Region-specific Per1 induction dissociates circadian and mood responses to light

Abstract Light is a major environmental cue that synchronizes circadian rhythms and modulates affective behaviors. In mammals, photic information reaches multiple brain regions, including the suprachiasmatic nuclei (SCN), the master circadian pacemaker, and the lateral habenula (LHb), a structure implicated in mood-related behaviors such as despair. Both regions harbor the light-inducible clock gene Per1 , which contributes to circadian phase shifting and behavioral regulation. Although light can simultaneously shift circadian phase and improve mood-related behaviors in mice and humans, it remains unclear whether these processes share a common mechanism. To address this question, we selectively deleted Per1 in SCN or LHb neurons of Per1 -floxed mice using region-specific viral Cre recombinase delivery. Loss of Per1 in the SCN reduced light-induced phase advances at circadian time (CT) 22, whereas deletion in the LHb had no effect on phase shifting. In contrast, light-induced improvement of despair-like behavior was abolished by Per1 deletion in the LHb but preserved in SCN-targeted knockouts. Furthermore, according to RT-PCR, Per1 -induction relied on different promoter usage. These findings demonstrate that the mood-related effects of light are independent from its circadian phase-shifting properties, revealing distinct Per1 -dependent mechanisms through which light regulates behavior. This dissociation suggests that light-based therapies could be optimized by targeting mood-regulating pathways without necessarily altering circadian activity cycles. Author summary The present study identifies Per1 as a molecular node through which light exerts two distinct therapeutic actions: circadian phase resetting via the SCN and mood improvement via the LHb. This dissociation has major translational implications. It suggests that the antidepressant effects of light therapy—widely used in seasonal affective disorder (SAD) and increasingly in major depressive disorder (MDD)—do not require circadian phase shifting and instead rely on a Per1 -dependent LHb pathway. Understanding this separation opens the door to more targeted, faster, and potentially more effective light-based interventions.