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Post 2: Dopamine Regulation of Mood Related Behaviors

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This week we approach two articles studying the effect of how Dopamine (DA) neurons modulate depression related behaviors in rodent models. I initially expected two highly coinciding articles when both studies by Chaudhury et al. and Tye et al. focused on the same topic using very similar methods, the same transgenic mice models and almost identical excitatory and inhibitory optogenetic receptors. However, upon delving into the research further I noticed their results falling parallel yet in opposite directions entirely. 

Chaudhury et al. had the overall results pointing to phasic stimulation of the VTA or ventral tegmental area, but not tonic, leading to a significant increase in a depression like phenotype, seen as a decrease in social interaction and decrease in sucrose preference. They initially induced depressive behavior in mice using a repeated social defeat stress paradigm. To test the causal link, they reversed the order and mice were exposed to a sub threshold defeat paradigm followed by VTA phasic firing by optogenetic stimulation. These mice showed similar results with instantaneous expression of susceptible phenotype (increased social avoidance, Fig. 2a) and decreased sucrose preference (Fig. 2b) They continued their experiments in such fashion, using electrophysiology to study neuron firing, showing an increase in phasic firing of VTA to NAc neurons and using a retrograde virus and optical induction to show yet again that phasic, but not tonic, firing of VTA neurons induced a susceptible phenotype. 

Tye et al. conducted similar experiments using AAV-ChR2-eYFP mice and rats with similar inhibition virus (NpHR) to inhibit neurons. They also tested for depressive behaviors using sucrose preference tests (to test for anhedonia) and escape related tests such as; the tail suspension test (TST) and the forced swim test (FST) (to test for depressive like behavior). In addition, Tye et al. used similar frequencies for optogenetic stimulation, 30 Hz every 5s and Chaudhury et al. used 20Hz for 40ms. The two papers differed only slightly in the route of stress induction where Chaudhury et al. used the repeated social defeat stress paradigm or a subthreshold social defeat paradigm and Tye et al. administered a chronic mild stress paradigm.

Tye et al. however, concluded that inhibition of VTA DA neurons produces depression related behaviors and that phasic activation acutely reversed CMS induced anhedonia in optically stimulated mice. They also recorded electrophysiological neuron firing and found that non CMS rats had a significantly greater proportion and number of spikes occurring within bursts that lasted longer. These data are in direct contrast to the results obtained by Chaudhury et al. 

It is quite surprising that such similar studies can result in antagonistic conclusions. This made me think about how this came to be. Some of the possibilities could be data preference and elimination of contradictory data as scientists generally like to see what they want to see. As well as complexities alluded to in both papers where these pathways and projections may have differing activation patterns dependent on context of activation and intensity of stress induced. Differences in behavioral paradigms could also lead to varying results and differences in stress administration, as well as other methodological techniques.



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