Circadian rhythms regulate fundamental physiological and behavioral functions, yet are increasingly disrupted by contemporary environmental stressors such as rotating shift work and social isolation. Although each disruptor independently compromises circadian homeostasis, their interactive effects remain insufficiently characterized. Given the role of social cues as non-photic zeitgebers, we investigated whether social isolation exacerbates behavioral and molecular circadian disruption induced by repeated light-dark phase shifts, and whether social interaction confers resilience. Male AKR mice were assigned to six experimental groups defined by housing condition (grouped or isolated) and lighting regimen, comprising a stable 12-hour light-dark cycle, successive delays, or successive advances, with 8-hour phase shifts imposed every fourth day across six cycles. Locomotor activity was assessed using wheel-running, and transcript levels of Per1, Cry1, Bmal1, and Clock were quantified in the prefrontal cortex and hippocampus by RT-qPCR. Both phase delay and advance protocols disrupted behavioral rhythms and dampened circadian amplitude, with successive advances producing more pronounced desynchronization than delays. These effects were significantly amplified by social isolation, which led to marked rhythm fragmentation, phase misalignment, and delayed re-entrainment. At the molecular level, isolated mice displayed downregulation of Per1 and Cry1, and upregulation of Bmal1, most prominently in the hippocampus. Notably, group housing preserved circadian stability across behavioral and transcriptional domains, implicating social cues as modulators of internal synchrony. These findings demonstrate that social isolation potentiates the circadian desynchrony elicited by rotating shift paradigms and identify social interaction as a non-photic signal capable of partially restoring rhythm coherence and clock gene expression.
