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George Flouret, Ph.D.
Department of Physiology
Ph.D., University of Wisconsin-Madison

My research is in the area of peptide hormone synthesis, breakdown and mode of action. We
have synthesized many agonists and antagonists of LHRH, which is a peptide messenger secreted by the brain, and which controls the secretion of LH and FSH by the anterior pituitary. Several of the LHRH antagonists we have designed have strong antiovulatory activity, and we are studying their susceptibility to enzymatic breakdown in various tissues, in vivo or in vitro. We have also designed highly potent oxytocin antagonists (OTAs), with the aim of inhibiting preterm labor. OT is one of the hormones that promote the contractions of labor. Some of our antagonists may be the most potent OTAs yet designed and successfully inhibit labor in the rat and the baboon. We are also investigating the binding of OT and OTAs by uterine receptors. An understanding of the characteristics of peptide hormone binding to receptors in target tissues as well as the mechanisms of enzymatic degradation of these substances enhances the likelihood that antagonists which have clinical significance may be developed both for LHRH and OT.

Recent Publications: Fejgin MD, Pak SC, Flouret G, Wilson Jr L 1994 Oxytocin antagonist inhibitory effect in the baboon and rat uterus may be overcome by the use of prostaglandins. Am J Obstet Gynecol 171:1076-1080.

Fak SC, Bertoncini D, Meyer W, Scaunas D, Flouret G, Wilson Jr L 1994 Comparison of binding affinity of oxytocin antagonists to human and rat uterine oxytocin receptors and their correlation to the rat uterine oxytocic bioassay. Biol Reprod 51:1140-1144.

Flouret G, Arnold ZS, Majewski T, Petousis NH, Mahan K, Farooqui F, Blum KA, Konopinska D, Natarajan S, Crich D 1995 Antiovulatory Antagonists of LHRH related to Antide. J Peptide Sci 1:89-105.

Ahn TG, Han SJ, Cho YS, An TH, Pak SC, Flouret G. In vivo activity of the potent oxytocin antagonist on uterine activity in the rat. In Vivo. 2004 Nov-Dec;18(6):763-6.

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Jon E. Levine, Ph.D.
Department of Neurobiology and Physiology
Ph.D., University of Illinois

We are particularly interested in the activity of neurons that synthesize and release
luteinizing hormone-releasing hormone (LHRH), a decapeptide that mediates hypothalamic regulation of pituitary gonadotropes, thereby controlling ovulatory cycles and other critical reproductive functions. Our studies also focus on other important neuromodulators of reproductive function, such as neuropeptideY (NPY). To study the activity of these and other peptidergic cell groups, we use in vivo microdialysisas well as in vitro superfusion of tissue and cell cultures to measure the ongoing release of peptideregulators under various physiological and pharmacological conditions. In situ hybridization andrelated molecular technologies are also used to analyze the physiological regulation of gene expression in these neurons. Three basic aspects of hypothalamic neuropeptide function are examined: the intrinsic cellular activities of these systems (e.g., mechanisms regulating pulsatile release patterns), the regulation of pituitary hormone secretion by hypothalamic peptidergic neurons, and the regulation of peptide neurosecretion and gene expression by hypothalamic neurotransmitters and gonadal steroid feedback mechanisms. Integrated studies at these three levels are directed at understanding basic reproductive processes, such as the generation of preovulatory gonadotropin surges. A midcycle surge of gonadotropins provides the endocrine trigger for ovulation in virtually all mammals and is dependent upon the sufficient and appropriate release of LHRH and other hypothalamic regulators, such as NPY. We are therefore attempting to gain a detailed understanding of the cellular mechanisms governing thesynthesis, release, and actions of these peptides throughout this critical periovulatory period. In other related studies, the participation of LHRH, NPY, and other peptidergic cell groups in homeostaticgonadal feedback mechanisms and photoperiodic regulation of the reproductive axis are also being examined. A long-term goal of this laboratory is to understand how these neuropeptidergic systems can coordinate several neural and endocrine activities to produce an appropriate homeostatic state, such as reproductive competency. It is also hoped that our studies may ultimately provide useful information in the treatment of some forms of infertility and in the development of new contraceptive strategies.

Recent Publications:

Miller BH, Olson SL, Turek FW, Levine JE, Horton TH, Takahashi JS. Circadian clock mutation disrupts estrous cyclicity and maintenance of pregnancy. Curr Biol. 2004 Aug 10;14(15):1367-73.

Szeto A, Gonzales JA, Spitzer SB, Levine JE, Zaias J, Saab PG, Schneiderman N, McCabe PM. Circulating levels of glucocorticoid hormones in WHHL and NZW rabbits: circadian cycle and response to repeated social encounter. Psychoneuroendocrinology. 2004 Aug;29(7):861-6.

Froment P, Staub C, Hembert S, Pisselet C, Magistrini M, Delaleu B, Seurin D, Levine JE, Johnson L, Binoux M, Monget P. Reproductive abnormalities in human insulin-like growth factor-binding protein-1 transgenic male mice. Endocrinology. 2004 Apr;145(4):2080-91.

Hill JW, Urban JH, Xu M, Levine JE. Estrogen Induces Neuropeptide Y (NPY) Y1 receptor gene expression and responsiveness to NPY in gonadotrope-enriched pituitary cell cultures. Endocrinology. 2004 May;145(5):2283-90.

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Eva Redei, Ph.D.
Departments of Phychology & Behavioral Sciences
and Molecular Pharmacology & Biological Chemistry
Ph.D., Eotvos Lorand University, Budapest, Hungary

The major focus of our research is to elucidate the molecular mechanisms of vulnerability to stress and to depression. One focus of our research is related to the recent characterization of the biological activity of a hypothalamic neuropeptide, prepro-TRH 178-199. This peptide inhibits ACTH and prolactin response to stress and shows anxiolytic and antidepressant activity in animal models of these behaviors. Ongoing work is aimed to clone the receptor for rat prepro-TRH 178-199 and its human analog, human prepro-TRH 158-183.

A second area of research is focused on the characterization of the inbred Wistar Kyoto (WKY) rat as a genetic animal model of depressive behavior and stress hyper-reactivity. This strain exhibits depressive-like behavior in numerous behavioral tests and exhibits hormonal abnormalities that are similar to those associated with depressive disorder in humans. These behavioral and hormonal differences between WKY and other inbred strains serve as phenotypes for quantitative trait loci (QTL) analysis, which we have recently started. Wistar Kyoto rats are also used to identify novel vulnerability genes that are expressed differentially in the amygdala and frontal cortex, brain regions involved in the psychopathology of human affective disorders, of “depressed” versus less “depressed” animals using the differential display RT-PCR technique.

We have been also investigating how environmental challenges in utero, such as fetal alcohol exposure, can lead to altered, and sexually dimorphic changes in the adult offspring neuroendocrine and immune functions. In addition to studying the biochemical mechanisms by which fetal alcohol exposure affects stress-responsiveness of the adult offspring, we are also studying its behavioral consequences. As early developmental, environmental insult seems to play a major role in depressed behavior in adulthood, and fetal alcohol exposure and prenatal stress share a common neuroendocrine “imprinting” mechanism, this approach could provide important information on where and when the developing fetus acquires changes in the expression of specific genes that contribute to this vulnerability later in life.

Recent Publications:

Baum AE, Solberg LC, Kopp P, Ahmadiyeh N, Churchill G, Takahashi JS, Jameson JL, Redei EE. Quantitative Trait Loci Associated with Elevated TSH in the Wistar-Kyoto Rat. Endocrinology. [Epub 2004 Oct 28].

Solberg LC, Baum AE, Ahmadiyeh N, Shimomura K, Li R, Turek FW, Churchill GA, Takahashi JS, Redei EE. Sex- and lineage-specific inheritance of depression-like behavior in the rat. Mamm Genome. 2004 Aug;15(8):648-62.

Redei EE. Old principles in new clothes. Pharmacogenomics J. 2004;4(4):219.

Slone-Wilcoxon J, Redei EE. Maternal-fetal glucocorticoid milieu programs hypothalamic-pituitary-thyroid function of adult offspring. Endocrinology. 2004 Sep;145(9):4068-72.

Ahmadiyeh N, Slone-Wilcoxon JL, Takahashi JS, Redei EE. Maternal behavior modulates X-linked inheritance of behavioral coping in the defensive burying test. Biol Psychiatry. 2004 Jun 1;55(11):1069-74.

Wilcoxon JS, Redei EE. Prenatal programming of adult thyroid function by alcohol and thyroid hormones. Am J Physiol Endocrinol Metab. 2004 Aug;287(2):E318-26. Epub 2004 Apr 27.

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Neena B. Schwartz, Ph.D.
Department of Neurobiology and Physiology Ph.D., Northwestern University

We are interested in the factors that regulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle stimulating hormone (FSH) by the anterior pituitary gland. Negative and positive feedback hormonal signals from the testis or ovary are important. Feedforward neuropeptide signals from the brain are also important, and gonadotropin releasing hormone (GnRH) is a well established and necessary signal from the hypothalamus. Our laboratory pioneered in demonstrating that estradiol and progesterone are inadequate negative feedback signals for suppression of FSH in the female lacking ovaries, and discovered a gonadal peptide inhibin, necessary for proper suppression of FSH. We have used GnRH antagonists to demonstrate relative lack of dependence of FSH on endogenous GnRH in males and females. We are currently investigating sex differences in hypothalamic and pituitary function, in vivo and in an in vitro perifusion organ culture system. Another discovery from the laboratory is that glucocorticoid hormones from the adrenal differentially affect LH and FSH in vivo and in vitro, suppressing LH secretion and enhancing FSH synthesis and secretion. These steroids are an important tool in examining the mode by which the gonadotrope cell can separately synthesize and secrete LH and FSH, and we are studying the effects in pituitaries in vivo and in vitro, measuring gonadotropin secretion rates and gene transcription levels, as well as direct glucocorticoid effects on the gene for the rat FSH-beta subunit. We are also investigating the interactions among progesterone receptors, activin and steroids on FSH synthesis and secretion.

Recent Publications:

Schwartz NB 1995 Follicle stimulating hormone and luteinizing hormone: a tale of two gonadotropins. Can J Physiol Pharmacol 73(6):675-684.

Szabo M, Knox KL, Ringstrom SJ, Perlyn CA, Sutandi P, Schwartz NB 1996 Mechanism of the inhibitory action of RU486 on the secondary follicle-stimulating hormone surge. Endocrinology 137:85-89.

Kilen SM, Szabo M, Strasser GA, McAndrews JM, Ringstrom SJ, Schwartz NB 1996 Corticosterone selectivity increases FSH subunit primary anterior pituitary cell culture without affecting its halflife. Endocrinology 137:3802-3807.

Ringstrom SJ, Szabo M, Kilen SM, Saberi S, Knox KL, Schwartz NB 1997 The antiprogestins RU486 and ZK98299 affect follicle-stimulating hormone secretion differently on estrus, but not on proestrus. Endocrinology 138:2286-2290.

Schwartz, Neena B. 1999 Neuroendocrine regulation of reproductive cyclicity,. In: Neuroendocrinology in Physiology and Medicine P.M. Conn and M.E. Freeman, Eds.), Humana Press Inc., Totowa, NJ, pp 135-145.

Szabo, M., Kilen, S.M., Nho, J. and Schwartz, N.B. 2000 Progesterone receptor A and B messenger ribonucleic acid levels in the anterior pituitary of rats are regulated by estrogen. Biol. Reprod., 62:95-102.

Bohnsack, B.L., Kilen, S.M., Tam, D.H.Y. and Schwartz, N.B. 2000 Follistatin suppresses steroid-enhanced follicle-stimulating hormone release in vitro. Biol. Reprod., 62:636-641.

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Catherine S. Woolley, Ph.D.
Department of Neurobiology and Physiology
Ph.D., Rockefeller University

Research in my lab is directed toward understanding the interaction(s) between endocrine rhythms and the limbic system of the mammalian brain. Specifically, we study how fluctuating levels of the ovarian steroid hormones, estradiol and progesterone, regulate structure and function of hippocampal circuitry. The hippocampus is a brain region that normally plays an important role in cognitive and sensory information processing and, under pathological conditions, is a circuit that can generate and propagate seizure activity. Our research uses a multi-disciplinary approach that combines light and electron microscopy, electrophysiological recording from hippocampal slices and behavioral testing to understand the "hows" and "whys" of steroid hormone regulation of synaptic connectivity within the hippocampus.

We have found that concerted action of estradiol and progesterone regulates excitatory input to a major group of hippocampal output cells, the CA1 pyramidal cells. Hormone-induced changes in the density and number excitatory synaptic contacts on CA1 pyramidal cells are associated with increased sensitivity to excitatory synaptic input, enhanced synaptic plasticity, and greater susceptibility to seizure activity.

Thus, by regulating the physical substrates of information flow in the brain: dendrites, axons and the synapses that connect them, steroid hormones such as estradiol and progesterone may predispose neural circuitry to function differently in different hormonal states. Our aim is to understand how hormone-induced structural and functional plasticity regulates both normal an pathological brain function.

Recent Publications:

Smith SS, Woolley CS. Cellular and molecular effects of steroid hormones on CNS excitability. Cleve Clin J Med. 2004 Feb;71 Suppl 2:S4-10.

Telgkamp P, Padgett DE, Ledoux VA, Woolley CS, Raman IM. Maintenance of high-frequency transmission at purkinje to cerebellar nuclear synapses by spillover from boutons with multiple release sites. Neuron. 2004 Jan 8;41(1):113-26.

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