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GABAergic neurons in the rostromedial tegmental nucleus (RMTg) receive major input from the lateral habenula (LHb), which conveys negative reward and motivation related information, and project intensively to midbrain dopamine neurons, including those in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). The RMTg-VTA circuit has been shown to be linked to the affective behavior, but the role of the RMTg-SNc circuit in aversion and depression has not been well understood. This study demonstrated that exciting or inhibiting VgatRMTg-SNc neurons was sufficient to increase or decrease immobility time in the forced swim test (FST), respectively. Furthermore, exciting the VgatRMTg-SNc pathway caused aversive behavior. Ninety percent of the SNc putative dopamine neurons were inhibited in extracellular recordings. Furthermore, inhibiting the VgatRMTg-SNc pathway reversed behavioral despair in chronic restraint stress (CRS) depression model mice. Manipulations of the pathway did not affect the hedonic value of the reward in the sucrose-preference test (SPT) or general motor function. In conclusion, these results indicate that the VgatRMTg-SNc pathway regulates aversive and despair behavior, which suggests that the RMTg may mediate the role of LHb in negative behaviors through regulating the activity of SNc neurons. • The activation of the RMTg-SNc pathway caused aversive and despair behavior. • Activating the pathway inhibited firing rates of SNc putative dopamine neurons. • Inhibiting the circuit reversed behavior despair in CRS depression model. [ABSTRACT FROM AUTHOR]