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

Abstract

Ventral tegmental area (VTA) dopamine (DA) neurons in the brain’s reward circuit play a crucial role in mediating stress responses1–4 including determining susceptibility vs. resilience to social stress-induced behavioural abnormalities5. VTA DA neurons exhibit two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing6–8. Phasic firing of the neurons, which is well known to encode reward signals6,7,9, is upregulated by repeated social defeat stress, a highly validated mouse model of depression5,8,10–13. Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no change in firing rate apparent in resilient individuals5,8. 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.

Nicotinic receptors mediate stress-nicotine detrimental interplay via dopamine cells’ activity

“…To model this scenario, we treated mice with chronic nicotine in the drinking water, and then combined it with a subthreshold defeat (SubSD) paradigm (Figure 3a). 25 We observed that SubSD triggered social aversion in mice chronically pretreated with nicotine, whereas it was ineffective in vehicle (saccharin)-pretreated mice (Figure 3b). Chronic nicotine treatment per se can induce enduring changes in VTA DA firing and bursting events (Figure 3c and Supplementary Figure S4b), and can also markedly impair DA neurons activation in response to a subsequent intravenous nicotine injection (Figure 3d).…”

“…The substhreshold SD (SubSD) paradigm was adapted from Chaudhury et al 25 Animals were individually introduced into a CD1 cage for 2 min of SD. The experimental and the CD1 mice were maintained separated through a partition for 20 min and then returned for 90 min to their home cage.…”

“…Increased DA neuron activity is a prerequisite for the subsequent behavioral manifestations of stress outcomes. [24][25][26][27] Indeed, pharmacological or optogenetic inhibition of VTA DA neurons promotes therapeutic-like effects as it reverses SD-induced social aversion and anhedonia. 24,25 Thus, VTA DA neurons are at a crossroad of nicotine's reinforcing effects and social stress-induced aversion.…”

“…[24][25][26][27] Indeed, pharmacological or optogenetic inhibition of VTA DA neurons promotes therapeutic-like effects as it reverses SD-induced social aversion and anhedonia. 24,25 Thus, VTA DA neurons are at a crossroad of nicotine's reinforcing effects and social stress-induced aversion. We hypothesized that nAChRs could be a pivotal molecular target, which would orchestrate the detrimental stress-nicotine interplay at the cellular and behavioral levels.…”

Chronic psychosocial stress in mice leads to changes in brain functional connectivity and metabolite levels comparable to human depression

“…Whilst optogenetic stimulation of a pathway in stressed mice is clearly a different situation to endogenous pathway activity in stressed mice, one can nonetheless extrapolate from this finding to the present study, and hypothesize increased ventral hippocampus -ventral striatum connectivity in CPS versus control mice; this was not observed. Using a two-day social defeat (so-called sub-threshold CSD), which itself does not induce social avoidance, it was demonstrated that optogenetic induction of phasic firing in ventral tegmental area (VTA) -nucleus accumbens neurons in such mice induced increased social avoidance, whilst in VTA -mPFC neurons it was optogenetic inhibition of phasic firing that induced increased social avoidance (Chaudhury et al, 2013). Because fMRI does not have sufficient resolution to allow identification of VTA, it is not possible to integrate the current study with these findings.…”