Biopsych seminar 2020

This weeks papers Reber et al. 2016 and Buffington et al. 2016 present a super interesting look into the gut-brain axis. Regarding both of these papers, it was amazing to see how potent favorable or unfavorable gut microbiome compositions are in affecting neuronal signaling and overall behavior. Reber et al. shows how immunoregulatory immunization with specifically heat killed M.vaccae can serve as a protective factor against chronic subordinate stress induce colotis as well as behavioral symptoms due to chronic stress as such. Interestringly, this paper depleted regulatory T cell activity via the anti CD25 antibody in order to show that the antiinflammatory mechanism induced by m vaccae immunization is depented on the secondary regulatory mechanisms offered by Treg proliferation and signaling. But, when T reg signaling was removed, this did not seem to cause a significant change in behavior . Therefore, this begs the consideration of what othe rmechanisms may be at play in order ...

April 13 Papers (Buffington et. al, Reber et. al) I found this week’s papers to be quite novel in that they both proposed potential treatments for neurodevelopmental or psychiatric disorders that target bacterial or microbial abnormalities and how these give rise to certain behavioral and physical symptoms associated with the disorders. I thought this was a very unusual yet interesting approach, and as I have not previously studied the gut-brain axis, these papers offered me a fresh perspective on researching psychiatric and neurodevelopmental disorders. They were also unconventional in their focus of the physical symptoms that often accompany mental disorders, as this is not something that I have seen many other papers touch upon very much. Particularly, I was surprised by the Reber et al paper’s focus on the link between psychiatric disorders and inflammation in organs other than the brain, such as the colon, and the Buffington et al paper’s description of a relationship between ...

The papers for this week focused on the relationship between the gut and the brain, known as the gut-brain axis. This is a topic that interests me because I am currently taking Microbiology and we often discuss effects of a healthy and diverse human microbiome. It is commonly said that what you eat affects how you think and feel, but I was interested to explore some of the evidence behind this anecdote and the gut-brain connection. These papers as well as others demonstrate that the microbiome has influence over brain function and behavior, but it is clear that there is still a lot to be learned about this relationship.  The first paper, Reber et al., studied how  injecting mice with a heat-killed preparation Of  M. vaccae,  a non-pathogenic bacterium that lives in soil, protects against various negative stress-related outcomes. The researchers concluded that the immunization reduced the stress response, inflammation, and subordinate responses to a dominant ag...

The Buffington and Reber papers both explored the effects of the gut microbiome on rodent behavior. Buffington et al studied how maternal high fat diets affected the social behavior of their offspring. Specifically, they identified one type of bacteria, L. reuteri, as a fundamental component of restoring normal social behaviors in mice with social deficits. Reber et al studied the bacteria, M. vaccae and how immunization with a heat-killed dose ameliorated stress responses in mice. After reading the Reber paper, I'm skeptical of the translatability of their results. We've discussed in class that it's difficult to model anxiety as we know it in rodents, and this paper, in my opinion, highlights this point. The authors use chronic subordinate colony housing (CSC) and single housed mice in their behavior experiments. These conditions are certainly stressful for mice, but it's looking at a very narrow section of what's considered stress with only one type of bacteria....

This week's articles were about the role of the gut-brain axis in neurodevelopment and stress. Reber and colleagues used a heat-killed version of the bacteria, M. vaccae, as a type of vaccine and found that administration to mouse models resulted in decreased response to chronic stress, prevented colitis related to stress, and reduced measures of anxiety. Reber et al. also used the inactivated M. vaccae in a mouse model of IBD and found that the bacteria prevented stress-induce flare-ups of colitis, but that this could be reversed by removing T cells. Buffington and colleagues instead examined the role of gut microbiota in maternal high-fat diets (MHFD) in the neurodevelopment and social behaviors of their offspring. Buffington et al. found that housing MHFD rats with the offspring of regular diet (MRD) rats prevented social deficits in their offspring. They also found that this co-housing arrangement prevented an imbalance in the gut bacteria Reber and colleagues' findings w...

Buffington et al. explore a mechanism by which maternal obesity can induce neuronal and subsequent behavioral disorders. Using a model of high-fat diet (MHFD)-induced obesity, the authors showcase the strong connection between the brain and the gut, and its impact on behavior. The findings are provocative; by exposing these offspring to the microbiome of control offspring, there was evidence of a rescued observed behavioral phenotype. Furthermore, a phylogenetic profiling of the gut microbiome revealed a decrease in L. reuteri within MHFD offspring, and introduction of live L. reuteri into the drinking water shows successful rescue of the behavioral issues in the MHFD offspring. L. reuteri-induced expression of oxytocin within the paraventricular nuclei of the hypothalamus provides a potential mechanistic explanation for the behavioral changes. I thought this paper provided robust support for the hypothesized interaction between the gut biome and the developing CNS, with tremendous po...

Buffington et al. (2016) and Reber et al. (2016) present quite fascinating approaches to studying the interactions or ‘axis’ between the rodent (and human) gut and brain. As the gut is a primary route for bringing things from the environment into our body, these two studies present very clear and convincing evidence for the relevance and translatable validity of their various hypotheses.   One of the most interesting conclusions to me from Buffington et al. was that co-housing three high-fat diet offspring with just one regular-diet offspring was enough to rescue their social behavior deficits and microbiome profiles. This is remarkable, and I would like to hear more about possible mechanisms for this transfer to actually occur. Although the article mentions that mice do eat each other’s feces to transfer microbiota, could there be a certain “threshold” or level of bacteria needed to observe this phenotype switch? That is, how many more high-fat diet mice could have been house...

Both Buffing et al. (2016) and Reber et al. (2016)  align very much with my current research interests: everything and anything involving the gut-brain axis. This interest was spurred by a class I have mentioned in several of my blog posts thus far: Brain, Behavior and Immunity. The knowledge that I gained from this class allowed me to have a more insightful perspective when reading these papers. Having read a decent amount of papers about the gut-brain axis, something that particularly stood out to me in the Buffing et al. (2016)  paper was social interaction not inducing LTP in the VTA of the maternal high-fat diet offspring. I thought it was interesting that they tied social interaction to the VTA which I usually think about more with physical rewards rather than social. Something I was thinking about while reading this is what nutrients were the mice on the high-fat diet deficient in? Do we even have a way of quantifying mice as nutrient deficient? Is it the fat of the ...

While I have not encountered a lot of gut-brain interaction literature yet. I found each paper unique and fascinating. Reber et al felt inaccessible for me. I felt like I didn’t understand what the goal of the paper really was and why they did the tests that they did. It seems like most of their relevant information got shoved into numerous supplementary figures and their behavior was quite difficult to follow. Multiple sections of their paper were supported with data found entirely in supplementary figures, which makes it difficult to follow the same conclusions. I have a few issues with the behavior they chose and because of this, I struggle to find driving conclusions from their work. I don’t understand why the CSC was not only the prior stressor but was also the acute stress condition both groups faced. To me, I feel like it would have made more sense to have the CSC be the prior stressor and then judge the effect on social behavior with maybe a three choice chamber test or te...

Buffington (2016) In the figures for experiments that measure interaction time, the authors included a graph for contact duration in addition to interaction time but they don’t mention contact duration in the text. What’s the relevance of contact duration here/what does it add? The results appear relatively consistent with the results of interaction time. I don’t think that the authors would waste previous figure space on graphs that don’t add any value. I thought the sociability vs. social novelty tests were interesting. I don’t know much about mice so I was a bit surprised that they prefer a new mouse over a familiar mouse. I would have expected them to prefer spending time with a familiar mouse but I guess it makes sense if they want to explore and investigate this novel mouse that has just entered their space. In the experiment examining the effect of social interaction on long-term potentiation in VTA DA neurons, the results show that interaction with an unfamiliar mouse trigger...

While I am far from an expert on it, the gut-brain axis is one of the topics that is most fascinating to me in neuroscience today. Philosophers have argued for hundreds of years whether or not the body and the mind are connected, and the influence of the gut on mental health and vice versa seems to be key evidence that they are. I was excited to have the opportunity to learn more about these brain-gut interactions through Buffington et al. (2016) and Reber et al. (2016) this week, particularly in considering how the results of these experiments could point to treatments that are relatively easily translatable for humans.   Due to my interest in the application of information about the gut-brain axis to human subjects, I put a lot of thought into what these papers may mean for the future of treatment and prevention of neurodevelopmental and anxiety disorders. Taking both papers into consideration, I wondered about the differences in the emergence of stress-related mental i...

I was very interested in going into this week's papers as through my time as a BNS student I have not encountered anything to do with the gut microbiome or the brain gut interaction. Reber et al. 2016 provided an expansive look at the effects of bacterial immunization on stress resilience in mice. However, I felt as though I left the paper with more questions than when I began reading it. Although they showed various ways in which the mice housed under the chronic stress paradigm improved in terms of proactive coping and decreased stress induced colitis, they also glazed over many behavioral paradigms looking at stress and anxiety that did not show consistent results. The connection of immunization using heat killed M. vaccae was also used to study the effects on microglia and the serotonergic system. Although this provides insight to how the effect of immunization can be used as a therapeutic or preventative measure, there was no real rhyme or reason as to why they looked at the...

The papers for this week aimed to investigate the role of the gut-brain axis in stress and neurodevelopmental disorders. While we know that our microbiome influences brain function and certainly has some down-stream effects on behavior, the exact mechanisms by which this happens are complex and still not fully understood.  Reber et al. demonstrated that immunization with an immunoregulatory environmental microorganism ( M. vaccae ) can rescue a stress phenotype induced with subordinate colony housing. I found the data in this paper very compelling, and the data clearly shows that immunized mice exhibit many more “proactive” behaviors than non-immunized mice, but I did wonder if there was a way to get a more complete picture of dominance status. Here, they compared the number of proactive behaviors (attacks, chasing) to reactive behaviors (flight, avoiding), to determine the dominance score of every animal. However, they only did this with male mice with other male aggressors, ...

            The papers this week were extremely interesting. I have very little knowledge about how our gut microbiome affects us, so these papers were quite shocking to me. The Buffington paper especially, stood out. It was well organized, well explained, and I am completely in agreement with the conclusions. Developing a non-invasive treatment for patients through probiotics would be amazing. More research obviously needs to be done, but I think this paper does a good job at establishing how one species of bacteria can affect the whole organism. I liked how the researchers brought in ASD because it was very clear what the clinical significance of this paper is. Since an increasingly amount of people in the United States are becoming obese, this topic is currently very relevant as well. Since rodents and people are different, I’d be very curious to see what the comparison of the gut microbiome is between humans with high fat diets compared to low fat...

In the topic of gut microbiota, the researchers Reber et al investigated numerous approaches to the effect that bacteria M. vaccae has on stress, colitis and anxiety behavior in mice. It was intriguing to read that there was a larger likelihood of stress-related disorders for people in countries with a diet low in microbiota, exposure to few old infected pathogens, and few organisms from the natural environment. It is expected that vulnerability to these factors would create an inflammatory response in the body, but instead, the lack of exposure increases the prevalence of stress disorders. As stress is a large umbrella term, I would like to see more research by these researchers specifically of how mineralocorticoid receptors for acute, pro-inflammatory activity would affect stress. A comparison/contrasting of this to the effect that glucocorticoid receptors (responsible for high and chronic stress exposure) would have may enable a deeper understanding of the topic. The relation of ...

The gut-brain-axis is starting to be more and more explored within the scientific literature for psychiatric illness. Reber et al examines the strand of bacterium M. vaccae and its effects on a stressed mouse model. To do this, they used either a chronic subordinate colony housing (CSC) or single housed control (SHC) paradigm with mice that were either injected with a heat killed M. vaccae which acted like an immunization, or vehicle. Their results included an analysis of  behavior, behavioral tests (open arm maze, light dark box, open field test, etc), microglia analysis, microbiome sequencing, Treg measures, and more. Ultimately, the study concluded that M. vaccae immunization led to proactive coping, a reduced stress response, less time in a subordinate position for mice, and reduced inflammation. I think this article highlights many benefits to a strong microbiome, however, it is only looking at one specific bacterium. I would like to see many of these measures repeated with m...

April 6 Papers (Venniro et. al, de Guglielmo et. al) The Venniro et. al paper explores the influence volitional social interaction has on drug addiction in rats. The study gave rats a choice between social interaction and self-administration of either methamphetamines or heroin, and the results showed that they vastly preferred social interaction even after long periods of forced abstinence from drugs. The effect was still present but decreased when social interaction was delayed or punished. These results held true regardless of sex, drug class or dose, abstinence duration, housing conditions, or level of addiction. Additionally, abstinence due to social interaction also protected against methamphetamine cravings, and this was linked to increased activation of protein kinase C-δ  (PKCδ )-expressing inhibitory neurons in the central amygdala (CeA) and inhibition of activity in the anterior ventral insular (AIV) cortex. What I appreciated the most about this paper is that it...

These papers were some of my favorite that we've read, especially the Venniro paper. In the Venniro paper, the authors sought to answer the question, "Can the option of social interaction override a rats desire for drug self-administration?" In particular, Venniro et al studied addictive behaviors using methamphetamines and heroin. Venniro et al studied one circuit-specific mechanism for this behavior, much like how the deGuglielmo paper focused their work on the functionality of the CRF^CeA-BNST pathway. The question that hte deGuglielmo paper primarily answered was, "are the CRF projections in the CeA-BNST pathway responsible for the behaviors seen in alcohol use disorder?" Both papers were, in my opinion, designed quite well for studying addiction.  Intermittently, I run into social media posts that tout how important social interaction is for preventing drug addiction; however, the Venniro paper is the first evidence I've seen of this that is scientifi...

In deGuglielmo et al. (2019) the authors show how neuronal ensembles in the central amygdala predominantly express CRF and project to the bed nucleus of the stria terminalis. Using optogenetic dissection, they demonstrate how inactivation of this pathway reduces the dependence-related escalation of alcohol drinking and abuse. The data presented in this paper are extremely robust and point to remarkable clinical implications in binge drinking disorders. I’m also curious if a similar pathway or neural circuit is activated in drug use and dependency, and furthermore if drug-alcohol interactions cause either a change or elevation in the recruitment of a CeA neuronal ensemble. I would also like to see a study conducted using female rats, and a subsequent comparison between males and females since sexual dimorphisms have been observed in alcohol consumption and modulation. Lastly, I think a cool follow-up study could include stress as a factor, to see whether that plays a role in the inten...

The article by Venniro and colleagues examined the role of volitional social interaction as a means of preventing drug seeking in addicted rats. This paper used methamphetamine and heroin as their drugs. I found this paper incredibly difficult to follow, partially due to the Nature Neuroscience organization, but mostly because it seemed like this was a jumble of conclusions. It seemed like perhaps this paper was written when the authors looked at datasets from old experiments and saw a chance to pull patterns they observed into one publication instead of running a new experiment to test that observation. That aside, I found the findings of this study a little odd and unexpected. It was my understanding that most people first experiment with drug taking in social situations due to social pressures to participate. So, when the authors reported that receiving a social reward would attenuate choice to use drugs (both methamphetamine and heroin)—that rats would choose social rewards over dr...

This week's article continued are topic of addiction, looking at alcohol dependance in rats. In 2019 Guglielmo wt al. published a study investigating the relationship of corticotropin releasing hormone (CRH) cells in the central amygdala on withdrawal and alcohol dependence. They were able to show that the inactivation of a CRH-dependent amygdolofugal pathway with optoginetics was able to reverse addiction-like behaviors in rats dependent on alcohol. This area was selected as a target because of the relationship with somatic withdrawal symptoms. The CRH cells make up about 80% of the central amygdala with is the area most implicated in withdrawal symptoms following alcohol abuse in rats. This study was able to show that by blocking this pathway, male rats who choose to abstain from alcohol use when given access to self administration. While this changed alcohol intake, it did not affect normal behaviors such as water intake, implying that the rats are still healthy minded and able ...

I enjoyed Venniro et al’s article, but I feel that their narrative suffered from the over-inclusion of too much data. To me, I wish the paper had been split into two separate articles, a methods piece, and a manipulation/exploration piece. I think that they spent a great deal of time in the discussion talking about the translational impact this new behavioral paradigm provides and discussing why it’s more accurate of human addiction. Because of this, they ignored the latter part of their research on implicating PCK∂ cells and the neuronal correlate of this behavior. I think that in terms of a nature article, I expect more of that in targeting specific neuronal populations and determining their role in a particular behavior. Additionally, I think that their methods suffered greatly from a lack of detailed explanation of every step of the timeline. I found their first figure on the whole quite confusing and still don’t quite understand what all of the graphs indicate. This behavior is i...