Paul E Micevych, PhD

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

The reproductive hormones estradiol and progesterone bathe our internal organs. They have profound influence over the central and peripheral nervous system. While these steroids have been studied for many years, recent advances indicate that many actions of estradiol in the nervous system are mediated by receptors located on the cell membrane, suggesting more of a neurotransmitter than a hormonal role. My lab is working to understand the multiple mechanisms and circuits through which estrogen and progesterone affect cell types in different systems to affect reproduction, behavior, pain transmission and neuroprotection.