1) how ovarian steroids act in neuroendocrine brain regions (e.g., hypothalamus and preoptic area) to coordinate female reproductive physiology and behavior, and
2) how estradiol and related estrogens promote neuronal survival after transient global ischemia
These two research questions are described in more detail below.
1) A major focus in the lab is the regulation of female reproductive physiology and behavior by the ovarian hormones, estradiol and progesterone. We wish to understand how hormonal modulation of synaptic transmission in specific brain regions coordinates the timing of ovulation with mating behavior (lordosis), thereby maximizing reproductive success. It is well known that estradiol acts via a ligand-activated transcription factor, estrogen receptor-á (ERá), to regulate female reproductive function. Recent findings from our lab indicate that hypothalamic insulin-like growth factor-1 (IGF-1) receptors act in concert with ERá to control gondatropin releasing hormone (GnRH) neurons and hence female reproductive function. We are now testing two related hypotheses: (1) that IGF-1 regulates estradiol-dependent afferent signals to GnRH neurons, and (2) that IGF-1 regulates GnRH neuronal responsiveness to afferent input. We are also working in collaboration with Genevieve Neal-Perry, M.D., Ph.D., to test the hypothesis that reduced IGF-1 receptor signaling in the aging brain may be responsible for attenuated neural responses to ovarian steroids and hence the delayed and attenuated luteinizing hormone (LH) surge that characterizes the perimenopause. Other experiments test the hypothesis that the delayed onset and reduced amplitude of the preovulatory LH surge in middle-aged female rats results from changes in the ability of ovarian steroids to modulate excitatory (glutamate and kisspeptin) and inhibitory (GABA) signals that regulate GnRH neurons. Recent findings suggest that intra-hypothalamic infusion of the neuropeptide kisspeptin, a potent activator of GnRH neurons, rescues LH surges in middle-aged females by enhancing local glutamate release.
