Long-term variable photoperiod disrupts serotonin signaling in prefrontal cortex and hippocampus, contributing to mood and cognitive deficits.

Circadian rhythm misalignment is strongly linked to mood and cognitive impairments, but the related molecular pathways are not fully elucidated. This research examined how long-term variable photoperiod (L-VP) influences emotional and cognitive functions, along with changes in serotonin (5-HT) signaling in the prefrontal cortex (PFC) and hippocampus of Wistar rats. Behavioral assessments revealed that L-VP induced anxiety-like behaviors, depressive phenotypes, and cognitive impairments, particularly during the subjective active phase (ZT12). Additionally, L-VP altered 5-HT metabolism, reducing 5-hydroxyindoleacetic acid (5-HIAA) levels and the 5-HIAA/5-HT ratio, indicating impaired serotonergic transmission. Expression of 5-HT receptors (5-HTR1A and 5-HTR2A) also exhibited circadian dysregulation, with reduced 5-HTR2A levels in the PFC. These findings suggest that chronic circadian misalignment disrupts 5-HT signaling in emotion- and cognition-related brain regions, contributing to mood and cognitive deficits. This study highlights the PFC and hippocampus as critical hubs for integrating circadian and emotional functions and explores potential therapeutic targets for circadian-related neuropsychiatric disorders.