Altered DA Encoding and Depression - Annissa DeSilva


The mesolimbic pathway is a dopaminergic pathway involved in the reward response. This pathway is suspected to be involved with anhedonia in depression. Chaudhury et al. and Tye et al. both used optogenetic techniques to selectively stimulate DA neurons projecting from the VTA to the NAc, however they found opposing results. Chaudhury et al. concluded that high frequency phasic stimulation of DA neurons projecting from VTA to the NAc induced the depressive symptoms in mice resilient to the social defeat stress test and inhibition of the VTA neurons induced the resilient phenotype in those who previously were susceptible based on the sucrose preference test and social interaction test. Tye et al, concluded that inhibition of VTA neurons after chronic mild stress (CMS) for 12 weeks reversed depressive symptoms and phasic activation of the neurons reversed the effects of CMS also using sucrose preference as the behavioral assay. The difference may lie in the implication that various chronic stressors can induce similar depression like symptoms through differing mechanisms of VTA-DA neuron alterations. Both papers reference other research that supports both that CMS may reduce VTA-DA firing and chronic severe stress may increase VTA-DA firing, thus the severity of stress effects plays a role in the response of the phasic stimulation of the DA neurons.  
CMS and the social defeat test both use stress to induce depressive like symptoms in very different ways. The social defeat model seems to be a valid model for producing depression, especially due to the interesting fact that not all mice exposed to the social defeat model develop depressive symptoms. However, it seems that social defeat paradigm not only elicits depressive symptoms but anxiety related symptoms and is also used to model for anxiety (Bartolomucci, Fuchs, Koolhaas, & Ohl, 2009). Chaudhury et al., uses the social interaction assay to test behavior related to social avoidance, a measure of depressive behavior but again many also cite it as a measure of both depression and anxiety. This is still a reasonable assay due to the high comorbidity of depression and anxiety, but it seems the mice may more closely imitate a “depression-anxiety” phenotype rather solely a depressive phenotype. Chaudhury also used the sucrose preference test as did Tye, to determine anhedonia in the animals. The anxiety produced from the social defeat paradigm could have affected the results of the sucrose preference test. Research that suggests that the sucrose preference test is highly variable dependent on the context of the experiment, and can be decreased by anxiety alone (Bondar, Kovalenko, Avgustinovich, Smagin, & Kudryavtseva, 2009). So, it is not unreasonable to question if the severe stress producing the “anxious depression” could have altered DA-VTA firing patterns and thus the behavior during the sucrose preference test differentially from Tye’s CMS depression model mice. Both authors identify that the source of stress can have differentiating effects on the firing of DA neurons in the VTA, I wonder if it is possible that if this differential effect on the neuron is tied stress that produces depression symptoms with or without anxiety. I think it would be interesting to see mice if mice treated with anti-anxiolytic’s under Chaudhury’s protocol still display social avoidance and decreased sucrose preference when DA neurons in the VTA are stimulated in a high phasic manner.  
Overall the comparison of the different phenotypes of depression exhibited relates to the much larger questions about the delineation between anxiety and depression and the symptoms these models produce. Are the “depressed” phenotypes, “anxiety” phenotypes and “anxious-depressed” phenotype that result from different paradigms different? and if so, should we study each etiology individually even if the symptom of interest spans multiple disorders?
Citations
Bartolomucci, A., Fuchs, E., Koolhaas, J. M., & Ohl, F. (2009). Acute and Chronic Social Defeat: Stress Protocols and Behavioral Testing. Mood and Anxiety Related Phenotypes in Mice Neuromethods, 261-275. doi:10.1007/978-1-60761-303-9_14
Bondar, N. P., Kovalenko, I. L., Avgustinovich, D. F., Smagin, D. A., & Kudryavtseva, N. N. (2009). Anhedonia in the Shadow of Chronic Social Defeat Stress, or when the Experimental Context Matters. The Open Behavioral Science Journal, 3(1), 17-27. doi:10.2174/1874230000903010017

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