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

Chowdhury, Srikanta; Matsubara, Takeo; Miyazaki, Takehide; Ono, Daisuke; Fukatsu, Noriaki; Abe, Manabu; Sakimura, Kenji; Sudo, Yuki; Yamanaka, Akihiro

doi:10.7554/elife.44928.037

Cited by 2 publications

(6 citation statements)

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“…6, A and B). Optical stimulation of the dorsal-intermediate lateral septum-to-ventral tegmental area projections reliably elicited transitions to the awake state from non-REM sleep, as evidenced by the decreased delta power and increased beta power (latency to wake: 139.5 [112.5,168.2] s vs. 4.0 [3.3, 4.8] s, P < 0.001; delta: 30.1 ± 6.0% vs. 16.0 ± 3.4%, P < 0.001; theta: 38.5 ± 5.5% vs. 35.9 ± 8.6%, P = 0.553; Beta: 4.5 [3.9, 5.4] % vs. 11.3 [7.3, 11.9] %, P = 0.050; gamma: 7.0 [6.0, 9.9] % vs. 18.3 [12.4, 23.6…”

Section: Dorsal-intermediate Lateral Septum Gabaergic Neuronsmentioning

confidence: 97%

“…4,8 Specifically, the ventral tegmental area dopaminergic circuit regulates sleep-related behaviors and maintains the behavioral and electrocortical awake state, 4 whereas the GABAergic neurons promote non-rapid eye movement (non-REM) sleep. 16 Previous lesion-based and pharmacologic studies have suggested that the lateral septum modulates the activities of the ventral tegmental area dopaminergic neurons by inhibiting GABAergic interneurons. 15 These findings led to our hypothesis that the lateral septum GABAergic neurons may be involved in sleep-wakefulness regulation through the lateral septum-ventral tegmental area circuit.…”

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GABAergic Neurons in the Dorsal–Intermediate Lateral Septum Regulate Sleep–Wakefulness and Anesthesia in Mice

et al. 2021

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Background The γ-aminobutyric acid–mediated (GABAergic) inhibitory system in the brain is critical for regulation of sleep–wake and general anesthesia. The lateral septum contains mainly GABAergic neurons, being cytoarchitectonically divided into the dorsal, intermediate, and ventral parts. This study hypothesized that GABAergic neurons of the lateral septum participate in the control of wakefulness and promote recovery from anesthesia. Methods By employing fiber photometry, chemogenetic and optogenetic neuronal manipulations, anterograde tracing, in vivo electrophysiology, and electroencephalogram/electromyography recordings in adult male mice, the authors measured the role of lateral septum GABAergic neurons to the control of sleep–wake transition and anesthesia emergence and the corresponding neuron circuits in arousal and emergence control. Results The GABAergic neurons of the lateral septum exhibited high activities during the awake state by in vivo fiber photometry recordings (awake vs. non–rapid eye movement sleep: 3.3 ± 1.4% vs. –1.3 ± 1.2%, P < 0.001, n = 7 mice/group; awake vs. anesthesia: 2.6 ± 1.2% vs. –1.3 ± 0.8%, P < 0.001, n = 7 mice/group). Using chemogenetic stimulation of lateral septum GABAergic neurons resulted in a 100.5% increase in wakefulness and a 51.2% reduction in non–rapid eye movement sleep. Optogenetic activation of these GABAergic neurons promoted wakefulness from sleep (median [25th, 75th percentiles]: 153.0 [115.9, 179.7] s to 4.0 [3.4, 4.6] s, P = 0.009, n = 5 mice/group) and accelerated emergence from isoflurane anesthesia (514.4 ± 122.2 s vs. 226.5 ± 53.3 s, P < 0.001, n = 8 mice/group). Furthermore, the authors demonstrated that the lateral septum GABAergic neurons send 70.7% (228 of 323 cells) of monosynaptic projections to the ventral tegmental area GABAergic neurons, preferentially inhibiting their activities and thus regulating wakefulness and isoflurane anesthesia depth. Conclusions The results uncover a fundamental role of the lateral septum GABAergic neurons and their circuit in maintaining awake state and promoting general anesthesia emergence time. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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Section: Dorsal-intermediate Lateral Septum Gabaergic Neuronsmentioning

confidence: 97%

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confidence: 99%

GABAergic Neurons in the Dorsal–Intermediate Lateral Septum Regulate Sleep–Wakefulness and Anesthesia in Mice

et al. 2021

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“…The mechanisms related to hyperactivity, anti-depressive behaviors, and reduced sleep amount during the dark period in VGAT-Cre DTA/VMP mice remain unclear. Recent studies revealed GABAergic projections from the VTA to the lateral hypothalamus (Taylor et al, 2014;Yu et al, 2019) and especially onto orexin neurons (Chowdhury et al, 2019), which are critical for maintaining wakefulness (Chemelli et al, 1999). Optogenetic activation of GABAergic VTA terminals in the lateral hypothalamus suppresses wakefulness (Chowdhury et al, 2019;Yu et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies revealed GABAergic projections from the VTA to the lateral hypothalamus (Taylor et al, 2014;Yu et al, 2019) and especially onto orexin neurons (Chowdhury et al, 2019), which are critical for maintaining wakefulness (Chemelli et al, 1999). Optogenetic activation of GABAergic VTA terminals in the lateral hypothalamus suppresses wakefulness (Chowdhury et al, 2019;Yu et al, 2019). Moreover, lateral hypothalamic kindling induces mania-like behaviors (Abulseoud et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…In humans, infarctions of the midbrain or pontine areas induces secondary mania (Antelmi et al, 2014;Caplan, 2010;Drake et al, 1990;Satzer and Bond, 2016;Shen et al, 2005). In the present study, we focused on the ventral medial midbrain/pons (VMP) area, a region that contains sleep-regulating GABAergic neurons (Chowdhury et al, 2019;Yu et al, 2019). To elucidate the physiologic functions of VMP GABAergic neurons, we selectively ablated these neurons in mice with Cre-dependent viral expression of the diphtheria toxin subunit A (DTA) in the VMP of vesicular GABA transporter (VGAT; a marker of GABAergic neurons) Cre mice (VGAT-Cre DTA/VMP mice: Figures 1A and 1B).…”

Section: Introductionmentioning

confidence: 99%

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Ablation of Ventral Midbrain/Pons GABA Neurons Induces Mania-like Behaviors with Altered Sleep Homeostasis and Dopamine D2R-mediated Sleep Reduction

et al. 2020

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Individuals with the neuropsychiatric disorder mania exhibit hyperactivity, elevated mood, and a decreased need for sleep. The brain areas and neuronal populations involved in mania-like behaviors, however, have not been elucidated. In this study, we found that ablating the ventral medial midbrain/pons (VMP) GABAergic neurons induced mania-like behaviors in mice, including hyperactivity, anti-depressive behaviors, reduced anxiety, increased risk-taking behaviors, distractibility, and an extremely shortened sleep time. Strikingly, these mice also showed no rebound sleep after sleep deprivation, suggesting abnormal sleep homeostatic regulation. Dopamine D 2 receptor deficiency largely abolished the sleep reduction induced by ablating the VMP GABAergic neurons without affecting the hyperactivity and anti-depressive behaviors. Our data demonstrate that VMP GABAergic neurons are involved in the expression of mania-like behaviors, which can be segregated to the short-sleep and other phenotypes on the basis of the dopamine D 2 receptors.

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

Cited by 2 publications

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GABAergic Neurons in the Dorsal–Intermediate Lateral Septum Regulate Sleep–Wakefulness and Anesthesia in Mice

GABAergic Neurons in the Dorsal–Intermediate Lateral Septum Regulate Sleep–Wakefulness and Anesthesia in Mice

Ablation of Ventral Midbrain/Pons GABA Neurons Induces Mania-like Behaviors with Altered Sleep Homeostasis and Dopamine D2R-mediated Sleep Reduction

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