Research in Dr. Anne Etgen's 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-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.
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.
Dr. Etgen is co-chair of the Professional Development Committee and chair of the Diversity in Neuroscience Subcommittee of the society for Neuroscience, and a member of the Society for the Study of Reproduction, International Brain Research Organization, and Society for Behavioral Neuroendocrinology.
Dr. Etgen completed her PhD in biological sciences with a specialty in neuroscience at the University of California, Irvine.
García-Juárez, M., Beyer, C., Gómora-Arrati, P., Lima-Hernández, F.J., Domínguez-Ordoñez, R., Eguibar, J.R., Etgen, A.M., González-Flores, O. (2012), The nitric oxide pathway participates in lordosis behavior induced by central administration of leptin. Neuropeptides 46(1):49-53.
Simpkins, J.W., Singh, M., Brock, C. and Etgen, A.M. (2012), Neuroprotection and estrogen receptors. Neuroendocrinology 96(2):119-130.
Inagaki, T., Kaneko, N., Zukin, R.S., Castillo, P.E., and Etgen, A.M. (2012), Estradiol attenuates ischemia-induced death of hippocampal neurons and enhances synaptic transmission in hippocampus of aged, long-term hormone-deprived female rats. PLoS ONE 7(6) e38018.
Santollo, J., Yao, D., Neal-Perry, G. and Etgen, A.M. (2012), Middle-aged female rats retain sensitivity to the anorexigenic effect of exogenous estradiol. Behav. Brain Res. 232(1):159-164.
De Butte-Smith, M., Zukin, R.S., and Etgen, A.M., Effects of global ischemia and estradiol pretreatment on phosphorylation of Akt, CREB and STAT3 in hippocampal CA1 of young and middle-aged female rats (2012). Brain Res. 1471:118-128.
Castro, C.C., Pagnussat, A.S., Worm, P., Pereira, L., Moura, N., Etgen, A.M. and Netto, C.A. (2012), Coumestrol has neuroprotective effects before and after global cerebral ischemia in female rats. Brain Res. 1474:82-90.
Lima-Hernández, F.J., Beyer, C., Gómora-Arrati, P., García-Juárez, M., Encarnación-Sánchez, J.L., Etgen, A.M., and González-Flores, O. (2012), Src kinase signaling mediates estrous behavior induced by 5b-reduced progestins, GnRH, prostaglandin E2 and vaginocervical stimulation in estrogen-primed rats. Horm. Behav. 62(5):579-584.
Inagaki, T. and Etgen, A.M. (2013), Neuroprotective action of acute estrogens: animal models of brain ischemia and clinical implications. Steroids 78(6):597-606.
García-Juárez, M., Beyer, C., Gómora-Arrati, P., Domínguez-Ordoñez, R., Lima-Hernández, F.J., Eguibar, J.R., Galicia-Aguas, Y.L., Etgen, A.M. and González-Flores, O. (2013), Lordosis facilitation by leptin in ovariectomized, estrogen-primed rats requires simultaneous or sequential activation of several protein kinase pathways. Pharmacol. Biochem. Behav. 110C:13-18.
Sehara, Y., Sawicka, K., Hwang, J.-Y., Latuszek-Barrantes, A., Etgen, A.M. and Zukin, R.S. (2013), Survivin is a transcriptional target of STAT3 critical to estradiol neuroprotection in global ischemia. J. Neurosci. 33(30):12364-12374.
Tada H, Kuroki Y, Funabashi T, Kamiya Y, Goto T, Suyama K, Sano A, Mitsushima D, Etgen AM, Takahashi T (2013), Phasic synaptic incorporation of GluR2-lacking AMPA receptors at gonadotropin-releasing hormone neurons is involved in the generation of the luteinizing hormone surge in female rats. Neuroscience 248:664-669.
Neal-Perry, G., Yao, D., Shu, J., Sun, Y. and Etgen, A.M. (2014), Insulin-like growth factor-1 regulates LH release by modulation of kisspeptin and NMDA mediated neurotransmission in young and middle-aged female rats. Endocrinology 155(5):1827-1837.
González-Flores, O., Lima-Hernández, F.J., Gómora-Arrati, P., Marcos Garcia-Juárez, M., Blaustein, J.D., Etgen, A.M., and Beyer, C. (2014), Estrogen receptors regulate the estrous behavior induced by progestins, peptides, and prostaglandin E2. Horm. Behav., in press.
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