Chronobiology & Neuroscience

Research in the Cassone laboratory is directed at the mechanisms and neuroendocrine pathways by which the biological clock regulates physiology and behavior in amniotic vertebrates. All eukaryotic and at least some prokaryotic organisms express a temporal organization as well as a spatial organization such that many molecular, physiological and behavioral events are strictly timed. This temporal organization reflects a biological clock derived primarily from endogenous cellular oscillators that are somehow coupled or entrained to the prevailing environmental cycles. Students in the laboratory are encouraged to develop independent projects based upon scientific questions within the framework of the laboratory's mission. Weekly lab meetings and personal supervision of laboratory projects help to integrate technically diverse but philosophically intimate graduate and undergraduate research.

Functional Genomics of the Avian Circadian Clock: The avian pineal gland is a circadian oscillator and photoreceptor, which regulates birds' physiology and behavior via the secretion of the hormone melatonin. While the molecular mechanisms underlying melatonin biosynthesis have been largely worked out, the molecular clockworks regulating the circadian rhythm, the photoentrainment and the link of the oscillators and photoreceptors to the melatonin output are unknown. Using functional genomics in collaboration with Dr. Terry Thomas, the lab is characterizing the changes in mRNAs encoding avian clock genes to identify the critical steps. Then, the translation of these gene products is blocked by RNA interference in a pineal cell culture system.

Mechanisms of Melatonin Action: By employing several brain imaging techniques, we have found that the sites of melatonin action include the hypothalamic suprachiasmatic nuclei (SCN) and many structures associated with visual function. We are studying the cellular and molecular mechanisms by which melatonin regulates neuronal function in these areas and the system level consequences of circadian regulation of visual processes. One of the most exciting sites of melatonin action in the brain is the astrocyte, a glial cell that is the most abundant central nervous cell-type. In collaboration with Dr. Mark Zoran, we have found that melatonin directly affects astrocytic metabolism and ionic conductances, and we are investigating the mechanisms by which melatonin alters glial function in vitro. We are also investigating the system and tissue level consequences of this regulation.

Mammalian Circadian Organization: We are addressing central issues in mammalian circadian organization at the cellular, molecular and physiological levels. First, in collaboration with Dr. David Earnest, we are studying the mechanisms of circadian rhythms in an immortalized cell-line derived from embryonic suprachiasmatic nucleus of rats. We have shown these cells to express circadian rhythms in vitro, to confer circadian rhythms to other in vitro cell cultures and to impose circadian rhythms on rat behavior in vivo when transplanted into the hypothalamus. We are interested in the mechanisms by which the SCN confers rhythmicity in vitro and in vivo. We are currently investigated mechanisms by which the cardiovascular system is affected by this clock.

Bell-Pedersen, D., V.M Cassone, D.J. Earnest, S.S. Golden, P. E. Hardin, T.L Thomas and M.J. Zoran (2005) Regulation of circadian rhythms by multiple oscillators: lessons from diverse organisms. Nature Reviews: Genetics 6: 544-556

Menger, G.J., K.P. Lu, T.L. Thomas, V.M. Cassone and D.J. Earnest (2005) Circadian profiling of the transcriptome in immortalized rat SCN cells. Physiol. Genom. 21(3):370-81.

Bailey, M.J, and V.M. Cassone (2005) Melanopsin expression in the chick retina and pineal gland. Mol. Brain Res.. 134: 345-348.

Peters, J.L., and V.M. Cassone (2005) Melatonin regulates circadian electroretinogram rhythms in a dose- and time-dependent fashion J. Pineal Res. 38:209-215

Peters, J.L., V.M. Cassone and M.J. Zoran (2005) Melatonin modulates inter-cellular calcium waves in brain astrocytes. Brain Res. 1031/1:10-19

Earnest, D.J., and V.M. Cassone (2005) Cell culture models for oscillator pacemaker function: Recipes for dishes with circadian clocks. Methods Enzymol. 393: 556-576.

Bailey, M.J., P. D. Beremand, R. Hammer, E. Reidel, T. L. Thomas, and V.M. Cassone (2004) Transcriptional profiling of circadian patterns of mRNA expression in the chick retina J. Biol. Chem. 50: 52247-52254 (Published on-line September 23, 2004 M405679200)

Allen, G., Y. Farnell, D. Bell-Pedersen, V.M. Cassone, and D.J. Earnest (2004) Effects of altered clock gene expression on the pacemaker properties of SCN2.2 cells and oscillatory properties of NIH/3T3 cells. Neuroscience 127: 989-999.

Bailey, M.J., and V.M. Cassone (2004) Opsin photoisomerases in the chick retina and pineal gland: characterization, localization and circadian regulation. Inv. Opthalm. Vis. Sci. 45: 769-775

Cassone, V.M. (2004) Evolution of the Pineal Gland. Encyclopedia of Endocrine Diseases. Volume 3. Elsevier Press. pp609-614

Bailey, M.J., Beremand, P.D., Hammer, R., Bell-Pedersen, D., Thomas, T.L. and V.M. Cassone (2003) Transcriptional profiling of the chick pineal gland, a photoreceptive circadian oscillator and pacemaker. Mol. Endocrinol. 17: 2084-2095

Cassone, V.M. and F.K. Stephan. 2002. Central and peripheral regulation of feeding and nutrition by the mammalian circadian clock: implications for nutrition during manned space flight. Nutrition 18: 814-819.

Adachi, A., A.K. Natesan, M. G. Whitfield-Rucker, S.E. Weigum and V.M. Cassone. 2002. Functional melatonin receptors and metabolic coupling in cultured chick astrocytes. Glia 39: 268-278.

Natesan, A.K. and V.M. Cassone. 2002. Melatonin receptor mRNA localization and rhythmicity in the retina of the domestic chicken, Gallus domesticus. Visual Neuroscience 19: 265-274.

Bailey, M.J. N.W. Chong, J. Xiong, and V.M. Cassone. 2002. Chickens' Cry2: Molecular analysis of an avian cryptochrome in retinal and pineal photoreceptors. FEBS Letters 513: 169-174.

Allen, G., J. Rappe, D.J. Earnest, and V.M. Cassone. 2001. Oscillating on borrowed time: Immortalized SCN cells confer circadian rhythmicity to cultured fibroblasts. J. Neuroscience 21: 7937-7943.

Cassone, V.M. 2000. The self-same beat of Time's wide wings. Proc. Natl. Acad. Sci. USA 97: 11677-11679.

McGoogan, J.S., W.Q. Wu, and V.M. Cassone. 2000. Inter-ocular interference and circadian regulation of the chick electroretinogram. Vision Research 40(20): 2869-2879.

Wu, W.Q., J.S. McGoogan, and V.M. Cassone. 2000. Circadian regulation of visually evoked potentials in the domestic pigeon, Columba livia. J. Biol. Rhythms 15: 317-328.

McGoogan, J.M. and V.M. Cassone. 1999. Circadian clock regulation of the electroretinogram of the chick: Effects of pinealectomy and exogenous melatonin. Amer. J. Physiol.: Regulatory, Integrative and Comparative Physiology 277: R1418-R1427.

Cassone, V.M., D.J. Earnest, F-Q. Liang, and M. Ratcliff. 1999. Immortal Time: Circadian Clock Properties of Rat Suprachiasmatic Cell Lines. Science 283: 693-695.

Chong, N.W., V.M. Cassone, M. Bernard, D.C. Klein and P.M. Iuvone. 1998. Circadian expression of tryptophan hydroxylase mRNA in the chicken retina. Mol. Brain Res. 61: 243-250.

Cassone, V.M., Natesan, A.K. 1997. Time and time again: The phylogeny of melatonin as a transducer of biological time. J. Biol. Rhythms 12: 489-497.

Klein, D.C., S.L. Coon, P.H. Roseboom, J.L. Weller, M. Bernard, J.A. Gastel, M. Zatz, P.M. Iuvone, I.R. Rodriguez, V. Begay, J. Falcon, G.M. Cahill, V.M. Cassone, R. Baler. 1997. The melatonin rhythm generating enzyme: molecular regulation of serotonin N-acetyltransferase in the pineal gland. Rec. Prog. Horm. Res. 52: 307-358.

Bernard, M., P. M. Iuvone, V.M. Cassone, P. Roseboom, S. Coon and D.C. Klein. 1997. Melatonin synthesis: photic and circadian regulation of serotonin N-acetyltransferase mRNA and activity in chicken pineal gland and retina. J. Neurochem. 68: 213-224.