Anne M. Etgen

Mechanisms of Hormone Action in the Brain

Research in this laboratory is focused on determining the cellular and molecular mechanisms by which ovarian steroid hormones regulate brain function. Investigations center on two topics: (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- α (ER α ), 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 ER α 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.

2) A second major research topic in the Etgen laboratory is the role of estradiol and IGF-1 in improving outcomes after global ischemia (e.g., in cardiac arrest). This project is being carried out in collaboration with R. Suzanne Zukin. We have shown that physiological levels of estradiol reduce both hippocampal neuron loss and ischemia-induced cognitive impairments in young female rats . These neuroprotective actions of estradiol require co-signaling by brain IGF-1 receptors and are mediated by the ERK/MAPK signaling pathway. We are now investigating whether the middle-aged brain retains its responsiveness to the neuroprotective actions of estradiol and IGF-1, and if the duration of hormone withdrawal influences the efficacy of hormone treatment. Our findings suggest that both estradiol and IGF-1 can rescue hippocampal neurons from ischemia-induced cell death in middle-aged females even after a prolonged interval of estrogen deprivation.

Selected Publications

Lederman, M.A., Lebesgue, D., Gonzalez, V.V., Merhi, Z., Shu, J., Etgen, A.M. and Neal-Perry, G.S. (2010), Age-related LH surge dysfunction correlates with reduced responsiveness of hypothalamic anteroventral periventricular nucleus kisspeptin neurons to estradiol positive feedback in middle-aged rats. Neuropharmacology 58:314-320.

De Butte-Smith, M., Gulinello, M., Zukin, R.S., and Etgen A.M. (2009), Chronic estradiol treatment increases CA1 cell survival but does not improve visual or spatial working memory performance after global ischemia in middle-aged female rats. Horm. Behav. 55:442-453.

González-Flores, O., Gómora-Arrati, P., Garcia-Juárez, M., Gómez-Camarillo, M.A., Lima-Hernández, F.J., Beyer, C. and Etgen, A.M. (2009), Nitric oxide and MAPK mediation of estrous behavior induced by GnRH, PGE 2 and db-cAMP in rats. Physiol. Behav. 96: 606–612 .

Lebesgue, D., Chevaleyre, V., Zukin, R.S. and Etgen, A.M. (2009), Estradiol rescues neurons from global ischemia-induced cell death: Multiple cellular pathways of neuroprotection. Steroids 74:555-561.

Neal-Perry, G.S., Lebesgue, D., Shu, J., Zeevalk, G.D., and Etgen, A.M. (2009), Kisspeptin restores the luteinizing hormone surge by modulating amino acid neurotransmission in the medial preoptic area of middle-aged female rats. Endocrinology 150:3699-3708.

Lebesgue, D., Reyna-Neyra, A., Huang, X., and Etgen, A.M. (2009), GPR30 differentially regulates short latency responses of luteinizing hormone and prolactin secretion to oestradiol. J. Neuroendocrinol. 21:743-752.

Gómora-Arrati, P., Beyer, C., Lima-Hernández, F.J., Garcia, M.H., Etgen, A.M., and González-Flores, O. (2008), GnRH mediates estrous behavior induced by ring A-reduced progestins and vaginocervical stimulation. Behav. Brain Res. 187:1-8.

Lee, A.W., Kyrozis, A., Chevaleyre, V., Kow, L.-M., Zhou, J., Devidze, N., Zhang, Q., Etgen, A.M. and Pfaff, D.W. (2008), Voltage-dependent calcium channels in ventromedial hypothalamic neurones of postnatal rats: Modulation by oestradiol and phenylephrine. J. Neuroendocrinology 20:188-198.

Lee, A.W., Kyrozis, A., Chevaleyre, V., Kow, L.M., Devidze, N., Zhang, Q., Etgen, A.M. and Pfaff, D.W. (2008), Estradiol modulation of phenylephrine-induced excitatory responses in ventromedial hypothalamic neurons of postnatal rats. Proc. Natl. Acad. Sci. USA 105(20):7333-7338 .

Neal-Perry, G.S., Zeevalk, G.D., Shu, J. and Etgen, A.M. (2008), Restoration of the luteinizing hormone surge in middle-aged female rats by altering the balance of GABA and glutamate transmission in the medial preoptic area. Biol. Reprod. 79:878-888.

González-Flores, O., Etgen, A.M., Komisaruk, B.K., Macias, A., Gómora-Arrati, P., Lima-Hernández, F.J. and Beyer, C. (2008), Facilitation of estrous behavior in estrogen primed rats by vaginocervical stimulation involves the activation of multiple signaling pathways and the progestin receptor. J. Neuroendocrinol. 20:1361-1367.

González-Flores, O., Beyer, C., Lima-Hernández, F.J., Gómora-Arrati, P., Gómez-Camarillo, M.A., Hoffman, K. and Etgen, A.M. (2007), Facilitation of estrous behavior by vaginal cervical stimulation in female rats involves a 1 -adrenergic receptor activation of the nitric oxide pathway. Behav. Brain Res. 176:237-243.

Jover-Mengual, T., Zukin, R.S. and Etgen, A.M. (2007), MAPK signaling is critical to estradiol protection of CA1 neurons in global ischemia. Endocrinology 148:1131-1143 .

Reyna-Neyra, A., Sarkar, G. and Etgen, A.M. (2007), Regulation of soluble guanylyl cyclase activity by estradiol and progesterone in the hypothalamus but not hippocampus of female rats. J. Neuroendocrinol. 19:418-425.

Todd, B.J., Fraley, G.S., Peck, A.S., Schwartz, G.S., and Etgen, A.M. (2007), Central IGF-I receptors play distinct roles in the control of reproduction, food intake and body weight in female rats. Biol. Reprod. 77:492-503.