Circadian disruption induces slow-to-recover cognitive impairment and hippocampal myelin loss: a study in human beings and mice

Circadian disruption, a common consequence of shift work, is associated with neuropsychiatric disorders and cognitive impairment. However, existing occupational studies lack generalizability and the underlying structural mechanisms remain unclear. The present study aimed to investigate the relationships between circadian disruption, cognitive impairment and hippocampal white matter integrity, as well as their changes following circadian rhythm restoration. We analyzed UK Biobank longitudinal cohort data, comparing cognitive performance (including reaction time, numeric memory, fluid intelligence, and prospective memory) and structural connectivity derived from diffusion magnetic resonance imaging (MRI) between shift and non-shift workers. Mouse models of chronic circadian disruption and recovery were established to complement the human findings. Compared with non-shift workers, shift workers exhibited cognitive impairment, with a maximum decrease of 14.81% in fluid intelligence scores; notably, their cognitive performance remained lower than that of never-shift workers even after ceasing shift work, with a maximum reduction of 7.73% in fluid intelligence. Higher Criticism analysis indicated alterations in whole-brain structural connectivity in shift workers, including the hippocampus, with approximately 90% of structural connectivity in the bilateral hippocampi showing a decrease (Cohen's d < 0). Murine models of 8-week circadian disruption confirmed cognitive impairment and myelin loss; furthermore, mice with 8 weeks of circadian rhythm restoration following chronic circadian disruption also displayed hippocampus-related cognitive function inferior to that of controls, as well as slow-to-recover myelin structure. This study indicates that circadian disruption induces slow-to-recover cognitive impairment; this impairment is hippocampus-associated, and the myelin architecture of the hippocampus also exhibits a slow-to-recover pattern.