The brain clearly plays a critical role in the transition to reproductive senescence. During the past funding period, we have found that during middle age, estradiol's ability to modulate the rhythmic neurochemical events, which are required for preovulatory GnRH/LH surges, diminishes. In addition, changes within the suprachiasmatic nucleus (SCN), the major circadian pacemaker, and its ability to drive diurnal neurochemical events lead to declining precision in the timing of the GnRH/LH surge. Our long-term objectives are to underatand the neural, cellular and molecular mechanisms by which estradiol and the circadian pacemaker act and interact to yield cyclic GnRH neuronal activity leading to LH surges at the proper time and of the proper amplitude and how these mechanisms change with age. This proposal focuses on events that occur in three regions of the hypothalamus: (a) the anteroventral periventicular. nucleus/periventricular preoptic area, (b) the organum vasculosum of the lamina terminalis/rostral medial preoptic nucleus and (c) the SCN. These three regions play critical and interactive roles regulating cyclic GnRH/LH surge& Together, the integrity of these regions is essential to maintain regular cyclic LH release and regular estrous cycles. The principal investigator will test the working hypothesis that changes in the ability of these brain regions to coordinate daily signals, respond to estracliol and/or communicate with GnRH neurons occur during middle age and lead to irregular esirous cycicity and reproductive decline. The investigators will address the following specific aims: (1) determine whether the diurnal patterns. of expression of key neuromodulators and/or their ability to cormmunicate with GnRH neurons are attenuated with age. Further, the investigators will assess whether these changes result from attenuated responsiveness to estradiOL (2) determine whether SCN neurons commulicate directly with GnRH neurons or indirectly through other neuronal phenotypes. The investigators will determine whether these direct and indirect connections to GnRH neurons change with age. (3) evaluate the role of astrocyte/neuron interactions in the age-related diminishing ability of estradiol or neuromodulators to influence GnRH expression and release. (4) assess whether age-related changes in responsiveness to estradiol result from changes in the receptor (ERa or ERb) and/or the ability of estrogen receptors to cross-talk with second messenger signaling systems.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Monjan, Andrew A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
Schools of Arts and Sciences
United States
Zip Code
Moran, Francisco M; Chen, Jiangang; Gee, Nancy A et al. (2013) Dehydroepiandrosterone sulfate levels reflect endogenous luteinizing hormone production and response to human chorionic gonadotropin challenge in older female macaque (Macaca fascicularis). Menopause 20:329-35
Brown, Candice M; Becker, Jessica O; Wise, Phyllis M et al. (2011) Simultaneous determination of 6 L-arginine metabolites in human and mouse plasma by using hydrophilic-interaction chromatography and electrospray tandem mass spectrometry. Clin Chem 57:701-9
Harrison, F E; May, J M; McDonald, M P (2010) Vitamin C deficiency increases basal exploratory activity but decreases scopolamine-induced activity in APP/PSEN1 transgenic mice. Pharmacol Biochem Behav 94:543-52
Brown, Candice M; Mulcahey, Tara A; Filipek, Nicole C et al. (2010) Production of proinflammatory cytokines and chemokines during neuroinflammation: novel roles for estrogen receptors alpha and beta. Endocrinology 151:4916-25
Brown, Candice M; Suzuki, Shotaro; Jelks, Karen A B et al. (2009) Estradiol is a potent protective, restorative, and trophic factor after brain injury. Semin Reprod Med 27:240-9
Suzuki, Shotaro; Brown, Candice M; Wise, Phyllis M (2009) Neuroprotective effects of estrogens following ischemic stroke. Front Neuroendocrinol 30:201-11
Downs, Jodi L; Wise, Phyllis M (2009) The role of the brain in female reproductive aging. Mol Cell Endocrinol 299:32-8
Wise, Phyllis M; Suzuki, Shotaro; Brown, Candice M (2009) Estradiol: a hormone with diverse and contradictory neuroprotective actions. Dialogues Clin Neurosci 11:297-303
Brown, Candice M; Dela Cruz, Christopher D; Yang, Enhua et al. (2008) Inducible nitric oxide synthase and estradiol exhibit complementary neuroprotective roles after ischemic brain injury. Exp Neurol 210:782-7
Jelks, Karen Bozak; Wylie, Rebecca; Floyd, Candace L et al. (2007) Estradiol targets synaptic proteins to induce glutamatergic synapse formation in cultured hippocampal neurons: critical role of estrogen receptor-alpha. J Neurosci 27:6903-13

Showing the most recent 10 out of 100 publications