Pollack et al

While Li. Et al. observes the effect of the antidepressant, Pollack et al.  observes the behavioral effects and uses adequate evidence about behavioral antidepressants in animal models by demonstrating the method of using learned safety in the experiments. Like many of the other articles we discussed, many of the tests used in the experiment included a forced swim test, unpredictable chronic mild stress and ablation of neurogenesis. Although these tests had much distinction on which group experienced more depression, I feel as if they should have included some more behavioral tests only because it would have shown perhaps more pathways when comparing both groups. However, using the two models of safety condition and fear condition was what I found interesting about this article. For each of the test the groups went through, it seemed that the learned safety group showed decrease in depression. This is almost a creative method of finding a way to create an antidepressant-like effects. It would be interesting to see the effects of the learned safety in an acute setting rather than a long term setting. We know that BDNF shows definite increase when it is in a long term setting, but with the conditions of the learned safety would it be possible to have some effect with BDNF? This method also reminded me of another technique called rTMS (repetitive transcranial magnetic stimulation) in which after a period of time, this method decrease depression in a non-invasive way. Using techniques like learned safety and rTMS can help researchers find ways of decreasing the side effects of that antidepressants may cause in humans. Validating these learned safety methods can ultimately continue to grow to find ways that behavioral effects of antidepressants can help humans with depression. 

Li et al

            I find it interesting that the Li study uses rats, whereas the Pollak study uses mice. Neither study goes into much detail about why they chose that particular animal, but I would be interested to see why one would be better or easier to use than the other. I would imagine they would be similar, but do no know enough about each one’s behavior patterns to say for sure. Another interesting comparison is the interventions that these two studies were using. Pollak was using behavioral changes, whereas Li was using antidepressants. It was particularly interesting that when comparing the sucrose preference tests, we find that there was no significant effect of the learned safety behavior in the Pollak study, but there was a significant difference for both types of antidepressants that were tested in the Li’s study. Another interesting difference is the region of the brain each study targets, as Li talks about the prefrontal cortex, but the Pollak study talks about the amygdala. Because the amygdala is associated with fear response, and the Pollak study was working with fear and learned safety, it would make sense that they expected changes there. The same goes for the Li article, because the prefrontal cortex is where they have found changes from these antidepressants in the past. The interesting thing when comparing these two articles, though, is that these are two very different pathways that result in the same effect, which involves depression and stress. This suggests multiple causes of the same symptoms, which would also require multiple treatment options.

Li et al

Li et al was a well-designed study using well-established paradigms. The authors investigate a potential solution to the delayed treatment response seen with SSRIs using glutamate N-methyl D-aspartate receptor. It is seen in the rat model that ketamine is effective in reversing the effects of behavioral, morphological and physiological effects of depression. While the chronic unpredictable stress paradigm and the behavioral tests used are well established, the authors concede that they did not use any brain imaging techniques to supplement their results.

            This study seeks to solve the problems that previous papers discussed in this class explored. For example, papers discussed in week 1, Santarelli et al and Bessa et al, examined the effects of SSRIs on hippocampal neurogenesis and neuronal remodeling respectively. They ask why there is a delayed response to treatment in the use of these drugs and propose that it is due to different neuronal models. This paper speaks to these models proposing that ketamine works to reduce atrophy and decreases in spine density while reversing behavioral effects such as anhedonia. Because results in treatment response can be seen quickly, ketamine amongst other gultamatergic NMDA receptor antagonist may be a potential candidate for treatment of depression. The authors did not focus on length of response or sustainability of response, which causes me to wonder how sustainable a treatment this would be for humans. The question remains whether using ketamine in humans could be sustained, and if it could, would it lead to abuse? Should ketamine be proposed only as a short-term solution to depression while introducing an SSRI? Because the effects of long-term ketamine use remains to be seen in an animal model, further research would be needed to demonstrate the sustainability of response, demonstrating no decline in efficacy and any possible interactions between ketamine and more traditional treatments of depression. 

Li et al.

In Li et al. they have presented the issues that we have seen frequently thus far regarding the efficacy of antidepressants, with only one third of patients showing significant mood improvement and, if they do have effect, the time in which they take to work. Li et al. presented convincing evidence that a single dose of one of the most common NMDA receptor antagonists, ketamine, could rapidly reverse (a) the behavioral deficits caused by CUS, (with a requirement for mTOR signalling), (b) the deficit in synaptic proteins resulting from CUS, (c) the deficit in spine density resulting from CUS, and (d) the deficit in synaptic functions resulting from CUS. Similar effects were also observed with a selective NR2B antagonist , Ro 25-691.

What I found interesting with this article, is that if one of the main problems with antidepressants is with the duration of how long they take to work, then couldn't there be a study done in which an NMDA receptor antagonist such as ketamine could be used at a safe dosage so that it could be combined with an antidepressant to use for the first three weeks? As we know if antidepressants do show to work, the minimal amount of time they take to have an effect is three weeks. I am not a scientist so I do not know obviously if this could be a reasonable idea to present and I researched this online and did not find anything that combined the two, but the article says that the effects of ketamine lasts for 7 days from a single dose, therefore perhaps the study could look at one dose of ketamine per week for three weeks, combined with an antidepressant and if this could help overcome the problem of the time lag of efficacy antidepressants currently take. I understand that ketamine has highly addictive qualities, so it may not be reasonable to expect to see it used so frequently in the future for depression, but perhaps the NR2B antagonist, RO 25-691 could be a more promising substitute as the results in this experiment show it has similar results.

I thought the article presented really high quality arguments for the rapid effects of ketamine and Ro 25-6981 except that we only really see results presented for a further explanation of the mechanisms and roles that antidepressants can take and the duration rapidity of ketamine that provides a base for research into the problem of that lag time antidepressant treatments have. However, I would have liked to see more specific results focussing on the percentages of rats that the ketamine and RO 25-691 worked in (the efficacy rates) as that wasn't entirely clear to me (maybe it was just me!). As I have mentioned above and we have seen so far, the efficacy of antidepressant treatments themselves has been a major issue thus far and is something that further needs to be looked at, especially with depression being such a prevalent disorder today.      

Tye et al Quandaries

1. Go Patriots! I know that this blog post is late and I apologize. 
2. This set of papers was particularly interesting based on the main research technique. Before this class I had never heard of optogenetics and after learning about it I am very excited to be included within this particular field of science. 
3. This technique will prove to be very useful to the field of neuroscience and I look forward to seeing how it is applied in the future. I am a little skeptical, however, on the specific research methods exhibited thus far in both the Tye et al and Chaudhury et al papers. I consider the utilization of optogenetics to be a very advanced technique and I would expect published papers to be able to thoroughly explain the significance of results obtained from the use of this technique. I am impressed with a majority of the results obtained from the Tye et al paper, but my expectations are lacking at the same time. I wish that they had assessed some other models of depression instead of just the two which they did. It appears as if they have satisfied most of their hypotheses, but that is not necessary for an influential paper. 
4. Tye et al did a decent job in assessing depression models of depression among their mice by quantifying the levels of anhedonia and lack of motivation using the sucrose preference test, the tail suspension test and the forced swimming test respectively, but they could have looked into other aspects as well. For example, they could have looked into changes in the volume of the hippocampi of the mice exposed to chronic stress, or changes in sleep patterns in the mice (I believe that both of these characteristics are common in humans). 
5. I am not saying that either group did not do a decent job of looking into which topic they chose and they have certainly made some strides in the field, but there is always a lot more work to be done. I look forward to seeing what is accomplished in the future. 

Dopamine and Depression

            In both papers, they were investigating the role dopamine neurons play in depression. While both papers used largely the same tests on mice to measure behavior, there were two tests unique to each paper. In the Tye paper, these were the Forced Swim Test and the Tail-suspension test. In the Chaudhury paper, these were the Social-Defeat stress/social interaction and Elevated Maze tests. This is interesting because in this case the Tye paper used two tests that measure how long until the mouse gives up, but the Chaudhury paper was testing both social avoidance and how long until the mouse gives up, or just if it does. I find it interesting that the Chaudhury paper also chose the social behavior to test, as this is also a symptom of depression in humans, and I feel it would be pertinent to test this in mice as well. I also found the difference between the maze test and the swimming and tail-suspension tests interesting, because the maze test gave the mouse a way out, and measured the delay on the mice after messing up, as opposed to measuring the time until giving up with the swimming and tail tests, where the mouse is put into a situation it can’t get itself out of.

            The two studies had similar results with regards to the sucrose preference test, however. When the phasic stimulation was applied, both tests found a decrease in sucrose preference, which is used as a measure for depressive effect on the mice’s mood. It was worth noting, though, that the Tye paper mentions that there was no difference in the open-field test, but in the Chaudhury paper they don’t mention the results of the open-field test. This would have made it easier to compare the two papers, and see if their results are consistent.

Tye et al., dopamine effects

         Depression is a very prevalent disease that causes many people discomfort over ranged periods of time. Whether or not dopamine neurons are relevant or not could not be tested until recent times because of a lack of necessary technology. It makes sense that the limbic region is localized for depression, considering the many mood-altering symptoms, and that the “pleasure center” nuclear accumbuns is where dopamine neuronal activity would affect mood changes.

        The methods used by Tye et al. seem to be good characterizations of their experiments and I found their time frame, as well as general methods to be more effective than Chaudhury et al. For example, the time-intensive chronic mild stress test took into account the long term clinical depression symptoms more accurately. They also establish a steady baseline of assays early on, by providing data showing that the selective inhibition of VTA dopamine neurons leads to anhedonia and other symptoms while phasic activation re-invigorates the chronic mild stress induced models. The NAc function being altered by the effects of VTA neuronal activation shows a good indication of the circuit dynamics of depressive systems.

        The results of the study could have tremendous impact on the pharmaspuetical industry. Considering that VTA dopamine neuron recruitment alters depression-related behaviors, it is a big go ahead for the industry to increase research and development into more drugs affecting the complex dopamine system.  Not only with drug development, further research into the pathway could allow a complete mapping of the downstream effects of dopamine pathways, allowing further determination of function and structure (at least in animal models). With the focus on specific targeted circuits, it seems that any significant result can lead to further research and eventually a breakthrough in the treatment of depression.  

        Additionally, the use of optogeneitcs in both studies allows us to get an idea of how important the technique is and shows how much research can progress with the use of channel rhodopsin. They also combined the technique with electrophysiology robustly. 

Chadbury et al and Tye et al

I found this articles a bit challenging to read but both articles displayed many methods of observing ventral tegmental area (VTA) dopamine neurons and its relationship to depression related behaviors.  Chadbury et al begins explaining how he targets specific VTA dopamine neurons by expressing channelrhodopsin-2 (CHR2) with enhanced yellow fluorescent protein (eYFP). Using optogenetics, they test by using methods of sucrose preference and social interaction tests. I think Chadbury et al. shows a clear and concise way of displaying groups of tonic ChR2, phasic CHR2 and phasic eYFP. We see that for social interaction,  target neurons with ChR2 (tonic)  group had a much higher time for social interaction than the other groups. However, it was interesting to see that the target group with ChR2 (phasic) had a decrease time in social interaction.  The sucrose preference test also showed similar results with the group with neurons with ChR2 (phasic)  having a decrease in sucrose water compared to the other groups.  All  tests that used the method in this article showed very similar results, validating that using phasic stimulation expressing ChR2 has some causal relationship with increase of firing VTA dopamine neurons.  Tye. et al, however finds some interesting results when looking at similar models. Instead of social interactions, they implemented chronic mild stress for a longer period of time and the amount of snuggling time that mice encountered when turning on the light stimulation increased with CHR2 and chronic mild stress.  Sucrose preference in the same group has also increased percentage when the stimulation was turned on.  Tye et al. also adds in the forced swim test measuring amounts of kicks per minute, showing us how each time the mouse is stimulated, there was an increase in amount of kicks.  Overall, I felt Tye et al. added more stimulation effects, which validated the increase in VTA dopamine neurons.