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Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior

By Xiao Yu, Wei Ba, Guangchao Zhao, Ying Ma, Edward C Harding, Lu Yin, Dan Wang, Youran Shi, Alexei L Vyssotski, Hailong Dong, Nicholas P Franks, William Wisden

Posted 27 Jun 2019
bioRxiv DOI: 10.1101/684142 (published DOI: 10.1038/s41380-020-0810-9)

The VTA, an important source of dopamine, regulates goal- and reward-directed and social behaviours, wakefulness and sleep. Hyper activation of dopamine neurons generates behavioural pathologies. But any roles of non-dopamine VTA neurons in psychiatric illness have been little explored. Lesioning or chemogenetically inhibiting VTA GABA neurons generated persistent wakefulness with mania-like qualities: locomotor activity was increased; sensitivity to D-amphetamine was heightened; immobility times decreased on the tail suspension and forced swim tests; and sucrose preference increased. Furthermore, after sleep deprivation, mice with lesioned VTA GABA neurons did not catch up on the lost NREM sleep, even though they were starting from an already highly sleep-deprived baseline, suggesting that the sleep homeostasis process was bypassed. The mania-like behaviours, including the sleep loss, were reversed by the mood-stabilising drug valproate, and re-emerged when valproate treatment was stopped. Lithium salts, however, had no effect. The mania like-behaviours partially depended on dopamine, because giving D1/D2/D3 receptor antagonists partially restored the behaviours, but also on VTA GABA neuron projections to the lateral hypothalamus. Optically or chemogenetically inhibiting VTA GABA neuron terminals in the lateral hypothalamus elevated locomotion and decreased immobility time during the tail suspension and forced swimming tests. VTA GABA neurons are centrally positioned to help set an animal's (and human's) level of mental and physical activity. Inputs that inhibit VTA GABA neurons intensify wakefulness (increased activity, enhanced alertness and motivation), qualities useful for acute survival. Taken to the extreme, however, decreased or failed inhibition from VTA GABA neurons produces mania-like qualities (hyperactivity, hedonia, decreased sleep).

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