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Post 2: Dopamine Circuits and Stress Recovery

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The papers by Chaudhury et al. and Tye et al. investigate the role of dopaminergic neurons in the VTA on the presence of a depressive phenotype. At first glance, their methodology seems similar: both papers, published in the same journal in 2012, induce depressive-like behaviors in mice and use optogenetics to activate or inhibit specific neuronal pathways. However, they reach drastically different results. When I first read these papers, I went around in circles trying to decide which study presented more “convincing evidence,” but then I realized that both provide clean, conclusive data. The real difference between these experimental designs are the behavioral paradigms used to induce a state of stress and the tests used to assess the effect of optogenetic inhibition/stimulation.
Specifically, Chaudhury et al. used a 10-day social defeat paradigm to induce social avoidance and decreased sucrose preference. Using this model, the researchers concluded that phasic stimulation of the VTA-Nucleus Accumbens pathway rapidly induced the depressive phenotype in previously resilient mice. In the presence of phasic stimulation, these mice exhibited a decrease in time in the interaction zone during the social-interaction test and a decrease in sucrose preference, compared to the controls. Inhibition of this pathway resulted in a statistically significant increase in both time in interaction zone and in sucrose preference. 
Conversely, Tye et al. induced two stress-related depressive symptoms, specifically decreased motivation and anhedonia, using the chronic mild stress paradigm. Then, they employed the forced swim test (FST) and tail suspension test (TST) as an assay for motivation of the mice, and the sucrose preference test as an assay for anhedonia. Using this paradigm, they found that optogenetic inhibition induces the depressive phenotype, which can be reversed by phasic stimulation of the VTA dopaminergic neurons. 
In essence, Chaudhury et al. explain that VTA stimulation leads to a depressive phenotype, while Tye et al. argue that it is actually VTA inhibition. However, as stated in the paper by Tye et al., “different stressors can cause opposite responses from VTA neurons depending on pre-exposure and severity.” Although the methods used in both papers to induce stress and to assay depressive phenotype are well-recognized in the scientific community, they are not identical, and the effects of stress on mesolimbic dopamine pathways can vary drastically. These differences in the behavioral paradigms could play a part in the conflicting conclusions presented in these papers, and also underscore why it is far from easy to study depression. Although neuroscience had led to the discovery to specific pathways that we know play a role in depression, the complex nature of the disorder implies that its causes could influence the same brain region in potentially opposite ways. These two papers, especially when taken in conjunction, show us just how important it is to keep studying disorders such as depression.  

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