Mammalian circadian rhythmicity is endogenously generated by a pacemaker in the suprachiasmatic nuclei and precisely entrained to the 24-hr day/night cycle by periodic environmental light cues. We show that light alters the immunoreactive levels of a transcriptional regulatory protein, Fos, in the suprachiasmatic nuclei of albino rats. Photic regulation of Fos immunoreactivity does not occur in other retino-recipient brain areas except for the intergeniculate leaflet, which appears to be involved in mediating some of the complex effects of light on expressed circadian rhythms. Our results point to a promising new functional marker for the cellular effects of light and suggest that the expression of Fos or a related nuclear protein may be part of the mechanism for photic entrainment of the circadian clock to environmental light/dark cycles.(12, 13) stimulation, and water deprivation (10). Recently, exposure of rats to flashing lights was reported to increase immunoreactive Fos in some cells of the inner nuclear and ganglion cell layers of the retina (14). To determine whether regional brain Fos expression might also be modulated by light, we used an affinity-purified antibody against a synthetic peptide of Fos (amino acids 132-154, a sequence that includes the probable DNA-binding domain) to perform immunohistochemistry on sections from the brains of Sprague-Dawley rats. We now report that light increases the levels of immunoreactive Fos in the SCN and hypothesize that events at the transcriptional level are part of the mechanism for photic entrainment of circadian rhythms to environmental light/ dark cycles. Some of these data have been reported previously in abstract form (15).Light-responsive neurons in the mammalian brain are organized into discrete circuits that are functionally, physiologically, and anatomically distinct. Thus, direct retinal projections to the superior colliculi are responsible for visually guided eye movements; visual inputs to the pretectum drive reflex pupillary function; and the optic pathway to the lateral geniculate nuclei relays information required for image formation. In addition to these classic connections, some retinal ganglion cells monosynaptically innervate the suprachiasmatic nuclei (SCN) in the anterior hypothalamus, site of an endogenous circadian clock (1). Activation of this retinohypothalamic tract appears to be both necessary and sufficient for precise entrainment of the period and phase of overt circadian rhythms to the natural day/night cycle (2). Such entrainment is achieved by light-induced phase shifts of the endogenous oscillation of the circadian pacemaker in the SCN; permanent advances or delays occur because the oscillator is differentially sensitive to light exposure at different phases of its free-running circadian cycle (3). The cellular mechanism of photic entrainment is unknown, but the search is underway (predominantly in organisms simpler than mammals) for molecular candidates at the membrane, cytoplasmic, and nuclear levels that might be a par...