GABA and glutamate neurons in the VTA regulate sleep and wakefulness

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.

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Fig. 1: Chemogenetic mapping for novel glutamatergic areas in the PH/MB that promote wakefulness identifies the VTA.
Fig. 2: VTAVglut2 neurons consolidate wakefulness and are selectively wake- and REM sleep-active.
Fig. 3: VTAVglut2 neurons promote wakefulness by their projections to the LH and NAc.
Fig. 4: VTAVglut2 and VTANos1 neurons promote wakefulness.
Fig. 5: Excitation of GABAergic neurons in the VTA induces sleep and their inhibition produces continuous wakefulness.
Fig. 6: VTAVgat neurons inhibit wakefulness; lesioning of VTAVgat neurons produces extended wakefulness, but VTAVgat neurons are selectively wake- and REM-active.
Fig. 7: VTAVgat neurons limit wakefulness in part by locally inhibiting dopamine and Vglut2 neurons in the VTA.
Fig. 8: VTAVgat neurons inhibit wakefulness in part via projections to the LH.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding authors on reasonable request.

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Acknowledgements

We thank M. Ungless (Faculty of Medicine, Imperial College London) for comments on the manuscript. Our work was supported by the Wellcome Trust (107839/Z/15/Z, N.P.F. and 107841/Z/15/Z, W.W), the UK Dementia Research Institute (W.W. and N.P.F.), the Funds for International Cooperation and Exchange of the National Natural Science Foundation of China (grant no. 81620108012, H.D. and N.P.F.), the China Scholarship Council (Y.M.), a Rubicon Fellowship (019.161LW.010) from the Netherlands Organization for Scientific Research (W.B.), an Imperial College Schrödinger Scholarship (G.M.), and an Imperial College Junior Research Fellowship (J.J.H.). D.B. and J.J.H. were also supported by The Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001055), the Medical Research Council (FC001055), and the Wellcome Trust (FC001055). The Facility for Imaging by Light Microscopy at Imperial College London is in part supported by funding from the Wellcome Trust (grant no. 104931/Z/14/Z) and BBSRC (grant no. BB/L015129/1).

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N.P.F. and W.W. conceived and, with X.Y. and H.D., designed the experiments. X.Y., W.L., Y.M., K.T., J.J.H., E.C.H., W.B., G.M., D.W., L.L., J.G., M.C., Y.L., R.Y., D.B., and Q. Y. performed the experiments and/or data analysis. A.L.V. provided the Neurologgers. N.P.F. and W.W. contributed to the data analysis and with H.D. supervised the project. N.P.F., X.Y., and W.W. wrote the paper.

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Correspondence to Hailong Dong or Nicholas P. Franks or William Wisden.

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Yu, X., Li, W., Ma, Y. et al. GABA and glutamate neurons in the VTA regulate sleep and wakefulness. Nat Neurosci 22, 106–119 (2019). https://doi.org/10.1038/s41593-018-0288-9

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