Molecular Basis of Entrainment to Light

In 1989, several groups of scientists independently reported that light could regulate the expression of the protoncogene c-fos in the SCN of rats and hamsters. The protein (c-Fos) belongs to the leucine zipper family of DNA-binding proteins and forms transcrip-tional regulatory complexes with other binding proteins. That light could physiologically regulate c-fos expression suggested that transcriptional control, via transcriptional regulatory proteins, was an important part of photoentrainment and might contribute to the mechanisms of circadian time-keeping. JunB appears to have a temporal pattern of expression similar to that of c-Fos and, thus, may also have an important role in light entrainment.

Following a light pulse administered during the subjective night in constant darkness, both c-fos mRNA and c-Fos protein are dramatically elevated in the retinorecipient areas of the SCN. This photoinduction of c-fos and c-Fos does not occur during the subjective day and, thus, photoinduction, like phase shifting, is phase-dependent. Circadian phase dependency of c-fos and c-Fos expression persists in vitro in SCN tissue slices. Thus, the gating of c-fos and c-Fos induction does not appear to require an intact retina or other neuronal structure. The mechanism that gates the photoresponsiveness of c-fos expression is unknown. However, phase dependency of c-Fos induction implies that the c-fos gene is clock-controlled. In contrast, photic stimulation of c-fos and c-Fos in another important CTS structure, the IGL, is not dependent on the circadian phase. The response to light in the SCN includes rapid and transient peak expression of mRNA after 30 min and peak expression of immunoreactive c-Fos protein 1-2 hr after onset of light administration.

There is a strong correlation between the photic induction of c-fos and the magnitude of phase shifts in behavioral rhythms. Further, the illumination threshold for gene expression is identical to the threshold for phase shifts. This correlation does not apply at high light intensities or with long photoperiods. Experimentation has indicated that about 20% of the total SCN neuron population consists of photo-inducible c-Fos cells. These cells are located in the ventrolateral portion of the SCN. The exact mechanism of c-fos induction in the SCN remains unclear. However, it appears that an initial intracellular elevation of Ca2+ and cyclic AMP results from glutamanergic stimulation from the RHT. This then leads to phosphorylation of Ca2+-cAMP response element-binding protein (CREB), an important transcription factor.

Only when Fos proteins are complexed as hetero-dimers, particularly with jun gene family members (c-Jun, JunB, JunD), will binding to the DNA regulatory element, AP-1, occur. AP-1-binding complexes may have constant or variable protein components, and it has been proposed that light, via c-Fos activation, alters the protein composition of the AP-1-binding complex, a regulator of transcription, altering its stability and binding affinity. The change in binding activity alters the transcription of SCN genes that have AP-1 sites on their promoters. To date, however, the trans-activating and trans-repressing activities of the various heterodimer complexes are unknown, and the identities of the AP-1-dependent genes remain to be elucidated. Exactly how the IEGs modulate Clock genes is not understood.

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Breaking Bulimia

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