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

Abstract

Ventral tegmental area (VTA) dopamine neurons in the brain’s reward circuit have a crucial role in mediating stress responses1,2,3,4, including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities5. VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing6,7,8. 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 depression5,8,10,11,12,13. Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals5,8. However, direct evidence—in real time—linking dopamine 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 show 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 dopamine 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, whereas inhibition of the VTA–mPFC projection promoted susceptibility. Overall, these studies reveal novel firing-pattern- and neural-circuit-specific mechanisms of depression.

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Figure 1: Phasic, but not tonic, optical stimulation of VTA dopamine neurons during a subthreshold social defeat induces a susceptible phenotype.
Figure 2: Phasic optical stimulation of VTA dopamine neurons during the social-interaction test instantly induces a susceptible phenotype in two social-defeat paradigms.
Figure 3: Bidirectional effect of modulating the VTA–NAc pathway on susceptibility to social defeat.
Figure 4: Effect of modulating the VTA–mPFC pathway on susceptibility to social defeat.

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Acknowledgements

This work was supported by the National Institute of Mental Health (R01 MH092306 to D.C. and M.H.H.), Johnson & Johnson IMHRO Rising Star Translational Research Award (M.H.H.), the National Research Service Awards (F31 MH095425 to J.J.W. and F32 MH096464 to A.K.F) and the Mount Sinai PREP R25 GM064118 (B.J.). We would like to thank K. Roy for help with some of the schematics in the figures, and we thank R. Cachope and J. Cheer for help with chronic fibre implantation techniques.

Author information

D.C., J.J.W., A.K.F., B.J., J.W.K., D.F., D.J.C., H.C.T., M.K.L., M.S.M.-R. and S.M.K. collected and analysed data. L.P., A.R.N. M.E., A.D., E.M., R.L.N., S.J.R., J.M.F., K.D. and E.J.N. generated and provided viral vectors and TH–Cre mice. D.C., J.J.W., E.J.N. and M.H.H. designed and wrote the paper.

Correspondence to Ming-Hu Han.

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Chaudhury, D., Walsh, J., Friedman, A. et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493, 532–536 (2013). https://doi.org/10.1038/nature11713

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