Circadian disruption is an emerging global health challenge. Shift work workers exposed to irregular light–dark schedules are susceptible to increase risk for sleep disturbance and cognitive decline. Similarly, long-COVID research has shown that nearly half of affected individuals report persistent sleep disturbances a year post-infection, often accompanied by fatigue, memory impairment, and brain fog. Together, these examples highlight a growing recognition: disrupted sleep and circadian misalignment are tightly linked to impaired cognition with implications for upregulation of the kynurenine pathway (see 2024 April/May highlight) and serotonin depletion (see 2023 Oct highlight).
A new study by Jing Liao and colleagues (2025) provides mechanistic insight into this relationship. Using a mouse model of irregular light–dark cycles, the authors showed marked deficits in recognition memory, spatial exploration, and hippocampal integrity after 15 weeks of circadian disruption. Metabolomic profiling indicated widespread metabolic alterations, with enrichment analyses converging on tryptophan metabolism. Further targeted tryptophan metabolomics revealed reduced serotonin and its precursors, alongside downregulation of tryptophan hydroxylase 1 and 2 (TPH1/TPH2) in the hippocampus. Notably, supplementation with 5-hydroxytryptophan (5-HTP) partially restored memory performance, linking serotonin availability directly to cognitive outcomes.
These findings align with human metabolomic studies in long-COVID and neurodegenerative disease, where altered tryptophan metabolism and reduced serotonin are consistently observed. The study suggest that circadian misalignment and serotonin pathway dysregulation may represent a shared mechanism underlying sleep disturbance and cognitive vulnerability across diverse conditions. The implications are clear: Research into stability of circadian rhythms is essential not only for restorative sleep but also for preserving cognitive resilience. Supporting serotonin metabolism through lifestyle, nutritional, or pharmacological interventions may offer new strategies to mitigate the neurocognitive costs of a ‘sleepless’ society.