Excitatory transmission from ventral pallidum to lateral habenula mediates depression

Objectives: Lateral habenula (LHb) is a key brain structure for mediating behavioural responses to aversive stimuli. It receives presynaptic inputs from ventral pallidum (VP) which relates to reward, motivation and hedonics. This study investigated the role of glutamatergic VP-LH projection in negative emotions and depression-like behaviour. Methods: The glutamatergic VP-LHb circuits in Vglut2-Cre mice were activated or inhibited using optogenetic manipulation. Real time place aversion test was performed to access aversive behaviour. Mice underwent chronic social defeat stress or subthreshold social defeat stress paradigm. Then social interaction test and tail suspension test were carried out to evaluate the stress-induced depression-like behaviours. Results: Activation of VP-LHb glutamatergic projections induced aversive behaviour in the real time place aversion test. Activation of this circuit induced depressive-like phenotype after social stress, while optogenetic inhibition of this circuit exerted an antidepressant effect in social stress susceptible mice. Local LHb ketamine administration rescued the depression-like phenotype caused by activation of this circuit. Conclusions: Data from our study demonstrated an involvement of the glutamatergic VP-LHb circuit in the stress-induced depression-related behaviours.