To understand how light might entrain a mammalian circadian clock, we examined the effects of light on mPer1, a sequence homolog of Drosophila per, that exhibits robust rhythmic expression in the SCN. mPer1 is rapidly induced by short duration exposure to light at levels sufficient to reset the clock, and dose-response curves reveal that mPer1 induction shows both reciprocity and a strong correlation with phase shifting of the overt rhythm. Thus, in both the phasing of dark expression and the response to light mPer1 is most similar to the Neurospora clock gene frq. Within the SCN there appears to be localization of the induction phenomenon, consistent with the localization of both light-sensitive and light-insensitive oscillators in this circadian center.

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Transcript levels of DBP, a member of the PAR leucine zipper transcription factor family, exhibit a robust rhythm in suprachiasmatic nuclei, the mammalian circadian center. Here we report that DBP is able to activate the promoter of a putative clock oscillating gene, mPer1, by directly binding to the mPer1 promoter. The mPer1 promoter is cooperatively activated by DBP and CLOCK-BMAL1. On the other hand, dbp transcription is activated by CLOCK-BMAL1 through E-boxes and inhibited by the mPER and mCRY proteins, as is the case for mPer1. Thus, a clock-controlled dbp gene may play an important role in central clock oscillation.Most eukaryotes and some prokaryotes have circadian (ϳ24-h) rhythms governed by endogenous oscillators that control daily rhythms in physiology and behavior. Recent molecular dissections in cyanobacteria, Neurospora, Drosophila, and mice have revealed that oscillations in the transcription of specific clock genes play a central role in the generation of circadian rhythms and that negative feedback loops, in which certain gene products suppress their own transcription, form central elements of the mechanism of the circadian oscillator conserved across species (5, 17).In mammals, the suprachiasmatic nucleus (SCN) is known as the anatomical locus of a dominant mammalian pacemaker for circadian behavior and hormonal rhythms (16,21). Following the initial discovery of mPer1 in the SCN (31) (Sun et al. reported the same gene, RIGUI, independently [28]), the first mammalian homologue of the Drosophila clock gene per (4, 13), many noticed that this gene is one of three genes of the mammalian period gene family; Per2 (1,26,29) and Per3 (30, 36) are also abundantly expressed in neurons of the SCN.Among mammalian per homologues, evidence has accumulated that at least mPer1 is a component constituting the central oscillatory mechanism. First, transcripts of mPer1 show a very robust rhythm in the SCN in mice (28, 31) and rats (35), even in extended constant dark (DD) conditions (27). Second, the auto-negative feedback loop seems to be closed for the mPer1 gene, as with the Drosophila per gene product PER, which negatively regulates the expression of its own gene (per) (11). The transcription of mPer1 was shown to be activated by the binding of the CLOCK-BMAL1 complex to the E-boxes (CACGTG) in the promoter region of the mPer1 gene (9), and this activation is specifically inhibited by PER1 protein and other negative elements, including PER2, PER3, TIM, CRY1, and CRY2 (14,18,23,24). Third and perhaps more important is the finding that mPer1 expression parallels the behavioral rhythm (27). mPer1 is rapidly induced by light in a time-of-day and tissue-specific manner that correlates well with the resetting behavior of the overt rhythm in locomotor activity. Moreover, the photic thresholds and dose responses for the two processes are quantitatively very similar, and each shows reciprocity between light intensity and duration (27).Besides the clock genes constituting this core oscillatory loop, a transcription fa...

The mechanism whereby brief light exposure resets the mammalian circadian clock in a phase dependent manner is not known, but is thought to involve Per gene expression. At the behavioural level, a light pulse produces phase delays in early subjective night, phase advances in late subjective night, and no phase shifts in mid-subjective night or subjective day. To understand the relationship between Per gene activity and behavioural phase shifts, we examined light-induced mPer1 and mPer2 expression in the suprachiasmatic nucleus (SCN) of the mouse, in the subjective night, with a view to understanding SCN heterogeneity. In the VIP-containing region of the SCN (termed `core'), light-induced mPer1 expression occurs at all times of the subjective night, while mPer2 induction is seen only in early subjective night. In the remaining regions of the SCN (termed `shell'), a phase delaying light pulse produces no mPer1 but significant mPer2 expression, while a phase advancing light pulse produces no mPer2 but substantial mPer1 induction. Moreover, following a light pulse during mid-subjective night, neither mPer1 nor mPer2 are induced in the shell. The results reveal that behavioural phase shifts occur only when light-induced Per gene expression spreads from the core to the shell SCN, with mPer1 expression in shell corresponding to phase advances, and mPer2 corresponding to phase delays. The results indicate that the time course and the localization of light-induced Per gene expression in SCN reveals important aspects of intra-SCN communication.

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