Distinguished Professor, Head and Neck Surgery
Distinguished Professor, Head and Neck Surgery
Research efforts in the Micevych laboratory involve understanding the cellular and molecular events underlying estrogen action on neurons and glial cells. Estrogen has profound effects on cognitive function and neuroprotection, as well as, reproductive functions. Estrogen affects the expression and activity of various neuropeptides and sex steroids. In particular they have focused on regulation mu-opioid and nociceptin receptors in the CNS regulation of sexual behavior. Recent experiments have demonstrated the synthesis of progesterone in the brain, its regulation by estrogen and physiologic functions of neuroprogesterone. RT-PCR and calcium imaging experiments in neurons and astrocytes have been used to elucidate the mechanisms of estrogen rapid signaling in both glial cells and neurons. The Micevych laboratory has demonstrated that estrogen can modulate nociceptive signaling through rapid actions on primary sensory neurons demonstrating a novel mechanism of estrogen modulation of pain. Additionally, the Micevych Laboratory has been studying the neuroprotective action of estrogen in the nigrostriatal dopamine system. These experiments underscore the broad range of estrogen signaling influencing both physiology and pathology.
The research of the laboratory is focused on steroid hormone interactions with the central nervous system. Throughout life, sex steroid hormones profoundly influence the structure and function of specific circuits that regulate reproduction and reproductive behaviors. Previous work had focused on the regulation of neuropeptide and transmitter expression. However, relatively little is known about the mechanisms by which steroids affect postsynaptic activation and signal transduction. The laboratory has three major interests: STEROID MODULATION OF mu-OPIOID RECEPTOR (MOR) ACTIVATION Estrogen treatment of ovariectomized rats initially has an inhibitory action on circuits mediating sexual receptivity (lordosis), but eventually induces sexual receptivity. We have determined that an important component of this inhibition is due to the activation of MOR circuits in the medial preoptic area. Taking advantage of G protein-coupled receptor (GPCR) internalization following activation of the receptor by an endogenous ligand, we determined that activation of MOR is correlated with an inhibition of lordosis. Behaviorally, progesterone augments estrogen action. We have determined that progesterone relieves MOR-mediated inhibition, through the termination of opioid release in the medial preoptic area. Is the MOR-inhibition dependent on estrogen receptors? Working with Dr. Emilie Rissman, (University of Virginia), we have determined that estrogen activation of MOR circuits is dependent on the expression of the estrogen receptor-a (ERa). Although MOR and opioid expression appears nominal in ERa knockout (ERaKO) mice, and MOR-selective opioids internalize MOR, estrogen does not induce internalization. These results and the rapid time course of internalization suggest that the ERa is acting through a nongenomic mechanism. REGULATION OF NEUROSTEROID BIOSYNTHESIS Although it is well known that the brain can synthesize neurosteroids, it has been difficult to determine the function of these steroids in the regulation of reproduction. We have recently determined that peripheral estrogen stimulates the synthesis of progesterone in the hypothalamus. This increased in progesterone is restricted to the hypothalamus and is necessary for the initiation of the LH surge. Examination of cells in vitro suggest that astrocytes are responsible for the estrogen-induced progesterone synthesis. This response to estrogen may be an important component of estrogen positive feedback regulates the LH surge. Males and aging females that do not exhibit positive feedback, that are lacking the ability to increase progesterone synthesis in the hypothalamus. NONGENOMIC ACTIONS OF ESTROGEN MODULATION To begin examining the nongenomic actions of estrogen on regulation of postsynaptic mechanisms, we have studied the response of Ca2+ in dorsal root ganglion (DRG) cells. DRG cells provide an accessible and practical solution to quantitatively study the chemosensitive properties of estrogen-sensitive neurons. These cells express ERa and a number of other well characterized Ca2+ channels. We have been studying the effects of estrogen on modulation of P2X receptors (ATP receptors) and activity of voltage dependent Ca2+ channels (VdCC) using digital videomicroscopy for [Ca2+]i changes. Recent results indicate that 17-beta estradiol inhibited ATP-mediated [Ca2+]i responses and attenuated Ca2+ rise by acting on L-type VDCC in both male and female DRG neurons