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The overall goal of the major project in my laboratory is to elucidate the neuroendocrine and circadian mechanisms controlling the preovulatory LH surge, and answer the question: what is the mechanism that controls the circadian timing of the preovulatory LH surge? This question is significant because circadian rhythms are essential for our health and well-being. Malfunctions in the circadian timing system are associated with sleep disorders, manic depression, memory impairment, increased cardiovascular disease, metabolic syndrome, and reduced response to chemotherapy. We are investigating the circadian timing mechanism that controls the preovulatory LH surge in Syrian hamsters. The results of this project will advance our understanding of how the master biological clock, the suprachiasmatic nucleus (SCN), controls circadian rhythms. The SCN controls numerous biological rhythms, including behavioral and hormonal rhythms, such as those in wheel-running and serum corticosterone levels. In rodents, there is also a circadian signal that is essential for occurrence of the preovulatory luteinizing hormone (LH) surge and occurs during a critical period each day. The LH surge causes ovulation, and consists of a large increase in release of LH from the anterior pituitary gland in response to hypothalamic gonadotropin releasing hormone (GnRH). During each estrous cycle, the GnRH and LH surges are triggered by a sustained rise in circulating estradiol concentrations produced by the developing preovulatory ovarian follicles. In rodents, the LH surge is also controlled by a circadian time of day signal. Recent evidence indicates that the GnRH neurons express clock genes, and mutations of a clock gene in mice cause prolonged estrous cycles and decreased fertility. In addition, there are direct projections from the SCN to the GnRH neurons. These findings strongly suggest that the SCN directly controls the intrinsic GnRH clock, and thereby regulates the circadian timing of the LH surge. We have begun collaborating with Dr. Marilyn Duncan in the department of Anatomy and Neurobiology and have established an in vivo model for phase-advancing the LH surge in order to determine whether a phase advance in clock gene expression occurs coordinately in the SCN and GnRH neurons. Using this model, we have shown that administration of phenobarbital at the time of the circadian signal for the LH surge delays the LH surge until the next day and when it occurs, it is phase-advanced. In addition, the wheel running activity rhythm was phase advanced and SCN Period 1 mRNA expression was decreased. These results suggest that phenobarbital advances the SCN pacemaker. We are now investigating whether there is a circadian pattern of expression of specific clock genes in the GnRH neurons in vivo, whether this pattern is dependent on the SCN, and whether it is required for the LH surge in Syrian hamsters. In addition we are beginning to identify the neurotransmitters that constitute the output signal from the SCN to the GnRH neurons using in vivo microdialysis to administer specific neurotransmitter agonists and antagonists in discrete brain regions such as the SCN. The results of these studies will clarify the role of circadian phase advances and of circadian clock genes in control of the LH surge
The second project in my laboratory is focused on the mechanisms whereby prenatal exposure to opiates permanently alters the response to stress. We are collaborating with Dr. Bada, Chief of Neonatology, and Dr. Randall in Physiology, to investigate the life-long changes in the hypothalamic-pituitary-adrenal (HPA) axis and the sympatho-adrenomedullary axis (SAM) that occur after exposure to oxycodone in utero. We have developed a rat model in which the elevation in circulating corticosterone levels in response to restraint stress is altered in a gender-specific manner in adult offspring that had been prenatally exposed to oxycodone. We are also collaborating with Dr. Susan Barron in Psychology to examine the effect of prenatal exposure to oxycodone on postnatal behavior, and with Dr. Melinda Wilson in Physiology to investigate changes in transcription and DNA methylation of the glucocorticoid receptor and estrogen receptor genes in those brain areas involved in the response to stress. In the future, we plan to investigate the effects of prenatal oxycodone on the neuropeptides and neurotransmitters that control the HPA axis, and how these are differentially affected by sex hormones.
Sithisarn, T., Bada, H.S., Dai, H., Randall, D.C. and Legan, S.J. Effects of perinatal cocaine exposure on open field behavior and response to corticotrophin releasing hormone (CRH) in rat offspring. Brain Res. 1370: 136-144, 2011.
Legan, S.J., Franklin, K.M., Peng, X.L., and Duncan, M.J. Novel wheel running blocks the preovulatory Luteinizing Hormone surge and advances the hamster circadian pacemaker. J. Biol. Rhythms 25:450-459, 2010.
Legan S.J., Donoghue, K.M., Franklin, K.M., Duncan, M.J. Phenobarbital blockade of the preovulatory LH surge: Association with phase-advanced circadian clock and altered suprachiasmatic nucleus Period1 gene expression. Am J Physiol Regul Integr Comp Physiol. 296:R1620-R1630, 2009.
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