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

By D. Chaudhury, J. Walsh, Allyson K. Friedman, B. Juarez, Stacy M. Ku, J. Koo, D. Ferguson, Hsing-Chen Tsai, L. Pomeranz, Daniel J. Christoffel and 12 more. Nature, 2012

1,066 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience

View Paper: https://www.semanticscholar.org/paper/66d4a5a453d8c82d27eea5d1efb67ec69aea64ad

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In Cellular and Molecular Neuroscience

Citations in the corpus

Social functioning in major depressive disorder. (2016, positive): “Conversely, inhibition of this pathway promotes resilience after social stress (Chaudhury et al., 2013).”
Reward and aversion in a heterogeneous midbrain dopamine system (2013, background): “…activation of VTA DA neuron phasic firing was shown to elicit a susceptible, depression-associated phenotype in mice undergoing a subthreshold social defeat protocol as well as in previously resilient animals that had been subjected to repeated social defeat stress (Chaudhury et al., 2012).”
Natural neural projection dynamics underlying social behavior. (2014, positive): “…play distinct roles in modulating reward and aversion based on connectivity to different upstream and downstream structures (Brischoux et al., 2009; Budygin et al., 2012; Chaudhury et al., 2013; Kalivas and Nakamura, 1999; Lammel et al., 2011, 2012; Mirenowicz and Schultz, 1996; Tye et al., 2013).”