Sandra L. Petersen

Research in our laboratory focus on: 1) understanding the molecular and cellular mechanisms underlying the brain signal for ovulation; 2) determining developmental mechanisms responsible for sex differences in the brain region that controls ovulation and 3) determining how exposure to environmental contaminants like dioxins interfere with the development of this brain region and gonadotoropi release patterns.

The Brain Signal for Ovulation

As ovarian follicles mature, they release increasing amounts of estradiol (E2). This increase in E2 triggers a number of signals that culminate in activation of gonadotropin-releasing hormone neurons (GnRH), which activate a surge of luteinizing hormone (LH) release from the pituitary gland. The LH surge then triggers ovulation. We previously showed that the anteroventral periventricular nucleus (AVPV) is a brain region in which E2 must act to trigger the LH surge. More recently we found that the targets of E2 in the AVPV are unique dual-phenotype GABA/Glutamate neurons. These neurons are more than twice as abundant in females than in males and they synapse on GnRH neurons. In the presence of E2, GABAergic vesicles in these synapses are high during the morning, but then decrease at the time of the LH surge, when glutamatergic neurons predominate in the dual-phenotype terminals. These findings are consistent with the idea that GABA inhibits the LH surge and glutamate stimulates it. We are currently using in vivo and in vitro approaches to determine how daily signals and E2 interact to change the rates of GABA and glutamatergic release from these dual-phenotype neurons, thereby stimulating GnRH and LH surge release.

Sandra L. Petersen

Molecular Neuroendocrinology of Reproduction

Development of Sex Differences in the AVPV

Only females show activation of GnRH neurons and LH surge release in response to E2; males show tonic, rather than cyclic patterns of LH release. The sex-specific patterns of LH release are established during the perinatal period and the resulting pattern is determined by whether or not animals are exposed to testosterone. If males are gonadectomized during the perinatal period, they are able to show female-typical LH surge release. Similarly, if females are exposed to testosterone, or E2 derived from testosterone, they lose the potential for LH surge release. Our work suggests that GABA/Glu neurons are more than twice as numerous in females as in males and that perinatal exposure to testosterone masculinizes the number of GABA/Glu neurons and abolishes the potential for LH surge release in treated females. These findings together with our previous findings that GABA/Glu neurons make up most of the AVPV and contain all the ER in the region, support the idea that these unique dual-phenotype neurons are key to the sex-specific signal for ovulation. We are currently investigating the developmental mechanisms underlying sex differences in GABA/Glu neurons of the AVPV.

Dioxins Interfere with Sexual Differentiation of the AVPV

Dioxins are ubiquitous environmental contaminants that are quite potent in disrupting neural development. Of particular concern are findings that exposure to the prototypic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin, prevents defeminization of the LH surge mechanisms such that exposed males show LH surge release. Dioxins and a number of dioxin-like compounds act through the arylhydrocarbon receptor (AhR) and often exert anti-estrogenic effects. We recently found that the AhR is found in GABA/glutamate neurons of the developing AVPV and that a single exposure to TCDD prevents the E2-dependent loss of GABA/Glu neurons in the region. Thus, males retain the female AVPV neuroanatomy and gonadotropin release pattern. We are now using genomics methods to identify sex-specific genes that are regulated by both E2 and TCDD.

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Dr. Petersen is Associate Dean of the Graduate School and Director of the Northeast Alliance for Graduate Education and the Professoriate.

Recent Publications:

Petersen, S.L., Krishnan, S. and Hudgens, E.D. (In Press). The aryl hydrocarbon receptor pathway and sexual differentiation of neuroendocrine functions. Endocrinology
Ottem, N.E. and Petersen, S.L. (2004). Dual-phenotype GABA/glutamate neurons in adult preoptic area: Sexual dimorphism and function. Journal of Neuroscience 24(37):8097-8105.
Hrabovszky, E., Kallo, I., Steinhauser, A., Merchenthaler, I., Coen, C.W., Petersen, S.L., Liposits, Z. (2004). Estrogen receptor-beta in oxytocin and vasopressin neurons of the rat and human hypothalamus: Immunocytochemical and in situ hybridization studies. J Comp Neurol. 473(3):315-33.
Petersen, S.L., Ottem, E.N., and Carpenter, C.D. (2003). Direct and indirect regulation of GnRH neurons by ovarian steroids. Biology of Reproduction 69:1771-1778.
Ottem, E.N. and Petersen, S.L. (Submitted). Individual neurons of the preoptico- hypothalamus may release both GABA and glutamate. Proceedings of the National Academy of Science USA.
Petersen, S.L., Curran, M.A., Marconi, S.A., Carptenter, C.D., Lubbers, L.S. and McAbee, M.D. (2000). Distribution of mRNAs encoding the aryl hydrocarbon receptor (AhR), aryl hydrocarbon receptor nuclear translocator (ARNT), and ARNT2 in the rat brain and brain stem. Journal of Comparative Neurology 427:428-439.

Hrabovszky, E., Shughrue, P.J., Merchenthaler, I., Hajszan, T., Carpenter, C.D., Liposits, Z.S. and Petersen, S.L. (2000). RAPID COMMUNICATION: Detection of estrogen receptor-ß messenger ribonucleic acid and ¹²⁵I-estrogen binding sites in luteinizing hormone-releasing hormone neurons of the rat brain. Endocrinology. 2000 Sep;141(9):3506-9.

Song, C.K., Petersen, S.L. Bartness, T.J. and Bittman, E.L. (2000). Cells in the Syrian hamster suprachiasmatic nucleus which express melatonin 1A mRNA are vasopressinergic. J. Neuroendocrinology 12(7).

Timms, B.G., Petersen, S.L. and Vom saal, F.S. (1999). Prostate gland growth during development is stimulated in both male and female rat fetuses by intrauterine proximity to female fetuses. J. Urology 161:1694-1701.

Sannella M, Petersen SL (1997) Evidence that LHRH neurons do not express genes encoding mu, delta or kappa opiate receptor mRNA. Endocrinology 138: 1667-1672.

Petersen S.L., LaFlamme K (1997) Progesterone increases levels of mu opioid receptor mRNA in the preoptic region and arcuate nucleus of ovariectomized, estradiol-treated female rats. Mol Brain Res 52: 32-37.

Petersen SL, Gardner E, Adelman J, McCrone S (1996) Examination of steroid-induced changes in LHRH gene transcription using ³³P- and ³⁵S-labeled probes specific for intron 2. Endocrinology 137: 234-239.
Hileman SM, Lubbers LS, Petersen SL, Kuehl DE, Scott CJ, Jackson GL (1996) Influence of testosterone on LHRH release, LHRH mRNA and proopiomelanocortin mRNA in male sheep. J Neuroendocrinol 8: 113-122.
Hrabovszky E, Petersen SL, Kallo I, Liposits ZS (1996) Acta Histochemica et Cytochemica 29 (Supplement): 760-761.
Zoeller RT, Simonyi A, Butnariu O, Fletcher DL, Rudeen KP, McCrone S, Petersen SL (1995) Effects of acute ethanol administration and cold exposure on the hypothalamic-pituitary-thyroid axis. Endocrine 3: 39-47.
Smith GW, McCrone S, Petersen SL, Smith MF (1995) Expression of messenger RNA encoding tissue inhibitor of metalloproteinases-2 (Timp-2) within ovine follicles and corpora lutea. Endocrinology 136: 570-576.
Petersen SL, McCrone S, Keller M, Shores S (1995) Effects of estrogen and progesterone on luteinizing hormone-releasing hormone messenger ribonucleic acid levels: Consideration of temporal and neuroanatomical variables. Endocrinology 136: 3604-3610.
Hrabovszky E, Vrontakis M, Petersen SL (1995) Triple-labeling method combining immunocytochemistry and in situ hybridization histochemistry. Demonstration of overlap between fos-immunoreactive and galanin mRNA-expressing subpopulations of luteinizing hormone-releasing hormone neurons in female rats. J Histochem Cytochem 43(4): 363-370.
Petersen SL, Keller ML, Carder SA, McCrone S (1993) Differential effects of estrogen and progesterone on levels of POMC mRNA levels in the arcuate nucleus: relationship to the timing of LH surge release. J Neuroendocrinology 5: 643-648.
Petersen SL, McCrone S, Coy D, Adelman JP, Mahan LC (1993) GABA_A receptor subunit mRNAs in cells of the preoptic area: Colocalization with LHRH mRNA using dual-label in situ hybridization histochemistry. Endocrine J 1: 29-34.
Petersen SL, McCrone S (1993) Use of dual-label in situ hybridization histochemistry to determine receptor complement of specific neurons. In: In Situ Hybridization Applications to Neurobiology, Valentino KL, Eberwine JH, Barchas JD, eds, Oxford University Press, New York.
Ashen MD, Hartman RD, Barraclough CA, Petersen SL, Hamlyn JMJ (1992) Vasopressin gene transcripts in mineralocorticoid hypertension: an in situ study. Hypertension 10: 1317-1326.
Selmanoff M, Shu C, Petersen SL, Barraclough CA, Zoeller RT (1991) Single cell levels of hypothalamic messenger ribonucleic acid encoding luteinizing hormone-releasing hormone in intact, castrated, and hyperprolactinemic male rats. Endocrinology 128: 459-466.
Bohler HC Jr, Tracer H, Merriam GR, Petersen SL (1991) Changes in proopiomelanocortin messenger ribonucleic acid levels in the rostral periarcuate region of the female rat during the estrous cycle. Endocrinology 128: 1265-1269.
Selmanoff M, Shu C, Hartman RD, Barraclough CA, Petersen SL (1991) Tyrosine hydroxylase and POMC mRNA in the arcuate region are increased by castration and hyperprolactinemia. Brain Res Mol Brain Res 10: 277-281.
Petersen SL, McCrone S, Keller M, Gardner E (1991) Rapid increase in LHRH mRNA levels following NMDA. Endocrinology 129: 1679-1681.
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