Circadian Rhythms, Reproduction, and Seasonal Changes in Brain Function
My laboratory studies the molecular and neural basis of endogenous daily (circadian) rhythms in mammals. We focus upon the suprachiasmatic nucleus of the hypothalamus (SCN), a master pacemaker critical not only to general activity rhythms but also to the estrous cycle, the rhythmic secretion of many hormones, and seasonal breeding. The restriction of reproduction to a particular time of year depends upon the discrimination of daylength. The circadian system accomplishes this by SCN-regulated secretion of the hormone melatonin by the pineal gland, and detection of melatonin duration using highly specific cell membrane receptors in the brain.
We analyze gene expression in the SCN by methods which include multiple label in situ hybridization and immunocytochemistry. Retinal input triggers the expression of immediate early genes, including analogs of the Drosophila period gene, per, in order to shift the phase of the circadian clock. Nightly secretion of melatonin provides another cue which may reset the clock and allow the detection of daylength by the SCN. We are characterizing specific SCN cell types which participate in generation of the circadian oscillation, its synchronization with the outside world, and communication with the rest of the brain and ultimately the entire animal.
The appropriate timing of ovulation is controlled not only by signals from the ovary, but also by the circadian clock. We find that projections of the SCN contact not only neurons which contain estrogen receptor, but also those which regulate the pituitary. Furthermore, estrogen-responsive cells reciprocate to regulate circadian rhythms through their projections to the SCN.
What seasonal changes in brain function drive fluctuations in reproduction, sexual behavior, and energy metabolism? We find that daylength regulates the incorporation of neurons born in adulthood. This effect is not attributable to changes in the secretion of gonadal hormones. Daylength and testosterone interact to regulate androgen and opiate receptor expression in hamster brain in ways which may explain seasonal changes in sexual behavior and endocrine feedback. We are discovering mechanisms by which the nervous system integrates environmental (photoperiodic) information with internal (hormonal) messages in order to adapt to season.
Bittman, EL 2019. Circadian function in multiple cell types is necessary for proper timing of the preovulatory LH surge. J. Biol Rhythms17:748730419873511. doi: 10.1177/0748730419873511. PMID:31530063
Manoogian ENC, Kumar A, Obed D, Bergan J, Bittman EL. 2018. Suprachiasmatic function in a circadian period mutant: Duper alters light-induced activation of vasoactive intestinal peptide cells and PERIOD1 immunostaining. Eur J Neurosci. 48(11):3319-3334. doi: 10.1111/ejn.14214. PMID:30346078
Bittman EL 2016. Timing in the Testis.J Biol Rhythms. 31(1):12-36. doi: 10.1177/0748730415618297. PMID: 26656623
Manoogian, ENC, Leise, TL, and Bittman, EL, 2015. Phase resetting in duper hamsters: Specificity to photic zeitgebers and circadian phase. J Biol Rhythms, 30(2):129-143. doi: 10.1177/0748730414568297. PMID: 25633984.
Bittman, E.L., 2014. Effects of the Duper Mutation on Responses to Light: Parametric and Non-parametric Responses, Range of Entrainment, and Masking. J. Biol. Rhythms, 29: 97-109 (Doi: 10.1177/0748730413520399).
Mahoney, C.E., McKinley Brewer, J., and Bittman, E.L. 2013. Central control of circadian phase in arousal-promoting neurons. PLoS ONE , 8(6): e67173. (Doi: 10.1371/journal.pone.0067173).
Bittman, E.L., Kilduff, T.S., Kriegsfeld, L.J., Szymusiak, R., Toth, L.A., and Turek, F.W. 2013. Animal care practices in experiments on biological rhythms and sleep. J. Amer. Assn. Lab Animal Sci., 52: 437-443.
Bittman, E.L., 2012. Does the precision of a biological clock depend upon its period? Effects of the duper and tau mutations in Syrian hamsters. PLoS One, 7(5): e36119. PMID: 22615753
Monecke, S., McKinley Brewer, J., Krug, S., Bittman, E.L. 2011. Duper: a mutation that shortens hamster circadian period.J. Biol. Rhythms, 26: 283-292. PMID21775287
Krug, S., Brewer, J.M., Bois, A.S., Bittman, E.L. 2011. Effects of the Duper mutation on circadian responses to light. J. Biol. Rhythms, 26:293-304. PMID 2177587
Mahoney, C.E., Brewer, D., Costello, M.K., Brewer, J.M., and Bittman, E.L. 2010. Lateralization of the central circadian pacemaker output: a test of neural control of peripheral oscillator phase. Amer. J. Physiol. Reg. Integ. Comp. Physiol. 299: R751-61. PMID: 20592176
Bittman, E.L. 2009. Vasopressin: more than just an output of the circadian pacemaker? Amer. J. Physiol. Reg. Integ. Comp. Physiol. 296: R821-3. PMID 19109364
Bittman, E.L. , Costello, M.K., and Brewer, J.M., 2007. Circadian organization of tau mutant hamsters: Aftereffects and splitting. J. Biol. Rhythms, 22: 425-431. PMID17876063
Guo, H., Brewer, J.M., Lehman, M.N., and Bittman, E.L. 2006. Suprachiasmatic regulation of circadian rhythms of gene expression in hamster peripheral organs: effects of transplanting the pacemaker. Journal of Neuroscience, 26: 6406-12.
Guo, H., Brewer, J.M., Champhekar, A., Harris, R.B.S., and Bittman, E.L. 2005. Differential Control of Peripheral Circadian Rhythms by Suprachiasmatic-dependent Neural Signals. Proc. Natl. Acad. Sci. 102: 3111-6.
Cheng, M.Y., Bittman, E.L., Hattar, S.S., Leslie, F., Yau, K-W, and Zhou, Q-Y. 2005. Light regulation of prokineticin 2 molecular rhythm in the suprachiasmatic circadian clock. BMC Neurocience, 17: 6-17.
Tetel M.J., Ungar, T.C., Hassan, B., and Bittman, E.L. 2004. Photoperiodic regulation of androgen receptor and steroid receptor coactivator-1 in Siberian hamster brain. Brain Research, Molecular Brain Research, 131: 79-87.
Tong, Y, Guo, H., Brewer, J.M., Lee, H, Lehman, M.N., and Bittman, E.L. 2004. Oscillating expression of haPer1 and haBmal1 in peripheral organs of Syrian hamsters. J. Biol. Rhythms. 19: 113-125. MEDLINE
Bittman, E.L., Doherty, L., Huang L., and Paroskie, A. 2003. Period gene expression in mouse endocrine tissues. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285: R561-569. MEDLINE
Bittman, E.,L., Ehrlich, D.A., Ogdahl, J.L., and Jetton, A.E. 2003. Photoperiod and testosterone regulate androgen receptor immunostaining in the Siberian hamster brain. Biol. Reprod. 69: 876-884. MEDLINE
Huang, L., and Bittman, E.L. 2002. Olfactory bulb cells generated in adult male golden hamsters are specifically activated by exposure to estrous females. Hormones and Behavior, 41: 343-50.
Fukuhara, C., Brewer, J.M., Dirden, J.C., Bittman, E.L., Tosini G., and Harrington, M.E. 2001. Neuropeptide Y rapidly reduces Period 1 and Period 2 mRNA levels in the hamster suprachiasmatic nucleus. Neuroscience Letters, 314: 119-122.
Song, C.K., Bartness, T.J., Petersen, S.L., and Bittman, E.L. 2000. Co-expression of melatonin (MEL1a) receptor and arginine vasopressin mRNAs in the Siberian hamster suprachiasmatic nucleus. J. Neuroendocrinol. 12: 627-634. MEDLINE
de la Iglesia, H.O., Blaustein, J.D., and Bittman, E.L. 1999. Estrogen receptor-immunoreactive neurons project to the suprachiasmatic nucleus of the female Syrian hamster. J. Neuroendocrinol. 11: 481-490. MEDLINE
Bittman, E.L., Tubbiola, M.L., Foltz, G., and Hegarty, C.M. 1999. Effects of photoperiod and androgen on pro-opiomelanocortin gene expression in the arcuate nucleus of golden hamsters. Endocrinol. 140: 197-206. MEDLINE
Meyer-Bernstein, E.L., Jetton, A.E., Matsumoto, S.-I., Markuns, J.F., Lehman, M.N., and Bittman, E.L. 1999. Effects of suprachiasmatic transplants on circadian rhythms of neuroendocrine function in golden hamsters. Endocrinol. 140: 207-218. MEDLINE
Huang, L., DeVries, G.J., and Bittman, E.L. 1998. Photoperiod regulates neuronal bromodeoxyuridine labeling in the brain of a seasonally breeding mammal. J. Neurobiol. 36: 410-420 . MEDLINE
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Vernadakis, A.J, Bemis, W.E., and Bittman, E.L. 1998. Localization and partial characterization of melatonin receptors in amphioxus, hagfish, lamprey and skate. Gen. Comp. Endocrinol. 110: 67-78. MEDLINE
Powers, J.B., Jetton, A.E., Mangels, R.A., and Bittman, E.L. 1997. Effects of photoperiod duration and melatonin signal characteristics on the reproductive systems of male Syrian hamsters. J. Neuroendocrinol. 9: 451-466. MEDLINE
Matsumoto, S., Basil, J., Jetton, A., Lehman, M.N., and Bittman, E.L. 1996. Control of phase and period of circadian rhythms restored by suprachiasmatic grafts. J. Biol Rhythms 11: 145-162.9. MEDLINE
Bittman, E.L., Jetton, A.E., Villalba, C., and De Vries, G.J. 1996. Effects of photoperiod and androgen on pituitary function and neuropeptide staining in Siberian hamsters. Amer. J. Physiol. 271: R64-72. MEDLINE
Maywood, E.S., Bittman, E.L., and Hastings, M.H. 1996. Lesions of the melatonin- and androgen-responsive tissues of the dorsomedial nucleus of the hypothalamus block the gonadal response of male Syrian hamsters to programmed infusions of melatonin. Biol. Reprod. 54: 470-477.
Maywood E.S., Bittman, E.L., Ebling, F.J.P., Barrett, P., Morgan, P., and Hastings, M.H. 1995. Regional distribution of iodomelatonin binding sites within the suprachiasmatic nucleus of the Syrian hamster and the Siberian hamster. J. Neuroendocrinol. 7: 215-225.
de la Iglesia, H.O., Blaustein, J.D., and Bittman, E.L. 1995. The suprachiasmatic area in the female hamster projects to neurons containing estrogen receptors and GnRH. NeuroReport 6: 1715-1722.
Tubbiola, M.L., and Bittman, E.L. 1995. Short days increase sensitivity to methadone inhibition of male copulatory behavior. Physiol. Behav. 58: 647-651.
Bittman, E.L., Thomas, E.M., and Zucker, I. 1994. Melatonin binding sites in sciurid and hystricomorph rodents: studies on ground squirrels and guinea pigs. Brain Res. 648: 73-79.
Tubbiola, M.L., and Bittman, E.L. 1994. Steroidal and photoperiodic regulation of opiate binding in male golden hamsters. J. Neuroendocrinol. 6: 317-322.
Department of Biology