Abstract
Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (CIH), which drives neurodegeneration through oxidative and inflammatory stress and heightened synaptic vulnerability. However, the molecular circuitry linking CIH to hippocampal dysfunction remains incompletely defined. In this study, Sprague–Dawley rats were exposed to CIH for 28 consecutive days, achieved by repeated hypoxia–reoxygenation cycles in a normobaric chamber. Hematoxylin–eosin (HE) staining was used to assess hippocampal histopathology. Hippocampal protein abundance of total STAT3 (t-STAT3), phosphorylated STAT3 (p-STAT3), and the M1mAChR was quantified by immunoblotting. Immunohistochemistry was performed to determine the regional and cellular localization of t-STAT3, p-STAT3, and M1mAChR within the hippocampus. The present study demonstrated that exposure to CIH produces marked hippocampal-dependent spatial learning and memory deficits, together with reduced hippocampal neuronal density and lower expression of the M1mAChR and STAT3. Notably, AG490, a selective JAK2 inhibitor, did not improve behavioral performance in CIH-exposed rats. By contrast, the selective M1mAChR agonist VU0364572 partially rescued the CIH-induced deficits, consistent with a neuroprotective role for M1mAChR activation in CIH-related dysfunction. Taken together, CIH induces hippocampal-dependent spatial learning and memory deficits accompanied by downregulation of hippocampal STAT3 and M1mAChR. The selective M1mAChR agonist VU0364572 partially reversed these deficits; however, this benefit required intact JAK2/STAT3 signaling (abolished by AG490). These findings support functional crosstalk between M1mAChR and JAK2/STAT3 in CIH-related hippocampal dysfunction, thereby contributing to improved learning and memory in rats.
Data availability
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
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Acknowledgements
This study was funded by the Young Scientific and Technological Talent Growth Project of Guizhou Provincial Department of Education (Grant No. Qianjiaoji [2024]145) and the Zunyi Municipal Science and Technology Support Program (Grant No. Zunshikehezhicheng [2025]41).
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QH and CH were responsible for overall supervision. QH and CH contributed to all experimental work. QJ contributed to data statistical analysis and written this article. HJ contributed to behavioral study design. XD and CF participated in biochemical parts of the experiment. FY drew these figures. ZC and PX designed this research. All the authors reviewed and approved the final manuscript.
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Huang, Q., Hu, C., Liu, H. et al. Activation of M1mAChR’s improves spatial learning and memory deficits in rats exposed to chronic intermittent hypoxia. Sci Rep (2026). https://doi.org/10.1038/s41598-025-34689-7
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DOI: https://doi.org/10.1038/s41598-025-34689-7
