Chronic Circadian Disturbance Reshapes Hippocampal Connectivity and Cognitive Function

Abstract

Circadian rhythms regulate a wide range of physiological and cognitive functions, yet the neural mechanisms linking circadian timing to memory remain poorly defined. Here, we identify a direct anatomical projection from the suprachiasmatic nucleus (SCN) to the dorsal hippocampus using complementary viral anterograde, retrograde, and monosynaptic tracing approaches, alongside established indirect pathways via septal and neuromodulatory regions. These findings revise prevailing models that restrict SCN influence on hippocampal function to polysynaptic routes. Functionally, chronic circadian disruption (CCD) induced region-specific metabolic alterations and widespread reorganization of brain-wide functional connectivity (FC). Hypometabolism emerged in the SCN, dentate gyrus, and perirhinal and entorhinal cortices, accompanied by loss of SCN- hippocampal connectivity and compensatory engagement of cortical and subcortical networks. In contrast, the serotonergic dorsal raphe nucleus showed selective hypermetabolism and increased connectivity with the SCN, prefrontal cortex, and hippocampus, suggesting altered neuromodulatory control under circadian misalignment. Behaviorally, CCD produced a selective impairment in object recognition memory, while spatial memory, working memory, cognitive flexibility, and hippocampal synaptic plasticity at the Schaffer collateral-CA1 synapse remained intact. Disrupted functional coupling within perirhinal-entorhinal- hippocampal and prefrontal-hippocampal circuits, together with altered SCN-medial septum- hippocampus connectivity, indicates that cognitive dysfunction arises from desynchronization of distributed brain networks rather than local synaptic failure. Together, these findings provide a new mechanistic framework linking circadian disruption to selective memory impairment and highlight network-level synchrony as a potential target for chronotherapeutic intervention.