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Genetic analysis of neurons involved in sleep-wake regulation

柏木, 光昭 筑波大学 DOI:10.15068/00161549

2020.10.06

概要

Mammalian sleep comprises two distinct states, rapid eye movement (REM or paradoxical) sleep and non-REM (NREM) sleep. Classical transection and pharmacological studies suggest that, in addition to the hypothalamus, the brainstem is essential for REM and NREM sleep. The role of the pons in REM sleep has been actively studied, however, those that of in NREM sleep remains less clear. Here, I identified a circuit distributed in the midbrain, pons, and medulla that promotes NREM sleep in mice. I focused on the sublaterodorsal tegmentum (SubLDT), an area implicated in dual regulation of REM and NREM sleep. Chemogenetic activation of the neurons positive for the neuropeptide neurotensin promote NREM sleep. In contrast, functional inactivation of these neurons with tetanus toxin resulted in decrease of NREM sleep, suggesting that these neurons play important role for NREM sleep regulation. Subsequent anterograde tracing and chemogenetic analyses identified putative downstream NREM sleep-promoting neurons in the dorsal deep mesencephalic nucleus (dDpMe), lateral part of the periaqueductal gray (lPAG), and medial vestibular nucleus (MVe), all of which were located in the brainstem and previously unknown population for regulating NREM sleep. Remarkably, all of these putative downstream NREM sleep promoting neurons were also neurotensinergic. Infusion of neurotensin peptide into the fourth ventricle, which faces dorsal surface of the pons and medulla, induced a behavioral quiescent with NREM sleep-like cortical activity. In contrast, mice deficient for neurotensin exhibited increased REM sleep, implicating the involvement of the neuropeptide itself. These findings identify a widely distributed NREM sleep-regulating circuit in the brainstem with a common molecular property.

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