3D Tissue Models

Michael Menaker.

TypeWhite Paper Summary

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.


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