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

Dipesh Chaudhury, Jessica J. Walsh, Allyson K. Friedman, Barbara Juarez, Stacy M. Ku, Ja Wook Koo, Deveroux Ferguson, Hsing Chen Tsai, Lisa Pomeranz, Daniel J. Christoffel, Alexander R. Nectow, Mats Ekstrand, Ana Domingos, Michelle S. Mazei-Robison, Ezekiell Mouzon, Mary Kay Lobo, Rachael L. Neve, Jeffrey M. Friedman, Scott J. Russo, Karl DeisserothEric J. Nestler, Ming Hu Han

Research output: Contribution to journalArticle

Abstract

Ventral tegmental area (VTA) dopamine neurons in the brain's reward circuit have a crucial role in mediating stress responses, including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities. VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing. Phasic firing of the neurons, which is well known to encode reward signals, is upregulated by repeated social-defeat stress, a highly validated mouse model of depression. Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals. 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.

Original languageEnglish (US)
Pages (from-to)532-536
Number of pages5
JournalNature
Volume493
Issue number7433
DOIs
StatePublished - Jan 24 2013

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    Chaudhury, D., Walsh, J. J., Friedman, A. K., Juarez, B., Ku, S. M., Koo, J. W., Ferguson, D., Tsai, H. C., Pomeranz, L., Christoffel, D. J., Nectow, A. R., Ekstrand, M., Domingos, A., Mazei-Robison, M. S., Mouzon, E., Lobo, M. K., Neve, R. L., Friedman, J. M., Russo, S. J., ... Han, M. H. (2013). Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature, 493(7433), 532-536. https://doi.org/10.1038/nature11713