered neural responsiveness to ovarian steroids in middle-aged females changes the balance of excitatory (glutamate, kisspeptin) and inhibitory (GABA) neurotransmission in the hypothalamus, leading to inadequate activation of gonadotropin releasing hormone (GnRH) neurons on the day of the preovulatory luteinizing hormone (LH) surge.

Project Goal: This translational project is designed to provide insight and augment comprehension of the cellular mechanisms that initiate the transition to the menopause and its associated clinicopathologies. We anticipate that these findings will provide a foundation for the development of targeted pharmacotherapy designed to prolong ovarian function and as a consequence, to extend the health benefits of continued ovarian steroid exposure.

Background: Female reproductive aging is a complex process that culminates in the loss of ovarian function and the physiological benefits of ovarian steroids. Prolonged ovarian steroid exposure confers an improved quality of life and reduces age-related morbidities in women.However, recent controversy about benefits of exogenous hormone therapy during the menopause underscores the need to identify the physiological mechanisms that give rise to the menopausal transition. While much is known about the role of the ovary in the menopausal transition, little is known about the role of the neuroendocrine axis.

 Approach : To develop a comprehensive understanding of the neural events involved in reproductive aging, we use in vivo brain microdialysis, brain infusion, in vitro brain slice assays, immunohistochemistry, microscopy, microsurgery, basic biochemistry and molecular biology techniques. Findings to date suggest that middle-aged female rats treated with physiological doses of ovarian steroids have dramatic reductions in hypothalamic release of glutamate and increased release of GABA, and that these changes in amino acid neurotransmission may be causally related to the delayed onset and reduced amplitude of the preovulatory LH surge. More recent studies suggest that altered hormonal regulation of kisspeptin, an excitatory hypothalamic neuropeptide critical for reproduction, is also a critical component of female reproductive aging. Kisspeptin infusion in to the hypothalamus increases glutamate, decreases GABA, and restores the LH surge in middle-aged rats. The NMDA receptor antagonist MK801 blocks kisspeptin restoration of the LH surge in middle-aged rats, suggesting that recovery of the LH surge results, in part, from increased hypothalamic glutamate neurotransmission. Currently, we are examining the possibility that there is an age-dependent change in the ability of ovarian steroids to regulate the expression of kisspeptin mRNA and protein in the hypothalamus, thereby decreasing the number and activity of hypothalamic kisspeptin neurons available to modulate glutamate, GABA, and GnRH neuronal activation.

In collaboration with Dr. Anne Etgen, we have begun to test the hypothesis that age-related depletions in central insulin-like growth factor-1 (IGF-1) may also reduce the ability of middle-aged rats to mount normal preovulatory LH surges. Preliminary results suggest that intrahypothalamic infusion of IGF-1 partially restores the LH surge in middle-aged rats. Future experiments will determine if IGF-1 signaling is essential for ovarian steroids to regulate hypothalamic glutamate, kisspeptin and/or GABA on the day of the LH surge and whether kisspeptin and IGF-1 use similar cellular pathways to activate GnRH neurons.

Selected Publications