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Week 2: Dopamine circuitry modulation and depression

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            This week we looked at two similar articles which focused on the neural circuits of the mid-brain, specifically the dopamine neurons in the ventral-tegmental area (VTA) as well as projections to the nucleus accumbens (NAc). The Chaudhury et al. paper investigates how different firing patterns of dopamine neurons (phasic or tonic) with the VTA and NAc regulate depression like behavior. After exposing the mice to 10-day social-defeat stress, Chaudhury found that susceptible (depressed) mice had increased phasic firing, while resilient mice (normal) mice had no changes in firing patterns. Using optogenetics to promote phasic firing, they immediately induce depression like behavior both susceptible and resilient mice, measured in increased social avoidance and decreased sucrose preference. Furthermore, they showed that inhibition of this pathway between the VTA and NAc would immediately induced a resilient phenotype.
The Tye et al. article which aimed to achieve similar goals in identifying the involvement of the dopamine pathway in the VTA and NA in depression phenotypes by exposing mice to 10 weeks of chronic-mild stress (CMS) and using optogenetics to either induce or inhibit firing in this reward pathway. This study found the increased firing of dopamine in the VTA was associated with immediate improvement of depressive phenotypes as shown by increased motor activity exhibited by increased escape behavior in the tail-suspension test (TST) and forced-swim test (FST), as well as improvement of anhedonia modeled by increased sucrose preference. These behaviors were immediately reduced when phasic firing of the dopamine neurons were inhibited, which caused a rapid onset of depressive phenotypes.  
            Upon reading several review articles investigating the comparison of these studies, I learned that all stress is not created equal. Exposure to severe and acute stress for 10 days, as opposed to 10 weeks of CMS, results in different neural changes. While phenotypically the mice may display the same depressive like behaviors of anhedonia, decreased motor activity, and social avoidance, the activity of dopamine neurons in the VTA increases during shot term high stress acuity, while in decreased in a CMS paradigm. These differences in neural circuitry as a result of contextual stress explains the differences between the behavioral outcomes of either excitation or inhibition of midbrain dopamine neurons in mice exposed to stress.
Depression is a complex disorder characterized by a myriad of phenotypes, many of which oppose each other. Clinical outcomes of depression can involve behaviors such as increased or decreased sleep, over or under eating, and heightened or dampened motor movements. Knowing that the cause of stress dictate different neuronal changes, it is conceivable that the phenotypes may not be the same, and therefore the treatments will not be universal. BY further investigating how various causes of stress affect the neural encoding of depression-related behavior, hopefully a more effective and individualized approach to the treatment of depression can be initiated.
           


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