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. Experiments in which we have transplanted the SCN to arrhythmic hamsters verify the critical role of this nucleus as a circadian clock, but indicate that the pathways by which it drives behavioral and endocrine rhythms may differ. 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 metatonin 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.

Eric Bittman Circadian Rhythms, Reproduction, and Seasonal Changes in Brain Function 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. Our data indicate that SCN cells which express the melatonin la receptor also contain vasopressin, which provides an important relay not only within the SCN but also to other regions of the brain. 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 produce the neurohormone gonadotropin releasing hormone (GnRH) in order to regulate the pituitary. Furthermore, estrogen-responsive cells reciprocate to regulate circadian rhythms through their projections to the SCN.

By applying the sodium channel blocker, tetrodotoxin, to the hamster SCN we have gained evidence that a sustained output of the circadian clock during the early morning of proestrus may be necessary for activation of the LH surge system. What seasonal changes in brain function drive fluctuations in reproduction, sexual behavior, and energy metabolism? We find that the incorporation of neurons born in adulthood in germinal regions of the hamster brain is regulated both by photoperiod and by testosterone. Furthermore, 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. The expression of pro-opiomelanocortin (POMC) mRNA within the arcuate nucleus and vasopressin within the amygdala, bed nucleus of the stria terminalis, and septum are also regulated by androgen and daylength. These may all constitute important mechanisms by which the nervous system integrates environmental (photoperiodic) information with internal (hormonal) messages in order to adapt to season.

Tubbiola, M.L., and Bittman, E.L. (1994) Steroidal and photoperiodic regulation of opiate binding in male golden hamsters. J Neuroendocrinol 6:317-322.

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. (1995). Short days increase sensitivity to methadone inhibition of male copulatory behavior. Physiol Behav 58:647-651.

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.

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.

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.

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)

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 Rhythms11:145-162.9 (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)

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)

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)
Full text of paper.

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)

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)

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

Song, C.K., Bartness, T.J., Petersen, S.L., and Bittman, E.L. (2000). Co-expression of melatonin (MEL_1a) receptor and arginine vasopressin mRNAs in the Siberian hamster suprachiasmatic nucleus. J. Neuroendocrinol., 12:627-634. MEDLINE

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.

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.

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.

Earlier Publications:

Bittman EL (1978) Hamster Refractoriness: The role of insensitivity of pineal target tissues. Science 202: 648-650.

Bittman EL, Goldman BD, Zucker I (1979) Testicular responses to melatonin are altered by lesions of the suprachiasmatic nuclei in golden hamsters. Biol Reprod 21: 647-656.

Bittman EL, Karsch FJ, Hopkins JW (1983) Role of the pineal gland in ovine photoperiodism: regulation of seasonal breeding and negative feedback effects of estradiol upon LH secretion. Endocrinol 113: 329-336.

Bittman EL, Dempsey RJ, Karsch FJ (1983) Pineal melatonin secretion drives the reproductive response to daylength in the ewe. Endocrinol 113: 2276-2283.

Bittman EL (1986) The role of rhythms in the response to melatonin. In: Photoperiodism Melatonin and the Pineal, Ciba Foundation Symposium #117, Pitman, London, pp. 149-169.

Bittman EL, Karsch FJ (1984) Nightly duration of pineal melatonin secretion determines the reproductive response to inhibitory day length in the ewe. Biol Reproduction 30: 585-593.

Lehman MN, Silver R, Gladstone WR, Kahn R, Gibson M, Bittman EL (1987) Circadian rhythms restored by neural transplant: integration between the graft and the host brain. J Neurosci 7: 1626-1638.

Bittman EL, Lehman MN (1987) Paraventricular neurons control hamster photoperiodism by a predominantly uncrossed descending pathway. Brain Res Bull 19: 687-694.

Bittman EL, Krey LC (1988) Influence of daylength on nuclear androgen receptor occupancy in neuroendocrine tissues of the golden hamster. Neuroendocrinol 47: 61-67.

Bittman EL, Crandell RG, Lehman MN (1988) Influences of the paraventricular and suprachiasmatic nuclei and olfactory bulbs on melatonin responses in the golden hamster. Biol Reprod 40: 118-126.

Krey LC, Ronchi E, Bittman EL (1989) Effects of daylength on androgen metabolism and on pulsatile luteinizing hormone secretion in male golden hamsters. Neuroendocrinology 50: 533-542.

Bittman EL, Blaustein JD (1990) Effects of day length on sheep neuroendocrine estrogen and progestin receptors. Am J Physiol 258: R135-R142.

Bittman EL, Hegarty CM, Layden MQ, Jonassen JA (1990) Photoperiodic regulation of steroid receptors, sexual behavior, pituitary mRNA in female golden hamsters. J Mol Endocrinol 5: 15-25.

Bittman EL, Weaver DR (1990) Distribution of melatonin receptors in neuroendocrine tissues of the ewe. Biol Reprod 43: 986-993.

Bittman EL, Bartness TJ, Goldman BD, De Vries GJ, (1991) Suprachiasmatic and paraventricular control of photoperiodism in siberian hamsters. Am J Physiol 260: R90-101.

Bartness TJ, Goldman BD, Bittman EL (1991) Suprachiasmatic lesions block responses to melatonin in siberian hamsters. Am J Physiol 260: R102-112.

Lehman MN, Silver R, Bittman EL (1991) Anatomy of suprachiasmatic nucleus grafts. In: Suprachiasmatic Nucleus:The Mind's Clock, Klein DC, Moore RY, Reppert SM eds., Oxford University Press, NY, pp. 349-374.

Bittman EL, Jonassen JA, Hegarty CM (1992) Influences of photoperiod and estradiol on pulsatile LH secretion and adenohypophyseal gene expression in ovariectomized golden hamsters. Biol Reprod 47: 66-71.

Bittman EL (1992) Melatonin: a durational signal regulating steroid-dependent and independent aspects of limbic and hypophyseal function. In: Melatonin and the Pineal Gland: From Basic Science to Clinical Application, Touitou Y, ed., Excerpta Medica, Amsterdam, pp. 151-158.

Bittman EL (1993) The sites and consequences of melatonin binding in mammals. Amer Zool 33: 200-211.

Bittman EL (1993) Melatonin binding sites. In: Receptors: Model Systems and Specific Receptors. Methods in Neurosciences, Conn PM ed., Volume 11, Academic Press, NY pp. 105-121.

Bartness TJ, Goldman BD, Hastings MH, Powers JB, Bittman EL (1993) The timed-infusion paradigm: what has it taught us about melatonin action? J Pineal Res 15: 161-190.

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