GABA neurons in the ventral tegmental area regulate non-rapid eye movement sleep in mice

Srikanta Chowdhury; Takanori Matsubara; Toh Miyazaki; Daisuke Ono; Noriaki Fukatsu; Manabu Abe; Kenji Sakimura; Yuki Sudo; Akihiro Yamanaka

doi:10.7554/eLife.44928

GABA neurons in the ventral tegmental area regulate non-rapid eye movement sleep in mice

Srikanta Chowdhury, Takanori Matsubara, Toh Miyazaki, Daisuke Ono, Noriaki Fukatsu, Manabu Abe, Kenji Sakimura, Yuki Sudo, Akihiro Yamanaka

Research output: Contribution to journal › Article › peer-review

38 Citations (Scopus)

Abstract

Sleep/wakefulness cycle is regulated by coordinated interactions between sleep- and wakefulness-regulating neural circuitry. However, the detailed mechanism is far from understood. Here, we found that glutamic acid decarboxylase 67-positive GABAergic neurons in the ventral tegmental area (VTA_Gad67+) are a key regulator of non-rapid eye movement (NREM) sleep in mice. VTA_Gad67+ project to multiple brain areas implicated in sleep/wakefulness regulation such as the lateral hypothalamus (LH). Chemogenetic activation of VTA_Gad67+ promoted NREM sleep with higher delta power whereas optogenetic inhibition of these induced prompt arousal from NREM sleep, even under highly somnolescent conditions, but not from REM sleep. VTA_Gad67+ showed the highest activity in NREM sleep and the lowest activity in REM sleep. Moreover, VTA_Gad67+ directly innervated and inhibited wake-promoting orexin/hypocretin neurons by releasing GABA. As such, optogenetic activation of VTA_Gad67+ terminals in the LH promoted NREM sleep. Taken together, we revealed that VTA_Gad67+ play an important role in the regulation of NREM sleep.

Original language	English
Article number	e44928
Journal	eLife
Volume	8
DOIs	https://doi.org/10.7554/eLife.44928
Publication status	Published - Jun 2019

ASJC Scopus subject areas

Neuroscience(all)
Immunology and Microbiology(all)
Biochemistry, Genetics and Molecular Biology(all)

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10.7554/eLife.44928

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title = "GABA neurons in the ventral tegmental area regulate non-rapid eye movement sleep in mice",

abstract = "Sleep/wakefulness cycle is regulated by coordinated interactions between sleep- and wakefulness-regulating neural circuitry. However, the detailed mechanism is far from understood. Here, we found that glutamic acid decarboxylase 67-positive GABAergic neurons in the ventral tegmental area (VTAGad67+) are a key regulator of non-rapid eye movement (NREM) sleep in mice. VTAGad67+ project to multiple brain areas implicated in sleep/wakefulness regulation such as the lateral hypothalamus (LH). Chemogenetic activation of VTAGad67+ promoted NREM sleep with higher delta power whereas optogenetic inhibition of these induced prompt arousal from NREM sleep, even under highly somnolescent conditions, but not from REM sleep. VTAGad67+ showed the highest activity in NREM sleep and the lowest activity in REM sleep. Moreover, VTAGad67+ directly innervated and inhibited wake-promoting orexin/hypocretin neurons by releasing GABA. As such, optogenetic activation of VTAGad67+ terminals in the LH promoted NREM sleep. Taken together, we revealed that VTAGad67+ play an important role in the regulation of NREM sleep.",

author = "Srikanta Chowdhury and Takanori Matsubara and Toh Miyazaki and Daisuke Ono and Noriaki Fukatsu and Manabu Abe and Kenji Sakimura and Yuki Sudo and Akihiro Yamanaka",

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AU - Chowdhury, Srikanta

AU - Matsubara, Takanori

AU - Miyazaki, Toh

AU - Ono, Daisuke

AU - Fukatsu, Noriaki

AU - Abe, Manabu

AU - Sakimura, Kenji

AU - Sudo, Yuki

AU - Yamanaka, Akihiro

PY - 2019/6

Y1 - 2019/6

N2 - Sleep/wakefulness cycle is regulated by coordinated interactions between sleep- and wakefulness-regulating neural circuitry. However, the detailed mechanism is far from understood. Here, we found that glutamic acid decarboxylase 67-positive GABAergic neurons in the ventral tegmental area (VTAGad67+) are a key regulator of non-rapid eye movement (NREM) sleep in mice. VTAGad67+ project to multiple brain areas implicated in sleep/wakefulness regulation such as the lateral hypothalamus (LH). Chemogenetic activation of VTAGad67+ promoted NREM sleep with higher delta power whereas optogenetic inhibition of these induced prompt arousal from NREM sleep, even under highly somnolescent conditions, but not from REM sleep. VTAGad67+ showed the highest activity in NREM sleep and the lowest activity in REM sleep. Moreover, VTAGad67+ directly innervated and inhibited wake-promoting orexin/hypocretin neurons by releasing GABA. As such, optogenetic activation of VTAGad67+ terminals in the LH promoted NREM sleep. Taken together, we revealed that VTAGad67+ play an important role in the regulation of NREM sleep.

AB - Sleep/wakefulness cycle is regulated by coordinated interactions between sleep- and wakefulness-regulating neural circuitry. However, the detailed mechanism is far from understood. Here, we found that glutamic acid decarboxylase 67-positive GABAergic neurons in the ventral tegmental area (VTAGad67+) are a key regulator of non-rapid eye movement (NREM) sleep in mice. VTAGad67+ project to multiple brain areas implicated in sleep/wakefulness regulation such as the lateral hypothalamus (LH). Chemogenetic activation of VTAGad67+ promoted NREM sleep with higher delta power whereas optogenetic inhibition of these induced prompt arousal from NREM sleep, even under highly somnolescent conditions, but not from REM sleep. VTAGad67+ showed the highest activity in NREM sleep and the lowest activity in REM sleep. Moreover, VTAGad67+ directly innervated and inhibited wake-promoting orexin/hypocretin neurons by releasing GABA. As such, optogenetic activation of VTAGad67+ terminals in the LH promoted NREM sleep. Taken together, we revealed that VTAGad67+ play an important role in the regulation of NREM sleep.

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GABA neurons in the ventral tegmental area regulate non-rapid eye movement sleep in mice

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