PT  - JOURNAL ARTICLE
AU  - Xiao Yu
AU  - Wei Ba
AU  - Guangchao Zhao
AU  - Ying Ma
AU  - Edward C. Harding
AU  - Lu Yin
AU  - Dan Wang
AU  - Youran Shi
AU  - Alexei L. Vyssotski
AU  - Hailong Dong
AU  - Nicholas P. Franks
AU  - William Wisden
TI  - Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior
AID  - 10.1101/684142
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 684142
4099  - http://biorxiv.org/content/early/2019/06/27/684142.short
4100  - http://biorxiv.org/content/early/2019/06/27/684142.full
AB  - The ventral tegmental area (VTA), an important source of dopamine, regulates goal- and reward-directed and social behaviors, wakefulness and sleep. Hyperactivation of dopamine neurons generates behavioral pathologies. But any roles of non-dopamine VTA neurons in psychiatric illness have been little explored. Lesioning or chemogenetically inhibiting VTA GABAergic (VTAVgat) 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 VTAVgat 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 behaviors, including the sleep loss, were reversed by the mood-stabilizing drug valproate, and re-emerged when valproate treatment was stopped. Lithium salts, however, had no effect. The mania like-behaviors partially depended on dopamine, because giving D1/D2/D3 receptor antagonists partially restored the behaviors, but also on VTAVgat projections to the lateral hypothalamus (LH). Optically or chemogenetically inhibiting VTAVgat terminals in the LH elevated locomotion and decreased immobility time during the tail suspension and forced swimming tests. VTAVgat neurons are centrally positioned to help set an animal’s (and human’s) level of mental and physical activity. Inputs that inhibit VTAVgat neurons intensify wakefulness (increased activity, enhanced alertness and motivation), qualities useful for acute survival. Taken to the extreme, however, decreased or failed inhibition from VTAVgat neurons produces mania-like qualities (hyperactivity, hedonia, decreased sleep).