Week 2

The combination of the Tye et al and Chaudhury et al papers serve as a unique opportunity to address the potential issues in interpretation and what that means for understanding the somewhat contradictory results. Tye et al claims that VTA-DA --> NAc activity is sufficient to alter the “encoding” of depression behaviors based on the fact that VTA-DA manipulations have bidirectional effects on depressive behaviors, whereas Chaudhury et al claims the opposite, that the VTA-NAc are responsible for stress susceptibility and therefore susceptibility to depressive behaviors. As a disclaimer, I find the Chaudhury et al data more convincing as it utilizes more specific methods of targeting VTA-DA projections of interest, the in vivo changes due to the stress paradigm are better characterized, and the stress paradigm itself seems more biologically relevant and therefore more likely to recapitulate true depressive neural changes and behavior.

A clear difference between the two papers that potentially explains the discrepancy in results is the method by which depression-like phenotypes were induced and subsequent neural changes recorded. CMS has been shown to produce the phenotypes of interest (reduced escape related behavior and decreased sucrose preference), but repeated acts of aggression by a conspecific seems to be a more biologically relevant method of stressing, and inducing “depression” in mice. It seems weird to say that there is a “better” way of inducing depression-like phenotypes and it is still unclear whether or not either one of these truly captures the many nuances of depressive symptoms, but I think it is worth acknowledging that a more biologically relevant stressor like social aggression might be more likely to produce relevant neural changes of interest. Additionally, the fact that Tye et al only looked at changes in VTA firing, not NAc, and didn’t even focus on the VTA-DA neurons in their recordings (Supplementary Figure 8) makes it hard to feel convinced by their results since the supposed in vivo changes that result in the depression phenotypes is poorly characterized. Without proper, detailed characterization of the circuitry, it makes it easy to miss a lot of holes in the logic leading up to their conclusion. Chaudhury et al precisely target and record from the VTA-NAc and VTA-mPFC neurons and the more fleshed out characterization of the circuit serves to bolster the validity of their results.

Due to the diversity of inputs and outputs to and from the VTA-DA neurons, the experiments in Tye et al paper seems insufficient to extrapolating and dissecting the intricacies of the “motivation” or depression pathway. Chaudhury et al. better characterize and precisely manipulate and record from the neurons/projections of interest using pseudorabies virus as the induction method of choice. The VTA-DA characterization and NAc characterization in tye et al are tied together only by the DA antagonist experiments that show administration of D1, D2 antagonist in the NAc blocks VTA stimulation induced reversal of depressive behaviors. But the blanket manipulations fail to address the many different projection to and from the VTA.

Some things I have considered while reading the Tye et al paper is that silencing the VTA-DA neurons may, as the authors state, be modulating motivation since the VTA (and NAc) are well known components in the reward pathway, however, it is also possible that the decrease in struggling behavior seen in VTA-DA inhibition could be a result of attenuated fear response, a hypothesis that is supported by the fact that the VTA-DA neurons receive considerable input from the central nucleus of the amygdala, an area previously characterized as playing a role in fear conditioning. It is important to note that the exact nature of the CeA-->VTA-DA projections seems to be unclear at present, apparent in the scarcity of papers regarding the subject. The bidirectional modulation of sucrose preference, though at odds with my “fear modulation” hypothesis, can be explained by the fact that activating and deactivating/activating a key component in the reward pathway reasonably and expectedly affects an animal’s response to rewarding stimuli, like sucrose solution.