Duske Julius, D'Souza Nicole, Mayer Dana, Dieterich Daniela C, Fendt Markus
Institute for Pharmacology and Toxicology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
Institute of Neurophysiology, Goethe University, Frankfurt, Germany.
Neuropsychopharmacology. 2025 Apr;50(5):762-771. doi: 10.1038/s41386-024-02017-8. Epub 2024 Oct 30.
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.
认知灵活性和工作记忆是由前额叶皮层介导的重要执行功能，可能会受到昼夜节律紊乱的影响，如慢性时差反应（CJL）或轮班工作。在本研究中，我们使用小鼠来研究：（1）模拟CJL是否会损害认知灵活性；（2）食欲素系统是否参与这种损害；（3）经鼻给予食欲素A是否能够逆转CJL诱导的认知灵活性和工作记忆缺陷。将小鼠置于标准明暗条件下或由一系列提前时间转移组成的模拟CJL环境中。实验（1）使用注意力集转换任务研究轻度CJL方案对认知灵活性的影响。实验（2）采用更强的CJL方案，并利用c-Fos和食欲素免疫组织化学检查CJL对食欲素系统的影响。实验（3）测试经鼻给予食欲素是否可以挽救CJL诱导的认知灵活性和工作记忆缺陷，后者通过测量Y迷宫中的自发交替来评估。目前的数据表明，CJL：（1）损害认知灵活性；（2）降低下丘脑外侧食欲素神经元的活性。（3）经鼻给予食欲素A可挽救CJL诱导的工作记忆和认知灵活性缺陷。这些发现表明，CJL等昼夜节律紊乱导致的执行功能损害是由前额叶皮层食欲素能输入失调引起的。经鼻给予食欲素A补偿食欲素能输入减少可能是治疗CJL或轮班工作引起的人类执行功能缺陷的一种潜在疗法。
