ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2025
Orexinergic modulation of chronic jet lag-induced deficits in mouse cognitive flexibility.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed.
- Differential and state-dependent effects of the GluN2A-selective positive allosteric modulator GNE-5729 on executive functions.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Article
- Sex-specific circadian and behavioral phenotypes in aged growth hormone receptor knockout mice.GeroScience · 2026Article
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5 authors.
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Abstract
Cognitive flexibility and working memory are important executive functions mediated by the prefrontal cortex and can be impaired by circadian rhythm disturbances such as chronic jet lag (CJL) or shift work. In the present study, we used mice to investigate whether (1) simulated CJL impairs cognitive flexibility, (2) the orexin system is involved in such impairment, and (3) nasal administration of orexin A is able to reverse CJL-induced deficits in cognitive flexibility and working memory. Mice were exposed to either standard light-dark conditions or simulated CJL consisting of series of advance time shifts. Experiment (1) investigated the effects of a mild CJL protocol on cognitive flexibility using the attentional set shifting task. Experiment (2) used a stronger CJL protocol and examined CJL effects on the orexin system utilizing c-Fos and orexin immunohistochemistry. Experiment (3) tested whether nasal orexin application can rescue CJL-induced deficits in cognitive flexibility and working memory, the latter by measuring spontaneous alternation in the Y-maze. The present data show that CJL (1) impairs cognitive flexibility and (2) reduces the activity of orexin neurons in the lateral hypothalamus. (3) Nasal administration of orexin A rescued CJL-induced deficits in working memory and cognitive flexibility. These findings suggest that executive function impairments by circadian rhythm disturbances such as CJL are caused by dysregulation of orexinergic input to the prefrontal cortex. Compensation of decreased orexinergic input by nasal administration of orexin A could be a potential therapy for CJL- or shift work-induced human deficits in executive functions.
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