GABA and glutamate neurons in the VTA regulate sleep and wakefulness.

Xiao Yu,Yuqi Li,Kyoko Tossell,Denis Burdakov,Juan Guo,Ming Chen,Qianzi Yang,Raquel Yustos,Nicholas P Franks,Giulia Miracca,Edward C Harding,Ying Ma,Alexei L Vyssotski,Long Li,William Wisden,Julia J Harris,Hailong Dong,Wen Li,Dan Wang,Wang Ba

doi:10.1038/s41593-018-0288-9

Abstract

We screened for novel circuits in the mouse brain that promote wakefulness. Chemogenetic activation experiments and electroencephalogram recordings pointed to glutamatergic/nitrergic (NOS1) and GABAergic neurons in the ventral tegmental area (VTA). Activating glutamatergic/NOS1 neurons, which were wake- and rapid eye movement (REM) sleep-active, produced wakefulness through projections to the nucleus accumbens and the lateral hypothalamus. Lesioning the glutamate cells impaired the consolidation of wakefulness. By contrast, activation of GABAergic VTA neurons elicited long-lasting non-rapid-eye-movement-like sleep resembling sedation. Lesioning these neurons produced an increase in wakefulness that persisted for at least 4 months. Surprisingly, these VTA GABAergic neurons were wake- and REM sleep-active. We suggest that GABAergic VTA neurons may limit wakefulness by inhibiting the arousal-promoting VTA glutamatergic and/or dopaminergic neurons and through projections to the lateral hypothalamus. Thus, in addition to its contribution to goal- and reward-directed behaviors, the VTA has a role in regulating sleep and wakefulness.

Highlights

We screened for novel circuits in the mouse brain that promote wakefulness
A smaller associated virus (AAV) injection volume into the posterior hypothalamic/midbrain area (PH/MB) of Vglut2-ires-Cre mice resulted in hM3Dq expression in the lateral hypothalamus (LH), MM and ventral tegmental area (VTA) (PH/MB)SVglut2-hM3Dq mice, Fig. 1d)
VTAVgat neurons limit wakefulness and induce NREM sleep—We looked for neurons in the VTA that could potentially restrain the wake-promoting activity of the VTAVglut2/Nos[1] neurons

Summary

Introduction

We screened for novel circuits in the mouse brain that promote wakefulness. Chemogenetic activation experiments and EEG recordings pointed to glutamatergic/nitrergic (NOS1) and GABAergic neurons in the VTA. To test if the VTANos[1] neurons are functionally the same as the VTAVglut[2] neurons in producing wakefulness, we chemogenetically activated the VTANos[1] neurons by delivering AAV-DIO-hM3Dq-mCherry into the VTA of Nos1-ires-Cre mice (Fig. 4b, c).

Results

Conclusion