11/17 Environmental Enrichment

          Ashokan et al. (2016) asked whether or not environmental enrichment reduces basolateral amygdala dendritic complexes that were increased by stress and anxiety, as well as stress-induced anxiety behaviors as a result of these molecular changes. Overall I think they were sufficient in supporting their hypothesis, but there are a few aspects of their experiments I would like to criticize. They showed that short-term environmental enrichment was sufficient enough to produce stress resiliency by continuous EE exposure over a period of about 16 days, give or take. In each experiment, the mice were exposed to chronic immobilization stress for only 2 hours a day for the first 10 days. I would've liked to have seen a more diverse set of experimental designs, such as CIS immediately preceding the behavioral test (rather than a few days before), or EE occurring for just a few days before or after exposure to CIS, and even perhaps long-term environmental enrichment paradigms. I found it rather surprising in Figure 5 how stress did not induce a significant change in serum corticosterone levels since it involves excessive secretion of corticosterone (although, there did appear to be greater levels of corticosterone in stressed animals than in control animals in the absence of EE). The fact that EE did not show any significant difference between control and stress mice can hint that EE may not affect corticosterone levels.

          I preferred the experimental design of Lehmann and Herkenham (2011)'s paper more than the previous one. Their designs were more diverse in both housing types (not only did they house mice in enriched and standard environments, but also they housed them in impoverished housing) and when the mice were exposed to the different types of housing (before or after lesions). I also like how they also included a wide variety of brain regions that are involved in abnormal activity during stress-related disorders, and how these brain structures are also found in humans as well. I wonder, since they only used short-term EE, if long-term EE would have the same effect as short-term EE or if the effects would be greater. Maybe that can be a future experiment.

11/17 Ashokan et al. / Lehmann and Herkenham

Ashokan et al. researched the effects of environmental enrichment on reducing the effects of stress through looking at changes dendritic complexity in the BLA and BDNF. They first identified the anxiolytic effects of EE on stressed animals, and then looked for the neuronal factors that caused the rescue effect. I was curious about why the authors mentioned that a running wheel was not provided. A wheel was provided in the Lehmann and Herkenham experiments. It would be interesting to see if their results changed by adding a running wheel.

Ashokan et al. concluded that environmental enrichment, even in a short period of adulthood, can support resilient behavior in mice. In the future, it would be interesting for them to test an enrichment paradigm that started after the stressful event for the research to be more translatable. Then, we would know if providing enrichment after a stressful time in a human’s life would foster resilient behavior in the future. It may be difficult to start enrichment while the human is going through stress.

Lehmann and Herkenham tested how environmental enrichment affects resilience of mice that were subjected to a social defeat paradigm and investigated the circuits involved in this process. From the cellular data, the researchers learned that the IL might be important to resilience. Lehmann and Herkenham ran behavioral tests after lesioning the IL. The EZM test yielded no significant results, and the L/D test showed a significant of infusion and an interaction between lesion and housing. Since these tests were both supposed to measure anxiety, I thought that they should have given similar results, especially since the results were similar when the mice were tested before the IL lesions. So, the lesion might affect a part of anxiety that is only relevant in the L/D test, not EZM.

I liked that it seemed like they focused on making their results as translatable as possible. They looked at brain regions in mice that were homologous to humans with depression, and the paradigm seems like it would be easy to translate humans. However, the lesion time point that I felt would most closely relate to a real world experience was before the mice got environmental enrichment. The results of the L/D, TST, FST, and SI showed that environmental enrichment after the lesion was not effective in rescuing the animals from anxiety or depressive behaviors. A lesion after environmental enrichment, however, did provide rescuing effects on these behaviors. These results suggest that in order for environmental enrichment to be an effective method of creating resilience, the human would have had to experience enrichment prior to a stressful event. This would not be useful when trying to treat a patient that experienced something stressful in the past.

Manufacturing Resiliency: An Investigation in Environmental Enrichment

The papers this week took very different approaches in designing experiments to test whether or not environmental enrichment (EE) can create resiliency to different forms of stress and stress effects.

The Ashokan et. al. paper used chronic immobilization stress (CIS) and countered it with EE. They chose to start the EE exposure at the same time that the CIS started. This kind of approach can be transferable to human models of chronic life stress. This approach would be analogous to an individual who is fortunate to have a wide variety of choice and enriching activities in their lives at the time that they begin to experience chronic stress. Perhaps this would not be representative of someone who comes from a low economic background and cannot afford such activities and might experience chronic stress from working multiple jobs. This group of researchers also made an interesting choice in using head dips as a measure of "active coping" behavior. To me, this seems like they are anthropomorphizing their lab animals to an inappropriate extent. Because of the non-specificity of the head dipping behavior, it seems to me that these animals could likely be exploring their environment.

The Lehmann and Herkenham on the other hand, used social defeat stress and countered it with EE. These researchers also chose to vary the time at which they gave the EE exposure, and the EE exposure never actually overlapped with the stressful experience. Because of this they were simulating a situation more similar to an individual who may have had a great experience a few days before experiencing trauma. However, this experiment is fundamentally different because the stress at hand is acute and not chronic. Although these two groups found that EE had similar effects in creating a resilient phenotype, the mechanism for this process was probably different.

On a final note, neither of these papers considered female animals in their experiments. I found this disappointing (as usual) but especially since both of these papers are fairly recent. At this point we understand that females are just simply different than males and furthermore, that many mental disorders occur more frequently in females than males.

Ayhan et al vs Burrows et al - Joe

Ayhan et al vs Burrows et al

Seminar in BioPsych

Fall 2016

Professor Shansky

Reading these two papers brought something to my attention that I remember being told during my first co-op, and I suppose I hadn’t thought about it thoroughly until now. During my first co-op, the post-doc I worked under once told me that he would never use mouse behavior to study complex mental disorders because it is inherently difficult to create an animal correlate of, say, schizophrenia (he was using electrophysiological techniques to understand how the brain processes innate olfactory valence). I shelved the idea until we delved into our readings about schizophrenia. Last week, and even more so this week, I’ve come to realize that these experiments using mouse models to probe the workings of schizophrenia are simply a small manipulation followed by a selection of tests (behavioral, histological, functional, etc.) to validate the small manipulation. The issue is that there is no standard for tests (each paper contains — in my eyes — an arbitrary selection of tests to attempt to validate the translatability of this model. Furthermore, the interpretations can get iffy because of the vast amount of things that are affected by the manipulation. Here’s what I mean:

Ayhan et al addressed the issue of introducing developmental abnormality to create a model for schizophrenia. It had been known previously that postnatal expression of DISC1 leads to developmental abnormalities resembling schizophrenia, but prenatal expression of DISC1 had not been addressed. While they successfully showed that expression during both time points leads to schizophrenic-like behavior (whatever that means), they did not address the comparability of Pre+Post vs Post groups. In many of the tests, they showed that these two groups showed significantly different responses than just the Pre group or the control did. But for some of the tests, the Pre+Post group was significantly different than the Pre group, indicating that something is going on when DISC1 is expressed during the prenatal period. It could be fruitful to delve deeper into the difference between these two groups. I also found it interesting that while DA levels were considerably lower in all groups exposed to DISC1 expression, DA turnover was not affected (as indicated by comparable DA/DOPAC ratios compared to control). In general, I’m not sure how much insight this paper provided.

Burrows et al, however, I thought was very interesting because it showed that a transgenic mouse that lacked a crucial receptor could show an amelioration in symptomatology with just a fuller and more eventful life. I’ve seen in the past environmental enrichment can have a plethora of positive effects, including neurogenesis and sociability. It was awesome to see that this could occur despite these mice lacking a receptor that’s been implicated in schizophrenia (is mGlu5 dysfunction sufficient to cause schizophrenia? who knows). While I thought it was great that they addressed the issue of male and female differences, I thought that this led to a difficulty to pinpoint definitive interpretations because there were so many groups and each test showed a different selection of groups responding. For example, let’s look at the prepulse inhibition test: there were four groups (SH WT, EE WT, SH KO, EE KO), and 2 sexes (males and females) and two frequencies (30ms ISI and 100ms ISI) — so 16 groups. There were no interactions at all for the 100ms groups, so just 8 groups. For the memory tasks, the mice showed better memory in the Morris water maze but not in the Y-maze (what does that mean? who knows). Moreover, the sex differences were not deeply discussed — just that there may be some differences between the two.

I’m not completely sold by these sets of experiments, but I also must admit that tracking down the etiology of such a complex mental disorder is a gargantuan task and many scientists have made valiant attempts at addressing it.

11/7 Schizophrenia Papers

          As a continuation of the schizophrenia model, this week's papers focused on the involvement of a DISC1 mutant (Ayhan et al., 2011) and a deficiency in metabotropic glutamate receptor 5 (Burrows et al., 2015) in schizophrenia. To begin with Ayhan et al., I thought they overall had a good argument.  I believe they included effective controls throughout their experiment. Since DISC1 is involved in both brain development and adult brain function, it was good that they tested the mutant gene both prenatally and postnatally. In addition, since schizophrenia is so complex and does not target just one neurotransmitter, I thought they did a good job testing the effects of a variety of monoamines that could all have links to schizophrenia. They could have been a little more consistent with including whether they used males or females in their figures, however. In Figure 3, they should have also included experiments done on female frontal cortices, rather than just males, as well as male hippocampuses, rather than just female ones. Finally, since schizophrenia typically affects human adults, this experiment should have been more specific about the postnatal expression in mice and done more tests or used more controls to clarify this.

          My favorite aspect of Burrows et al. was their inclusion of how the environment interacts with genetic predisposition in the schizophrenia model. The fact that environmental enrichment can improve schizophrenia-like behaviors in a variety of different behavioral tasks  (and, in some cases, improve so much that the KO matches the WT like in Figure 2b/c) in mice can be extremely useful in studying the onset, progression, and treatment of schizophrenia in humans. In this paper, they exposed the mice to EE prior to the different behavioral tests, so I wonder if the exact time you are exposed to EE makes a difference on behavior... is it just right before the test or can it be long before? What about exposure after a test, and then a re-test to measure if that had an effect? Maybe they can examine this in a future experiment.
(also, who thought it was a good idea to make the KO EE line in Figure 1 whitish gray? You can't even see it!!)

11/7 Ayhan and Burrows

Ayhan et al. used a genetic approach to model schizophrenia. They used a tTA transgenic mouse expressing the mutant hDISC1 gene. Genetic studies had previously identified DISC1 to be important to schizophrenia in both neurodevelopment and adulthood. In Ayhan et al.’s experiments, mice expressed hDISC1 prenatally, postnatally, pre- and postnatally, or not at all. I liked that they used experimental groups that accounted for problems with the gene that could occur developmentally or during adulthood, when schizophrenia symptoms occur.

Males were used in most experiments, but females were used in some tests, but not all. The tail suspension test and forced swim tests were done only on females. In other tests, like drug induced locomotion and open field interaction test, only males were used. Since they decided to include females in their experiment, it would have been better to see them used in all tests so the results could be more easily compared and interpreted.

Burrows et al. tried to alleviate the effects of knocking out the glutamatergic receptor mGlu5 by providing mice with an enriched environment rather than standard housing. On most of their behavioral tests, they saw that an enriched environment alleviated the schizophrenia related symptoms in mice. They saw many positive results with environmental enrichment, like reduced hyperactivity and less deficit in PPI.  However, environmental enrichment did not improve all aspects of schizophrenia tested; novelty preference in the Y maze was not affected. This research is important because environmental enrichment would be a viable translational approach to treating schizophrenia in humans. Mice began enriched housing at 4 weeks, which is around the time of adolescence in humans. Since symptoms of schizophrenia usually begin to occur shortly after adolescence, the results of this experiment may be useful to humans.

Something that bothered me about the methods was that drug-induced hyperlocomotion preceded prepulse inhibition. Even though the tests were about 3 weeks apart, I was wondering if there were any lasting changes in the brain after the drug was administered that could affect the way mice behaved in PPI.

There's a first time for everything: Exploring new topics in modeling schizophrenia

This week I had some questions and concerns about the papers. Both papers present  ideas that we have not previously encountered in our class discussions thus far. The Ayhan et al paper is the first paper that we have read that both utilized female animals and discussed sex differences in behavior and neuroanatomy. The Burrows et al paper is the first paper that we have read that not only presents a developmental model of schizophrenia, but proposed that an enriched environment might ameliorate schizophrenia related symptoms. 

I found it interesting and slightly confusing that in discussing differences between male and female mice, the Ayhan et al paper refers to these differences as "gender-differences." In other papers I have always seen these discussed as "sex differences." The difference in wording is subtle but was slightly off-putting since gender is a social construct. Because mice don't exist within a higher society, the idea of these differences being because of a socially constructed idea is inaccurate. However, it is probably just a simple mistake in semantics. 

I was also surprised at the way that the Ayhan et. al. paper presented their data. Although they claim to address sex differences, they never present data from male and female animals within the same graph. The only hint that they even completed their experiments in both sexes is hidden in the text. For example, when listing the results of the TST and FST they state that, "expression of mutant hDISC1 had no effects on these behaviors in male mice of either group (data not shown)." Despite the fact that they show that there are no differences between the male experimental groups, the paper still fails to actively compare them to the female groups. Without doing this, stating that there are significant sex differences seems like a bold statement. 

In regards to the Burrows et al paper I was pleasantly surprised to read a paper that proposed a solution that could temper the effects of an aggressive developmental model of schizophrenia. Although the model is by no means all-encompassing of every aspect of schizophrenia, the fact that there is some positive influence from an enriched environment makes me hopeful that there are some preventative measures parents can take in preventing schizophrenia and other mental illnesses. If an enriched environment can help reduce schizophrenia like symptoms in mice, I would be interested in knowing if there are studies in early education in humans and how it relates to schizophrenia later in life.