Abstract
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 hr, 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.
Highlights
Hypersomnolence disorder (HD) is characterized by an irresistible need for sleep and an inability to stay awake during major waking episodes, which results in reduced function and overall worse life quality, highlighting its public health importance[1]
Immunohistochemistry results showed a 306% higher number of c-fos-positive cells in the paraventricular nucleus of the hypothalamus (PVH) from mice sacrificed in the active period (23:00) compared with those sacrificed in the inactive period (11:00) (Figure 1A, B), indicating that the PVH might be an important wake-promoting nucleus
We found that chemogenetic activation of PVHvglut2 neurons induced an increase in heart rate and temperature for 3 h, both of which peaked at about 2 h after injection and returned to the baseline level at about 3 h following administration of CNO
Summary
Hypersomnolence disorder (HD) is characterized by an irresistible need for sleep and an inability to stay awake during major waking episodes, which results in reduced function and overall worse life quality, highlighting its public health importance[1]. The lateral hypothalamic area (LH), parabrachial complex (PB), tuberomammilary nucleus (TMN), paraventricular nucleus of the thalamus (PVT), ventral tegmental area (VTA), and supramammillary nucleus (SUM) have been demonstrated to be involved in arousal regulation [6, 9,10,11,12,13] Among these wake-promoting nuclei, only LH orexinergic and PB glutamatergic neurons have been shown to be related to hypersomnia. Patients with Parkinson’s disease (PD), Alzheimer’s disease (AD), Kleine-Levin Syndrome, and idiopathic hypersomnia (IH), in which LH orexinergic and PB glutamatergic neurons are thought to function normally, still show hypersomnolence [19] These results suggest that the key hypersomnolence control nucleus remains unidentified.
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