MICHAEL MENAKER

Contact Information

Research Interests

Behavioral and Physiological Analysis of Vertebrate Circadian Rhythms

We are working to understand the over-all organization of the circadian systems of vertebrates. Currently we have focused our attention on a transgenic rat model in which one of the circadian clock genes (Per1) has been linked to a luciferase reporter, so that whenever the gene is expressed low levels of light are produced. Using sensitive photomultipliers we are able to track the circadian expression patterns of the Per1 gene in brain slices and in various cultured peripheral tissues. Thus we are able to ask and answer questions that have not previously been approachable such as: Do the clocks in all tissues remain in synchrony following a change in the timing of the light cycle to which the animals are exposed? What are the signals from the brain that influence the clocks in peripheral tissues? How do the temporal relationships among clocks in the brain and those in peripheral structures change during postnatal development?

We have also become interested in circadian oscillators within the brain. Of these, the suprachiasmatic nucleus (SCN) is considered to be the "master oscillator." However, there are clearly other structures in the brain that can act as synchronizers of behavior and physiology. If the SCN is eliminated by lesion, rhythmicity is abolished, but can be restored either by the presentation of timed meals or by chronic application of psychostimulants. We are particularly interested in identifying the oscillator responsible for the generation of this rhythmicity and studying its molecular mechanism and its interaction with the SCN.

We are also studying light inputs to the circadian system, in particular the properties of a subclass of retinal ganglion cells that are intrinsically photosensitive and send their axons directly to clock centers in the brain.

Because circadian rhythmicity is a fundamental property of virtually all living things, understanding of its basic mechanisms is certain to bring practical benefits. Knowledge that we develop will have obvious applications to the problems associated with jet lag, shift work, and abnormal sleep patterns, but may also provide important insights into pathological mental states such as depression, and will inform the use of timed application of drugs and other treatments.

Wheel running activity of C57BL/6 mice treated with MAP. Chronic MAP was administered for the duration and dose indicated by the arrow on the left of the actogram. A. Intact mice were kept in 12/12 LD for 4 days and then released to DD. MAP significantly increased the total daily activity, duration of activity (alpha) and the period length within 8 days. 33% of the mice showed two rhtyhmic components which showed relative coordination. All effects disappeared after withdrawal. B. MAP induced robust rhythms in SCN-lesioned mice in DD. C. Similar rhythms were also induced by MAP in LL-treated arrhythmic intact mice. Only one rhythmic component was observed in either SCN-lesioned or LL-treated arrhtyhmic mice. (Tataroğlu, et al., 2006).

Recent Publications:

1. Yamazaki S, Numano R, Abe M, Hida A, Takahashi R-I, Ueda M, Block GD, Sakaki Y, Menaker M, Tei H (2000) Resetting central and peripheral circadian oscillators in transgenic rats. Science 288: 682-685.

2. Stokkan K-A, Yamazaki S, Tei H, Sakaki Y, and Menaker M (2001) Entrainment of the circadian clock in the liver by feeding. Science 291; 490-493.

3. Abe M, Herzog ED, Yamazaki S, Straume M, Tei H, Sakaki Y, Menaker M, Block GD (2002) Circadian rhythms in isolated brain regions. J Neurosci 22(1): 350-356.

4. Davidson AJ, Stokkan K-A, Yamazaki S, Menaker M (2002) Food-anticipatory activity and liver Per1-luciferase expression in diabetic transgenic rats. Physiol & Behav 76: 21-26.

5. Yamazaki S, Straume M, Tei H, Sakaki Y, Menaker M, Block GD (2002) Effects of aging on central and peripheral mammalian clocks. Proc Natl Acad Sci USA 99(16):10801-10806.

6. Doyle SE, Menaker M (2002) Circadian rhythmicity in dopamine content of mammalian retina: Role of the photoreceptors. Journal of Neurochemistry 83: 211 219.

7. Doyle SE, Grace MS, McIvor W, Menaker M (2002) Circadian Rhythms of Dopamine in Mouse Retina: The Role of Melatonin. Visual Neuroscience 19: 593-601.

8. Davidson AJ, Poole AS, Yamazaki S, Menaker M (2003) Is the food-entrainable oscillator in the digestive system? Genes, Brain, and Behavior 2:1-8.

9. Yoo S-H, Yamazaki S, Lowrey PL, Shimomura K, Ko CH, Buhr ED, Siepka SM, Hong H-K, Oh WJ, Yoo OJ, Menaker M, Takahashi JS (2004) Real-Time Reporting of Mouse PERIOD2 Protein Expression Reveals Self-Sustained Circadian Oscillators in Peripheral Tissues: A Reassessment of the Role of the Suprachiasmatic Nucleus. Proc Natl Acad Sciences 101(15): 5339-5346.

10. Davidson AJ, Tataroğlu Ö, Menaker M (2005) Chapter 26. Circadian Effects of Timed Meals (and Other Rewards). In Circadian Rhythms (Methods in Enzymology, vol 393, Young M W (ed), Elvesier Academic Press, San Diego, pp.509-523.

11. Yoshikawa T, Yamazaki S, Menaker M (2005) Effects of preparation time on phase of cultured tissues reveal complexity of circadian organization. J Biol Rhythms 20(6): 500-512. DOI: 10.1177/0748730405280775

12. Numano R, Yamazaki S, Umeda N, Sujino M, Takahashi R, Ueda M, Mori A, Yamada K, Sakaki Y, Inouye ST, Menaker M, Tei H (2006) Constitutive expression of the Period1 gene impairs behavioral and molecular circadian rhythms. PNAS 103(10): 3716-3721.

13. Tataroğlu Ö, Davidson AJ, Benvenuto LJ, Menaker M (2006) The methamphetamine-sensitive circadian oscillator (MASCO) in mice. J Biol Rhythms 21(3):185-194.

14. Menaker M (2006) Circadian organization in the real world. PNAS 103: 3015-3016.

15. Doyle SE, Castrucci AM, McCall M, Provencio I, Menaker M (2006) Non-visual light responses in the Rpe65 knockout mouse: rod loss restores sensitivity to the melanopsin system. Proc Natl Acad Sci USA 103(27): 10432-10437.

16. Davidson AJ, Sellix MT, Daniel J,  Yamazaki S, Menaker M,  & Block GD (2006) Jet-lag increases mortality in aged mice. Current Biology 16 (21): R914-916.

17. Doyle SE, Menaker M (in press) Circadian photoreception in vertebrates. 72^nd Cold Spring Harbor Symposium on Quantitative Biology: Clocks & Rhythms.