Circadian rhythm disruption causes cognitive impairment through the basal forebrain-hippocampal cholinergic system

Circadian rhythm disruption is associated with cognitive impairments, yet the mechanisms involving cholinergic signaling remain elusive. This study investigated whether shift work alters cholinergic factors and impairs cognition through the basal forebrain–hippocampal pathway. In human subjects, we assessed cognitive performance using the Montreal Cognitive Assessment (MoCA) and measured serum cholinergic biomarkers in shift workers and non-shift workers. In parallel, male C57BL/6 J mice subjected to circadian disruption were used to model shift-work–induced cognitive deficits, and male ChAT-IRES-Cre mice were employed for optogenetic interrogation of the basal forebrain–hippocampal cholinergic projection. Shift workers exhibited lower MoCA scores and altered cholinergic factor profiles compared with non-shift workers. In mice, circadian disruption caused cognitive impairment, reduced cholinergic neuron excitability, and disrupted synaptic transmission in the basal forebrain–hippocampal circuit. Optogenetic activation of this cholinergic pathway rescued cognitive performance in ChAT-IRES-Cre mice. These findings suggest that shift work–associated cognitive decline may involve cholinergic dysregulation, and that the basal forebrain–hippocampal cholinergic projection represents a potential circuit-level target for circadian-related cognitive impairment. Circadian disruption modeling unveils the role of basal forebrain–hippocampal cholinergic signaling in shift-work cognition and mice.