Rapid regulation of depression-related behaviors by control of midbrain dopamine neurons

Ventral tegmental area (VTA) dopamine (DA) neurons in the brain’s reward circuit play a crucial role in mediating stress responses(1–4) including determining susceptibility vs. resilience to social stress-induced behavioural abnormalities(5). VTA DA neurons exhibit two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing(6–8). Phasic firing of the neurons, which is well known to encode reward signals(6,7,9), is upregulated by repeated social defeat stress, a highly validated mouse model of depression(5,8,10–13). Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no change in firing rate apparent in resilient individuals(5,8). However, direct evidence linking—in real-time—DA neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here, we took advantage of the temporal precision and cell type- and projection pathway-specificity of optogenetics to demonstrate that enhanced phasic firing of these neurons mediates susceptibility to social defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing, in VTA DA neurons of mice undergoing a subthreshold social defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social defeat stress. Furthermore, we show differences in projection pathway-specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social defeat stress. Conversely, optogenetic inhibition of the VTA-NAc projection induced resilience, while inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing pattern- and neural circuit-specific mechanisms of depression.