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

Article

关键词: VENTRAL TEGMENTAL AREA;    SOCIAL DEFEAT STRESS;    ANTIDEPRESSANT ACTION;    REWARD CIRCUIT;    IN-VIVO;    SUSCEPTIBILITY;    STIMULATION;    INHIBITION;    EXPRESSION;    RESPONSES;   

DOI  :  10.1038/nature11713

来源: SCIE

【 摘 要 】

Ventral tegmental area(VTA) dopamine neurons in the brain's reward circuit have a crucial role in mediating stress responses(1-4), including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities(5). VTA dopamine neurons show 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 apparent change in firing rate in resilient individuals(5,8). 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.

【 授权许可】

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