Both Chaudhury and Tye et al explore the role of midbrain dopamine systems in depressive behaviors using optogenetic techniques. Each paper uses similar techniques, examine similar questions, but arrive at opposing conclusions. Based on results, Tye et al’s group concludes that VTA dopaminergic projections to the Nucleus accumbens (NAc) decreased depressive-like behavior as observed through motivational and anhedonia behavioral assays. Interestingly, Chadhury et al comes to the opposite conclusion that it is actually these same VTA to NAc dopaminergic projections that increase susceptibility to depressive like behavior in a social defeat paradigm. To remedy this discrepancy in each interpretation, the methods and study designs must be examined.
Tye et al first inhibited VTA neurons and used yellow fluorescent to visualize this. When VTA neurons were inhibited, the research team saw an increase in depressive behavior observed through motivation and anhedonia paradigms. Specifically the team focuses on three main tests throughout the duration of the research: the forced swim test (FST), tail suspension test (TST), and sucrose preference test (SPT). Using optogenetics, the rodent’s VTA was inhibited, and during this time they did not prefer the sucrose over water, but this immediately reversed when the inhibition was halted. Next, the group looked at what activation of the VTA would do under high and low chronic mild stress (CMS). With the VTA activated, the CMS group performed at the same level as the non-CMS group in the SPT and TST. Tye et al linked this to the NAc and also concluded the VTA to NAc projections were necessary for motivation behavior because blocking glutamate in the NAc decreased struggling on the TST. All of these results led the researchers to conclude that VTA to NAc dopaminergic projections can bidirectionally affect depressive behaviors. Conversely, Chaudhury et al concluded that VTA to NAc projections increase susceptibility to depressive behaviors, but VTA to PFC connections were protective against depressive behaviors. The major difference between the two papers was the main behavioral assay used to assess depression. For Chaudhury et al, it was a social defeat paradigm with social avoidance and sucrose preference test. The group found that phasic firing of dopamine (DA) neurons mediates increased susceptibility to social defeat stress, and the activation of these neurons can even make ‘resilient’ rodents susceptible. Brain slices from these mice showed an increase VTA to NAc firing pathway, and inhibiting this pathway kept the resilient mice resilient. Additionally, the group explored the role of context on the depressive symptoms and found that CMS and VTA to NAc activation is stress-induced context specific. Context and severe stress increased VTA activity. Lastly, Chaudhury et al found that VTA to PFC projections were necessary for resilience to depressive behavior.
Unfortunately, I do not have an answer as to which paper is ‘right’ in their conclusions, just that they differ. While they were looking at differing behavioral assays, they were similar enough that a similar response should have been observed, however, they were drastically different. Potentially, the behaviors make sense as the depressive symptoms could have been context specific and multiple mechanisms working at once, so maybe each context highlighted a different mechanism? Chadhury et al did focus more on specific pathways, and while Tye et al only looked at the VTA-NAc pathway. Maybe the researchers should have been examining more connections and how they influence one another. These papers highlight the convoluted nature of research and how science can veer more towards the ambiguous instead of the concise.
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