Chemogenetic manipulation of mPFC neurons counteracts cognitive deficits but leaves sleep disturbances unaffected in a mouse model of chronic intermittent hypoxia

Chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnea, gives rise to cognitive deficits and sleep disruption. To investigate the role of the medial prefrontal cortex (mPFC), male mice were subjected to CIH for 4 weeks (8 h/day). Brain-wide Fos B screening revealed specific hyperactivation in the infralimbic (IL) subregion of the mPFC. Following chemogenetic virus injection into the mPFC, cognitive function was assessed using novel object/location recognition and the Morris water maze, sleep architecture was recorded via EEG/EMG, and synaptic markers were examined by western blotting and immunofluorescence. The results showed that CIH impaired cognitive function and reduced the density of both excitatory and inhibitory synaptic proteins in the mPFC-IL. Chemogenetic inhibition of mPFC-IL neurons attenuated these cognitive deficits and elevated synaptic protein levels, but failed to ameliorate the CIH-induced reduction in REM sleep and increased sleep-state transitions. In conclusion, the mPFC is a critical hub for CIH-induced cognitive impairment, and its targeted inhibition can restore cognitive and synaptic function. However, sleep architecture disruptions are governed by distinct mechanisms, indicating a dissociation between CIH-mediated cognitive and sleep pathologies. Significance Statement Obstructive sleep apnea often causes cognitive impairment, yet the brain mechanisms remain unclear. We found that chronic intermittent hypoxia triggers hyperactivation in a specific subregion of the medial prefrontal cortex, which critically drives cognitive deficits. Suppressing this region restored cognitive function but did not improve accompanying sleep disturbances. This dissociation reveals that cognitive and sleep impairments arise from distinct neural circuits, offering a new target for treating cognitive dysfunction in sleep apnea.