Dysfunctions of the paraventricular hypothalamic nucleus induce hypersomnia in mice

Hypersomnolence disorder (HD) is characterized by excessive sleep, which is a common sequela following stroke, infection or tumorigenesis. HD is traditionally thought to be associated with lesions of wake-promoting nuclei. However, lesions of a single wake-promoting nucleus, or even two simultaneously, did not exert serious HD. Therefore, the specific nucleus and neural circuitry for HD remain unknown. Here, we observed that the paraventricular nucleus of the hypothalamus (PVH) exhibited higher c-fos expression during the active period (23:00) than during the inactive period (11:00) in mice. Therefore, we speculated that the PVH, in which most neurons are glutamatergic, may represent one of the key arousal-controlling centers. By using vesicular glutamate transporter 2 (vglut2Cre) mice together with fiber photometry, multichannel electrophysiological recordings, and genetic approaches, we found that PVHvglut2 neurons were most active during wakefulness. Chemogenetic activation of PVHvglut2 neurons induced wakefulness for 9 h, and photostimulation of PVHvglut2→parabrachial complex/ventral lateral septum circuits immediately drove transitions from sleep to wakefulness. Moreover, lesioning or chemogenetic inhibition of PVHvglut2 neurons dramatically decreased wakefulness. These results indicate that the PVH is critical for arousal promotion and maintenance.

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 23 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.

Paraventricular hypothalamic nucleus are essential for arousal promotion and maintenance

Adequate wakefulness is fundamental for proper daytime functioning. Clinical observations indicate that the paramedian region of the hypothalamus is a critical node for controlling wakefulness. However, the specific nucleus and neural circuitry for this function remain unknown. Here, we found that inhibition of PVHvglut2 neurons induced 3-h increase of NREM sleep. Chemogenetic activation of PVHvglut2 neurons potently induced 9-h wakefulness, and PVHCRH neuronal activation also exerted wakefulness. Photostimulation of PVHvglut2→parabrachial complex/ventral lateral septum circuits immediately drove transitions from NREM to wakefulness. Furthermore, using in vivo fiber photometry or multichannel electrophysiological recordings in mice, we find arousal-dependent increases in population activity of PVHvglut2 neurons. Most importantly, ablation of PVHvglut2 neurons dramatically led mice to hypersomnia-like behaviors. These results demonstrate that PVHvglut2 neurons are essential for physiologic arousal in the hypothalamus.