Robert J. Handa, PhD Professor Phone: 970-491-7130 Member Education |
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Workshop on Steroid Hormones and Brain Function
US/Japan International Symposium on Neuroplasticity, Development and Steroid Hormone Action
Research Interests -- Steroid Hormone Receptors and Sex Differences in Brain Function
Sex differences in the central nervous system arise as a result of the influence of gonadal steroid hormones acting during development and adulthood. The actions of these steroid hormones are mediated via specific intracellular receptors. Current studies in my laboratory have examined the regulation of androgen and estrogen receptor synthesis and the neurobiological and neuroendocrine systems modulated by these receptors. We are presently using several model systems to explore the actions of sex steroids in the brain and pituitary gland. Our data show that androgens inhibit the neuroendocrine response (hormone secretion and neuropeptide synthesis) to physical and psychological stressors, whereas estrogen augments the response. The recent cloning of a novel, beta form of estrogen receptor, which is present in brain regions functionally relevant to neuroendocrine regulation may provide further insight into the mechanisms by which steroid hormones regulate stress responses. These studies are important given the previously reported sex differences in stress hormone secretion, the dysregulation of the control of stress hormone secretion which accompanies behavior disorders such as depression and the fluctuations in gonadal hormones which occur throughout life including decreases with the normal aging process. These studies also are attempting to define the varied strategies adopted by males and females to cope with stressors which can deleteriously affect reproduction.
We also are investigating the effects of estrogen and androgen on glutamate receptor mediated neurotoxicity. Previous studies have established that adrenal hormone secretion (glucocorticoids) can exacerbate glutamate receptor mediated neurotoxicity in the hippocampus. Our studies have demonstrated that a high concentration of androgen receptor exists in the hippocampus and these receptors may actually serve a neuroprotective function opposite that described for glucocorticoids. Ongoing and proposed studies are using in vivo and in vitro approaches to examine the hypothesis that androgens act directly on hippocampal pyramidal neurons to protect them from excitotoxic insults. These studies are important given that estrogen and testosterone decrease in aged individuals and thus, may influence the ability of neurons to survive following potentially neurotoxic insults.
Gonadal steroid hormone receptors are well-known transcription factors; however, the mechanisms by which gonadal steroids can influence gene expression are varied. Steroid hormones may affect neuroendocrine gene expression directly, or through changes in other cellular pathways. Sex steroids have powerful and widespread influences throughout the brain and ultimately, the actions of gonadal steroids must be examined in context of known neural circuits and neuroendocrine regulators. Our studies are aimed at determining some of the mechanisms underlying age-, development- and sex-related differences in the cellular and behavioral responses to intracellular and environmental signals and cues.
Representative Publications
Lund TD, Rovis T, Chung WCJ, Handa RJ. 2005. Novel actions of estrogen
receptor beta on anxiety-related behaviors.
Endocrinology146:797-807.
Suzuki S, Handa RJ. 2005. Estrogen receptor (ER)-b, but not ER-a is expressed in prolactin containing neurons of the female rat paraventricular and supraoptic nuclei: a comparison with other neuropeptides. J Comp Neurol 484:28-42.
Lund TD, Hinds LR, Handa RJ. 2006. 5a-dihydrotestosterone and its metabolite, 5a-androstan-3b, 17b-diol inhibit the hypothalamo-pituitary adrenal response to stress by acting through estrogen receptor beta expressing neurons in the hypothalamus. J Neurosci 26:1448-1456.
Pak TR, Chung WCJ, Roberts JL, Handa RJ. 2006. Ligand-independent effects of estrogen receptor beta on mouse gonadotropin releasing hormone (GnRH) promoter activity. Endocrinology 147:1924-1931.
Sandau US, Handa RJ. 2007. Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex. Neuroscience:144:482-494.
Pak TR, Chung WCJ, Hinds LR, Handa RJ. 2007. Estrogen receptor-beta mediates
DHT-induced stimulation of the arginine vasopressin promoter in neuronal
cells. Endocrinology (e-published ahead of print, 4/07).
