Dysfunctions of the paraventricular hypothalamic nucleus induce hypersomnia in human and mice

Hypersomnolence disorder (HD) is characterized by excessive sleep, which is a common sequela following stroke, infections or tumorigenesis. HD was traditionally thought to be associated with lesions of wake-promoting nuclei. However, lesion of a single, even two or more wake-promoting nucleuses simultaneously did not exert serious HD. The specific nucleus and neural circuitry for HD remain unknown. Here, we observed that three patients with lesions around the paraventricular nucleus of the hypothalamus (PVH) showed hypersomnolence lasting more than 20 h per day and their excessive sleep decreased with the recovery of the PVH area. Therefore, we hypothesized that the PVH might play an essential role in the occurrence of HD. Using multichannel electrophysiological recording and fiber photometry, we found that PVHvglut2 neurons were preferentially active during wakefulness. Chemogenetic activation of PVHvglut2 neurons potently induced 9-h wakefulness, and PVHCRH, PVHPDYN and PVHOT neuronal activation also exerted wakefulness. Most importantly, ablation of PVHvglut2 neurons drastically induced hypersomnia-like behaviors (30.6% reduction in wakefulness). These results indicate that dysfunctions of the PVH is crucial for physiological arousal and pathogenesis underlying HD.