Tuesday, January 31, 2017

Week 3

      I really enjoyed this week's readings. I found the writing to be clear, concise and I feel that I can get behind the results each paper provides. I also found reading about the continuation of the research a great way to see the development of this topic. The hippocampus is an interesting brain region to me and I was excited to read about the experiments performed.
      In the 2013 paper I was able to grasp the concepts of the paradigm and results rather quickly, which isn't always the case for me when I read scientific papers. I did note that the animals were anesthetized, causing me to wonder whether there would be any changes in non-anesthetized animals. I've read a few papers whose sole purpose is to repeat previous experiments in non-anesthetized animals and some have found altered results. One part of their discussion that confused me was towards the end where they claimed to be able to look at false and genuine memories at different stages in the memory process - I'm not quite sure if I understood in the figures/paper where they were able to pull this claim from and personally think there needs to be a little more support for this statement.
     What I found most interesting was the difference between the DG and CA1 results. I was not surprised that only DG stimulation of A-active cells increased context-dependent freezing, rather I would have been surprised if CA1 stimulation produced the same. My understanding is that while they may share some similar functions, the DG and CA1 contribute to different steps in memory and emotional processing. I think that the results provided in the paper give important insight to the role of the DG as well as possibilities for therapeutic advancements. Future experiments could include replications of this paper but looking at area CA3, as well as using retrograde and anterograde viruses to look at changes in projection activity from the DG to the other areas of the hippocampus
     I appreciated that the 2015 expanded the concepts of the first while simultaneously tying back to depression and a little bit of neurogenesis. My primary, and for now brief, discussion point with this paper is noticing that there were differential results with the mPFC which we previously saw in week 2's papers. The mPFC seemingly is playing a distinct role in depressive phenotypes and recovery which makes me want to do some more research on what has been determined about its involvement and what makes it different than the other areas in these experiments.

Sunday, January 29, 2017

Week 2

I found both articles to be very interesting in how they were able to show a possible connection between Dopamine neuron stimulation/inhibition (mostly focusing on VTA) and the altering of behaviors that they interpreted to be depression related. Although I don't think that dopamine by itself is to blame for depression because how do we explain why SSRIs work for depression which I think was also mentioned by one of the studies. The second thing is that VTA dopamine pathway has been implicated in rewarding effects. I think this might be an explanation for Sucrose testing results when the pathway is inhibited because those mice that go through this inhibition probably can't feel the rewarding effects of drinking the sucrose water, which I think is probably a big part of depression( not being able to feel rewarding effects). Going off the VTA pathway inhibition in the study I wonder if people who present depressive symptoms probably have that high of an inhibition in the VTA dopamine pathway, which again if true might possibly maybe undermine the study's method of just inhibiting the pathway that heavily because it's not looking at maybe a more realistic depression model. But Isolating the VTA dopamine pathway gives us important information in its role in depression, I would definitely like to see this information this study yielded to be implemented in the analysis of those subjects with a more generalized depressive symptoms.

Tye vs. Chaudhury

I read the papers being previously aware of the contradictory results in the back of my mind and I wasn’t exactly surprised by them nor was I swayed in either direction. I’ve always been of the belief that if you try hard enough, you can find evidence to back up whatever it is you want to prove. That being said, I had a hard time picking between the two papers, as I felt naturally inclined to sort of declare a winner based on the contradictory nature of them. Although they arrive at different conclusions even though they essentially are asking the same question, I think both Tye and Chaudhury could both be presenting reasonable results that could be further investigated and could both be proven true or at least further supported. 
There were no red flags in either paper that dissuaded me from either one so I was left being at peace with both conclusions. My one point of dissonance was that the differences in the stress induced by the CMS paradigm as opposed to the SDP paradigm could possibly play a role in the opposing results. The CMS seems less intense than the SDP to me and I think the effects may be mediated by the differences in the tests. 
It was a lot easier for me to agree or disagree with a paper last week but I couldn’t really do that with these papers and I don’t know if that is a testament to the good quality of both papers or just me not fully grasping the details. I assume, after further discussion tomorrow, I will probably arrive at a better conclusion.

Week 2

I was glad I read the Chaudhury et al. paper first because it made me aware of the differences between phasic and tonic firing and why both authors used phasic activation for their experiments. And though I know format should not affect my opinion of content, the fact that the articles were in the same format assisted in my ability to compare them. At first glance, I thought Tye et al. was clearer, but later I realized both experiments were well done and could convince me of their findings.

One thing I liked from Chaudhury et al. was how they looked at the VTA neurons that projected to both the NAc and the mPFC. It was interesting how the activation vs. the inhibition of these neurons resulted in different behavioral outcomes. These particular results are significant in my opinion, because in such a complex disorder, it is important to understand every part of the involved circuits in order to study depression and how antidepressants work. I was also interested in their use of the subthreshold social defeat paradigm because I was unfamiliar with it. Though I read through the methods to try to get a better grasp on the paradigm, I was still a little confused on how they quantified subthreshold defeat, for it seemed like a relative term to me that would be different depending on the mouse.

For the Tye et al. paper, I appreciated how thorough they were in their holistic approach. They tested the symptoms of depression (anhedonia and lack of motivation) along with utilizing a CMS paradigm. Since depression is such a complex disease, to be able to truly study it, you need a realistic model and I think Tye et al. has achieved the most realistic one that we have seen so far. And though they found reduced firing in the mice depression models while Chaudhury et al. found a higher firing rate, they explained how the two different methods to model depression may have resulted in opposite results. For CMS could reduce dopamine firing over the long period of time, but the more severe stressors over a short period of time from the social defeat paradigm could increase firing.

In all, I like that both papers, especially Tye et al., acknowledged how complex the circuitry in depression is, rather than attempting to make big generalizations from one set of data like the week one papers.

Week 2: Tye and Chaudhury

         Both Tye and Chaudhury used optogenetics to investigate the relationship between phasic firing of dopaminergic neurons in the VTA. The biggest area of overlap in their research was the decision to concentrate on VTA dopaminergic neurons that project to the NAc. Tye et al. determined that VTA to NAc dopaminergic innervation is important in reversing the depressive-like symptoms brought about by chronic mild stress. Interestingly enough, Chaudhury et al. seemed to come to the reverse conclusion, stating that optical induction of phasic firing in the VTA-NAc neurons induced the susceptible phenotype (this is characterized by social avoidance and reduced sucrose preference).
There are a couple of differences in their methods that may have accounted for the opposing conclusions. Tye et. al induced depressive-like symptoms in mice by using the CMS paradigm, as well as the tail suspension test, the forced swim test, and the sucrose preference test. One thing I loved about this paper was that they thought to administer an open field test as well, to make sure that the reason for more or less struggling during the TST and FST was not a change in locomotor activity induced by the activation or inhibition of the VTA. On the other hand, Chaudhury used something known as the social defeat stress paradigm in concert with the sucrose preference test and the social-interaction test.
Although it looks like the two papers have completely different findings, I think that further research could possibly validate them both. While the CMS paradigm is a mild stressor (and a better animal model of depression, in my opinion), the social-defeat stress paradigm is more severe. It may be possible that dopaminergic innervation of the NAc is beneficial during less intense stress, and detrimental during harsher stress. Chaudhury mentions that chronic mild stressors inhibit VTA activity, whereas severe stressors increase VTA activity, so it makes sense that the ideal amount of VTA activity differs based on the type of stress. I am interested in seeing how other projections from dopaminergic neurons in the VTA can mediate the stress response. More specifically, I am curious to know what Tye would have observed had they investigated the VTA-mPFC pathway, like Chaudhury did.

Chaudhury & Tye

I had an incredibly hard time reading Chaudhury et al.’s paper. I don’t know too much about the difference between normal and Letter submissions to journals, but it seemed like the paper was made more complicated and less effective in its conclusion and discussion by not having enough space to go fully in-depth. Although it was concise and the results were appropriately evaluated, I was disappointed with the lack of body in the paper. Perhaps this is personal preference; perhaps it’s a fault in my reading level.

On a similar note, I found Chaudhury’s paper to be lacking in defense of its methods. Even after looking over the schematic in the supplementary figures, it isn’t clear to me what is “subthreshold” about the social-defeat stress paradigm. While reading, I took this to mean that the stress is below the threshold to cause a depressive phenotype or is below the threshold to cause a stress reaction, but even these two versions of my interpretation are different enough to warrant explanation; my understanding of the paper depends on it. Additionally, I found Tye et al.’s animal model of depression to be the superior experimental measure – it was thoughtful to consider locomotion, especially considering that Chaudhury’s only two measures of depression (social avoidance and anhedonia) are both somewhat related to reward.

Lastly, I’d be interested to see future research on the functional interaction between the circuits that were studied, particularly because of the stark differences in excitability between the VTA-NAc and VTA-mPFC pathways. I also wonder if the effect of these experiments on non-dopamine neurons in the VTA is significant enough to change the functional properties of these circuits in relation to the depressive phenotype.

Week 2

These article are not as easily critiqued compared to last weeks papers. Besides the fact that they are shorter and a bit easier to manage, I find both articles to be thoughtful and well composed. Its incredibly interesting that through two different methods, they produce rather contradictory results to relatively the same question. Both Tye and Chaudhury attempt to understand and identify the link between the dopamine VTA neurons and depressive-like behavior. However where Tye produces evidence of selective inhibition of the VTA-DA neurons leads to increase in depressive symptoms, Chaudhury finds that selective stimulation of the VTA-DA neuron leads to depressive symptoms.

I have been trying to understand how these differing results would arrive by examining the difference between them. The Chaudhury model of depression relies on the Social Defeat Paradigm vs the Tye model uses Chronic Mild Stress to induce depression. I believe CMS to be validated animal model of depression, but Chaudhury also offers convincing use of the SDP in other papers as well. I do like Chaudhury's use of susceptible vs resilient mice, as he labels them by their behavioral patterns, rather than their transgenic identities, or their measured exposure to stress. This makes their immediate change in phenotype when stimulated with phasic firing, a much more compelling change than when a chronically stressed mouse regains its normal function.

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.

week 2

Although both papers employ the use of optogenetic tools to understand the dopaminergic circuitry involved in depression, I find myself preferring Tye’s paper to Chaudhary’s for several reasons. For starters, I am not entirely convinced that social defeat is the only or perhaps the most efficient way to induce depression-like symptoms. “Chronic mild stress and chronic social-defeat stress have been shown recently to produce different changes in extracellular levels of several neurotransmitters in a number of brain areas18. These findings raise the possibility that, in addition to context, the severity of stress is another important determinant of stress regulation of dopamine-neuron firing.” If this is true, Chaudhary et al. could have used an additional paradigm or other “severe ” or “less severe” tests to compare the effects or strengthen the conclusion proposed. In contrast, Tye et al. employ the use of various tests and use the CMS model, which I believe (and I maybe wrong) is a better approach in inducing stress in the animal. Therefore, I found Tye’s approach to be more in depth and meticulous, whereas Chaudhary’s approach felt more superficial – even though they did explore additional downstream pathways (VTA-mPFC).

I also found it interesting that even though both these papers are investigating the firing pattern of the same neurons in a “stressful” paradigm, the results seem to outline complete contradictory interactions. Tye’s paper highlights how “selective inhibition of VTA dopamine neurons acutely produces depression-related behaviour in measures of both motivation and anhedonia, and that phasic activation of VTA dopamine neurons acutely rescues a chronic mild stress- induced depression-like phenotype, in a phenomenon that requires functioning of dopamine receptors in the NAc. Whereas Chaudhary’s paper found that “functional importance of increased phasic, but not tonic, firing of  VTA dopamine neurons during exposure to stress for promoting susceptibility for depression-like behavioural abnormalities.” I’m not sure if this difference may be due to using different paradigms or experimental protocol (days exposed to stressor), or perhaps an entirely different factor altogether, but I’m curious to find out!