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Anne M. EtgenProfessor Forchheimer Building
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Mechanisms of Hormone Action in the Brain
In collaboration with Dr. Genevieve Neal-Perry, we have begun to test the hypothesis that hypothalamic dysfunction plays a critical role in female reproductive senescence. Specifically, the role of hypothalamic excitatory (glutamate; Glu) and inhibitory ( g-aminobutyric acid; GABA) amino acid neurotransmitter release in the development of abnormal patterns of preovulatory luteinizing hormone release are being precisely quantified in rats with in vivo brain microdialysis and serial blood sampling. Findings to date suggest that middle-aged female rats have dramatic reductions in hypothalamic release of Glu, and that this is correlated with a delay in the onset and a reduction in the amplitude of luteinizing hormone release. Collaborative studies are also being conducted with the laboratory of Dr. R. Suzanne Zukin to examine mechanisms by which E 2 affords neuroprotection in the hippocampus following ischemia and reperfusion similar to that produced by cardiac arrest or during cardiac surgery. Our findings suggest that E 2 prevents the onset of apoptotic cell death in vulnerable hippocampal neurons and preserves hippocampal-dependent cognitive function. These studies suggest that postmenopausal estrogen replacement therapy could ameliorate ischemia-induced brain injury.
Selected Publications
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This laboratory is determining the cellular and molecular mechanisms by which steroid hormones regulate neuronal function. A major focus in the lab is the regulation of female reproductive physiology and behavior by the ovarian hormones, estradiol (E2) and progesterone (P). 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. Our work shows that hormonal regulation of reproduction involves coordinated modulation of both stimulus-evoked norepinephrine (NE) release and NE receptor linkage to multiple intracellular signaling pathways in the hypothalamus and preoptic area. At least two distinct mechanisms of hormone action have been identified: 1) regulation of gene transcription, most notably of the a 1B-adrenoceptor, and 2) regulation of b-, a 1- and a 2-adrenoceptor coupling to G proteins, which in turn link to intracellular effectors such as adenylyl cyclase, phospholipase C, nitric oxide synthase and soluble guanylyl cyclase. Work in progress suggests that E 2 and P work in concert to increase nitric oxide-dependent production of cyclic GMP by soluble guanylyl cyclase in the hypothalamus. Recent experiments also indicate that insulin-like growth factor-I (IGF-I) works in concert with E 2 to induce a 1B-adrenoceptor expression, to amplify a 1-adrenoceptor signaling in the brain, and to promote ovulation and reproductive behavior. We are now testing the hypothesis that IGF-I is a metabolic signal that helps the brain determine whether nutritional status is sufficient to support female reproductive function. We are also assessing the role of mitogen-activated protein kinase in P regulation of reproduction. 