We are interested in the molecular mechanisms underlying circadian rhythms and their links to various clinical disorders, such as insomnia and depression (1 2 3). The origins of our molecular understanding of human circadian rhythms can be traced to genetic studies in the fruit fly, Drosophila melanogaster. Since the cloning of the first clock gene period in Drosophila in the1980s, the cloning of new fly rhythm genes has led to the discovery of their mammalian counterparts, reflecting their remarkable evolutionary conservation. Indeed, a mutation in a human homolog of Drosophila period is responsible for an inherited sleep disorder, advanced sleep phase syndrome (ASPS) (4). Across evolutionary boundaries, transcriptional feedback loops form the core of circadian pacemakers. We believe the most efficient strategy to identify new components of human circadian feedback loops is through a molecular genetic approach in Drosophila. The wealth of genetic tools and short generation time (~10 days) facilitate high throughput phenotype-driven screens that will be required to decipher the functional significance of the human genome. Current efforts in our laboratory are focused on cloning a novel circadian rhythm mutant as well as the identification of molecular and cellular links between central pacemakers and output genes and behaviors.

The most prominent circadian behavior is the sleep-wake cycle. Sleep itself is as important as food; animals deprived of sleep live approximately as long (2-3 weeks) as they live without food (5 6). Approximately 60 million Americans experience suboptimal sleep, leading to loss in productivity, health and even fatal accidents (7). Although not for lack of effort, traditional neuroscience approaches have been unable to provide a compelling explanation for our need to sleep. The behavioral state of sleep is principally defined by circadian control, homeostatic regulation and characteristic drug responses. Astonishingly, fruit flies exhibit inactive states with all of these cardinal features (8 9). Flies are active in the day and inactive at night. Deprived of sleep, flies will compensate with extra rest. Fly sleep will even be perturbed by caffeine. It is hypothesized that the accumulation of specific molecules during wakefulness promotes the restorative process of sleep. To identify these molecules, we are screening for mutants that alter the quantity, quality, or pharmacology of sleep in flies.

Selected References:

• Zhao J, Kilman VL, Keegan K, Peng Y, Emery P, Rosbash M, and Allada R (2003).  Drosophila Clock can generate ectopic clocks.  Cell (In press).

• Lin J-M, Kilman VL, Keegan K, Paddock B, Emery-Le M, Rosbash M, and Allada R (2002). A Role for Casein Kinase 2_ in the Drosophila Circadian Clock. Nature 420, 816-820. Advance online publication, 24 November 2002 (doi:10.1038/nature01235) [full text].

• Nash HA, Scott RL, Lear BC, and Allada R (2002). An Unusual Cation Channel Mediates Photic Control of Locomotion in Drosophila.  Current Biology 12, 2152-2158. [full text].

• Allada R., Emery P., Takahashi J., Rosbash M. 2001. Stopping Time: The genetics of fly and mouse circadian clocks. Annu. Rev. Neurosci. 24:1091-1119. [full text].

•Allada R., White N.E., So W.V., Hall J.C., Rosbash M. 1998. A mutant Drosophilahomolog of mammalian Clock disrupts circadian rhythms and transcription of periodand timeless. Cell 93: 791-805. [full text]

• Rosbash M, Allada R, Dembinska M, Guo WQ, Le M, Marrus S, Qian Z, Rutila J, Yaglom J, Zeng, H. 1996. A Drosophila Circadian Clock. Cold Spring Harbor Symp. Quant. Biol. LXI: 265-278.

• Allada R. and Nash, H.A. 1993. Drosophila melanogaster as a Model for Study of General Anesthesia: The Quantitative Response to Clinical Anesthetics and Alkanes. Anesth. Analg. 77: 19-26.

GBB Papers

Antoch MP, Song EJ, Chang AM, Vitaterna MH, Zhao Y, Wilsbacher LD, Sangoram AM, King DP, Pinto LH, Takahashi JS. Functional identification of the mouse circadian Clock gene by transgenic BAC rescue. Cell. 1997 May 16;89(4):655-67. Download PDF

Bibb JA, Chen J, Taylor JR, Svenningsson P, Nishi A, Snyder GL, Yan Z, Sagawa ZK, Ouimet CC, Nairn AC, Nestler EJ, Greengard P. Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature. 2001 Mar 15;410(6826):376-80. Download PDF

Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M.Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999 Aug 20;98(4):437-51. Download PDF

de Bono M, Bargmann CI. Natural variation in a neuropeptide Y receptor homolog modifies social behavior and food response in C. elegans. Cell. 1998 Sep 4;94(5):679-89. Download PDF

Dubnau J, Grady L, Kitamoto T, Tully T. Disruption of neurotransmission in Drosophila mushroom body blocks retrieval but not acquisition of memory. Nature. 2001 May 24;411(6836):476-80. Download PDF

Feng R, Rampon C, Tang YP, Shrom D, Jin J, Kyin M, Sopher B, Martin GM, Kim SH, Langdon RB, Sisodia SS, Tsien JZ. Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron. 2001 Dec 6;32(5):911-26. Download PDF

Fernandez-Funez P, Nino-Rosales ML, de Gouyon B, She WC, Luchak JM, Martinez P, Turiegano E, Benito J, Capovilla M, Skinner PJ, McCall A, Canal I, Orr HT, Zoghbi HY, Botas J. Identification of genes that modify ataxin-1-induced neurodegeneration. Nature. 2000 Nov 2;408(6808):101-6. Download PDF

Greer JM, Capecchi MR. Hoxb8 is required for normal grooming behavior in mice. Neuron. 2002 Jan 3;33(1):23-34. Download PDF

Hendricks JC, Williams JA, Panckeri K, Kirk D, Tello M, Yin JC, Sehgal A. A non-circadian role for cAMP signaling and CREB activity in Drosophila rest homeostasis. Nat Neurosci. 2001 Nov;4(11):1108-15. Download PDF

King DP, Zhao Y, Sangoram AM, Wilsbacher LD, Tanaka M, Antoch MP, Steeves TD, Vitaterna MH, Kornhauser JM, Lowrey PL, Turek FW, Takahashi JS. Positional cloning of the mouse circadian clock gene. Cell. 1997 May 16;89(4):641-53. Download PDF

Kloss B, Rothenfluh A, Young MW, Saez L. Phosphorylation of period is influenced by cycling physical associations of double-time, period, and timeless in the Drosophila clock. Neuron. 2001 Jun;30(3):699-706. Download PDF

Kloss B, Price JL, Saez L, Blau J, Rothenfluh A, Wesley CS, Young MW. The Drosophila clock gene double-time encodes a protein closely related to human casein kinase Iepsilon.Cell. 1998 Jul 10;94(1):97-107. Download PDF

Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature. 2001 Oct 4;413(6855):519-23. Download PDF

Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 2001 Aug 24;293(5534):1487-91. Download PDF

Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. 1999 Aug 6;98(3):365-76. Download PDF

Lowrey PL, Shimomura K, Antoch MP, Yamazaki S, Zemenides PD, Ralph MR, Menaker M, Takahashi JS. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science. 2000 Apr 21;288(5465):483-92. Download PDF

Martinek S, Inonog S, Manoukian AS, Young MW. A role for the segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock. Cell. 2001 Jun 15;105(6):769-79. Download PDF

McGuire SE, Le PT, Davis RL. The role of Drosophila mushroom body signaling in olfactory memory. Science. 2001 Aug 17;293(5533):1330-3. Download PDF

Moore MS, DeZazzo J, Luk AY, Tully T, Singh CM, Heberlein U. Ethanol intoxication in Drosophila: Genetic and pharmacological evidence for regulation by the cAMP signaling pathway. Cell. 1998 Jun 12;93(6):997-1007. Download PDF

Osborne KA, Robichon A, Burgess E, Butland S, Shaw RA, Coulthard A, Pereira HS, Greenspan RJ, Sokolowski MB. Natural behavior polymorphism due to a cGMP-dependent protein kinase of Drosophila. Science. 1997 Aug 8;277(5327):834-6. Download PDF

Price JL, Blau J, Rothenfluh A, Abodeely M, Kloss B, Young MW. double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell. 1998 Jul 10;94(1):83-95. Download PDF

Rice G, Anderson C, Risch N, Ebers G. Male homosexuality: absence of linkage to microsatellite markers at Xq28. Science. 1999 Apr 23;284(5414):665-7 Download PDF

Ryner LC, Goodwin SF, Castrillon DH, Anand A, Villella A, Baker BS, Hall JC, Taylor BJ, Wasserman SA. Control of male sexual behavior and sexual orientation in Drosophila by the fruitless gene. Cell. 1996 Dec 13;87(6):1079-89. Download PDF

Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, Tsien JZ. Genetic enhancement of learning and memory in mice. Nature. 1999 Sep 2;401(6748):63-9. Download PDF

Waddell S, Armstrong JD, Kitamoto T, Kaiser K, Quinn WG. The amnesiac gene product is expressed in two neurons in the Drosophila brain that are critical for memory. Cell. 2000 Nov 22;103(5):805-13. Download PDF