Abstract: Objective To establish and evaluate an animal model of high-altitude daytime dysfunction with the Traditional Chinese Medicine (TCM) syndrome of “phlegm-turbidity obstructing the orifices” in order to provide data for research on the pathological mechanisms and for screening therapeutic drugs for daytime dysfunction in high-altitude environments. Methods In the model screening experiment, C57BL/6J mice were divided into a control group (NC), sleep deprivation intervention groups (SD3-HH0, SD3-HH1, SD3-HH2), hypobaric hypoxia intervention groups (HH3-SD0, HH3-SD1, HH3-SD2), and the HH3-SD3 group, with 12 mice in each group. Optimal modeling conditions were selected by observing body weight changes, blood routine parameters, and histopathological alterations. In the model evaluation experiment, C57BL/6J mice were randomly divided into a control group (NC), a model group (HH3-SD1), a caffeine group (CAF, 15 mg·kg^-1), and an acetazolamide group (ACZ, 100 mg·kg^-1), with 12 mice in each group. The treatment groups received daily intragastric administration that started 2 days before the experiment and continued until the end of the experiment while the model and control groups received an equivalent volume of normal saline. In addition, SD rats (n=4) were used for sleep EEG monitoring via a self-control method. The daytime functional status and TCM syndrome of the model animals were evaluated via sleep-wake EEG monitoring, behavioral tests (grip strength test, Morris water maze), transcriptome sequencing, and ELISA techniques. Results An animal model of high-altitude daytime dysfunction with the syndrome of “phlegm-turbidity obstructing the orifices” was established by exposing rats to hypobaric hypoxia equivalent to 5 500 meters for 72 hours, with rotating sleep deprivation (one full rotation every 42 seconds, in alternating directions) during the final 24 hours. The model animals showed disrupted sleep architecture (decreased total waking hours, increased total sleep time), aggravated fatigue, and impaired learning and memory abilities. Concurrently, pathological changes included blood-brain barrier damage, hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, enhanced oxidative stress and inflammatory responses, and decreased levels of brain-derived neurotrophic factor (BDNF) and monoamine neurotransmitters. Transcriptome analysis revealed significant enrichment of the circadian rhythm pathway in the hypothalamus and the PI3K-Akt signaling pathway in the hippocampus. Conclusion The established animal model of high-altitude daytime dysfunction can effectively simulate the clinical manifestations and pathological features of the “phlegm-turbidity obstructing the orifices” syndrome under high-altitude conditions. It reveals a good correlation between pathological phenotypes and manifestations of this TCM syndrome, providing a reliable experimental platform for studying the pathological mechanisms of high-altitude daytime dysfunction and for conducting drug screening and efficacy evaluation.

Key words: High-Altitude Daytime Dysfunction, Syndrome of Phlegm-Turbidity Obstructing the Orifices, Animal Model, Sleep Deprivation, Hypobaric Hypoxia, Traditional Chinese Medicine Syndrome, Rats, Mice