Paul E Micevych Ph.D.

Research interest:
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.

Samantha J. Butler, Ph.D.

Academic Titles/Accomplishments/Affiliations: Member, Neuroscience GPB Home Area Associate Professor, Neurobiology Research interest: The extraordinarily diverse functions of the nervous system, from cognition to movement, are possible because neurons are assembled into precisely ordered networks that permit them to rapidly and accurately communicate with their synaptic targets. The Butler laboratory seeks to understand the mechanisms that establish these neuronal networks during development with the long-term goal of determining how this process may be co-opted to regenerate diseased or damaged circuits. Working the developing spinal cord, we have shown that molecules previously identified as morphogens, such as the Bone Morphogenetic Proteins (BMPs) family of growth factors, can also act as axon guidance signals. We are now determining the key intrinsic factors that translate the ability of the BMPs to direct cell fate and axon guidance decisions, two strikingly different processes in the generation of neural circuits. During the course of these studies, we have identified a critical mechanism by which the rate of axon outgrowth is controlled during embryogenesis, thereby permitting neural circuits to develop in synchrony with the rest of the embryo. The Butler laboratory is currently assessing how this mechanism can be harnessed to accelerate the regeneration of injured peripheral nerves. The successful implementation of this technology could result in significantly improved recovery times for patients with damaged nervous systems. Samantha received her B.A from Cambridge University, working in Michael Akam’s laboratory, where she was instilled with a love of developing systems. She joined Yash Hiromi’s lab, then at Princeton University, for her Ph.D. studying the genetic mechanisms that establish cell fate in the Drosophila eye.  Since neurons had become increasingly important to her as she lost them during her years as a graduate student, she joined Jane Dodd’s laboratory at Columbia University to examine axon guidance mechanisms in the developing vertebrate spinal cord. In her own laboratory as an Associate Professor at UCLA, Samantha explores how the developmental mechanisms that first establish neural circuits can be reused to ameliorate damaged or diseased nervous systems.  She is funded by the NIH, CIRM, Department of Defense, March of Dimes and the Craig H. Neilsen and Jean Perkins foundations Publications Gaber Zachary B, Butler Samantha J, Novitch Bennett G   PLZF Regulates Fibroblast Growth Factor Responsiveness and Maintenance of Neural Progenitors PLoS biology, 2013; 11(10): e1001676.

Kong J. H., Butler S. J., Novitch B. G.   My brain told me to do it Developmental cell, 2013; 25(5): 436-8.
Yamauchi K., Varadarajan S. G., Li J. E., Butler S. J.   Type Ib BMP receptors mediate the rate of commissural axon extension through inhibition of cofilin activity Development, 2013; 140(2): 333-42.
Hazen V. M., Andrews M. G., Umans L., Crenshaw E. B., Zwijsen A., Butler S. J.   BMP receptor-activated Smads confer diverse functions during the development of the dorsal spinal cordDevelopmental biology, 2012; 367(2): 216-27.
Hazen V. M., Phan K. D., Hudiburgh S., Butler S. J.   Inhibitory Smads differentially regulate cell fate specification and axon dynamics in the dorsal spinal cord Developmental biology, 2011; 356(2): 566-75.
Phan K. D., Croteau L.-P., Kam J. W. K., Kania A., Cloutier J.-F., Butler S. J.   Neogenin may functionally substitute for Dcc in chicken PloS one, 2011; 6(7): e22072.
Phan K. D., Hazen V. M., Frendo M.E., Jia Z.-P., Butler S.J.   The bone morphogenetic protein roof plate chemorepellent regulates the rate of commissural axonal growth Journal of Neuroscience, 2010; 30(46): 15430-40.
Hazen V. M., Phan K.D., Yamauchi K., Butler S. J.   Assaying the ability of diffusible signaling molecules to reorient embryonic spinal commissural axons JoVE, 2010; 31(37): .
Novitch B. G., Butler S. J.   Reducing the mystery of neuronal differentiation Cell, 2009; 138(6): 1062-4.
Yamauchi K., Phan K. D., Butler S. J.   BMP type I receptor complexes have distinct activities mediating cell fate and axon guidance decisions Development, 2008; 135(6): 1119-28.
Butler S. J., Tear G.   Getting axons onto the right path: the role of transcription factors in axon guidance Development, 2007; 134(3): 439-48.
Butler S. J., Dodd J.   A role for BMP heterodimers in roof plate-mediated repulsion of commissural axons Neuron, 2003; 38(3): 389-401.
Augsburger A., Schuchardt A., Hoskins S., Dodd J., Butler S.   BMPs as mediators of roof plate repulsion of commissural neurons Neuron, 1999; 24(1): 127-41.

Butler S. J., Ray S., Hiromi Y.   klingon, a novel member of the Drosophila immunoglobulin superfamily, is required for the development of the R7 photoreceptor neuron Development, 1997; 124(4): 781-92.