Sunday, March 26, 2017

week 8

Holly et al. adopted a very clear and systematic approach to investigate the role of sex and estrous cycle differences in behavioral and neural sensitization to cocaine. Although they have been successful in outlining the role of sex differences in these behaviors, the role of estrous cycle differences has been under studied. They were only able to show estrous cycle differences in Experiment 1, but not in Experiment 2 & 3, and their explanation due to fluctuations of ovarian hormones across the binge was not convincing as this limitation could have been foreseen. Additionally, although they do highlight the role of estradiol in enhancing behavioral and neural sensitization, they failed to offer an explanation as to why this effect was seen. In other words, what might estradiol be doing that’s causing this heightened behavioral and neural response? What interaction does stress and estradiol have?

As for the Vassoler et al. paper, it was interesting to see a paternal transmission effect. One would assume that coc-spired offspring would display an enhanced sensitization to cocaine considering how there are various studies that show addiction might be genetically linked, thus it was interesting to see a cocaine – resistance phenotype. Since BDNF serves a protective function, it is not surprising that coc-sired male offspring had increased BDNF mRNA expression but what particular significance does exon IV have? I wish they had addressed that or provided more information on the role of exon IV. The paternal expression route becomes clear when the result of increased sperm Bdnf promoters is introduced, but I was still pretty confused as to what kind of association they were trying to propose. Are some acetylated histones retained and passed down to the male progeny?

Week 8

I’ve been interested in sex differences in research ever since being in Professor Shansky’s lab and learning about the huge impact of the estrous cycle on PTSD in female rats. After that experience, I couldn’t believe that the norm in research was to apply results from all-male animal experiments to all humans. In Holly et. al, I was surprised to see that females expressed a greater behavioral sensitization than males at all stages of their estrous cycles. I expected rats in estrus to be the only ones displaying this difference, with rats in non-estrus phases exhibiting the same behavioral sensitization as males. If I remember correctly from my days in the lab, it seems that fluctuating estrogen levels (depending on which phase of the estrous cycle the rat is in) somehow modulated dopamine levels, and I wonder if the same thing is going on here. I wish they gave more data specific to each part of the estrous cycle- not just in the locomotion task. I think there would be some interesting and possibly significant differences to observe. I was also confused about why they had the rats on a reverse light-dark cycle, and I wonder if this had any significance or purpose.

In general, I found the findings of the Vassoler et. al paper pretty fascinating. I did not expect at all for the male offspring of the cocaine-addicted fathers to actually have a delayed acquisition of cocaine self-administration. This suggests that having a cocaine-addicted father actually has protective benefits for male offspring, which really contradicts the notion that drug addiction is inheritable. Their observation of increased BDNF mRNA and protein levels in the mPFC of male offspring served as a good explanation for what they were observing, but it left me wondering why this same increase was not observed in female offspring. I would be really interested in seeing this experiment done with a much larger sample size, and with the father rats put into groups that are exposed to different levels of cocaine throughout the 60 days. I wonder if researchers would see a point where there is a shift, i.e up to a certain amount of paternal exposure to cocaine administration is protective (such as in this paper), but any amount past that is actually detrimental.

week 8


Holly et al
I found this study very interesting, because it states that stress plays a role in our responses to drugs.And that also Episodic Defeat creates stronger effects in females which might be amplified by Estrous. I think that this research provides us with good  data to use in future studies. They also give us info that suggests that after the stress paradigm that there is no Significant difference in percentage of DA in the Nac but after cocaine administration that number goes up. I think that's an interesting finding.

Vassoler
This was another interesting study because I feel like rarely we talk about the environmental effects on the father influencing sperm. I think that it Was really cool/weird that the fathers( who had been given cocaine) offspring had actually had a decrease in the self administration of cocaine, maybe indicating that it's possible to inherit a certain level of resistance to drugs, plus I would have thought that it would go the other way that maybe they would have increased self administration. It would be interesting to see a correlational study that delves into human offspring of a father addicted to cocaine with a non addicted mother and vice versa and if their offspring had become addicted to drugs and measure what is the ratio between mother and father. One of the knocks I had against the paper is that they did not test for other cocaine behaviors. But overall really interesting and I hope that it is expanded upon with follow up studies.

Week 8


            There is a major problem in biological research, especially in neuroscience and psychology, with a lack of representation of both sexes in experiments. Countless tests are published using data solely from male model organisms, meaning that whatever conclusions are drawn from the results about the disease or phenotype or genes at hand may only be applicable to male brains, yet these conclusions are made to be all-encompassing, regardless of sex. However, as seen in both papers this week, this is not the case as even simple modulations to the brain such as exposure to cocaine can have drastically different results for male and female rats. Namely, Holly et al.’s findings – which I personally found more compelling in their simplicity – demonstrated that female rats have longer “binge” periods when given the option of self-administration of cocaine and have greater extracellular density of dopamine in the nucleus accumbens, especially when stressed. This experiment offers multiple lanes of further research, including differential stress behaviors between males and females when exposed to other pharmacological manipulations (perhaps ketamine to investigate schizophrenic phenotypes), the possibly protecting effects of testosterone or other hormones more expressed in males (and vice versa for estradiol), or perhaps manipulation of the levels of the opposite hormone in the opposite sex and testing said modulations. These modulations can also be used to study the effects of cocaine on BDNF expression as found in the Vassoler et al paper. As they found a greater expression of BDNF in cocaine-exposed male rats, perhaps the parallels between BDNF, testosterone, estradiol, and dopamine expression in response to cocaine exposure may be a valid course of action for study, specifically if one has protecting or enhancing effects on another, and if cessation of expression of one induces differential behavioral and phenotypic results.

Week 8

This is going to be a harsh assessment and I completely understand if people don’t agree with me on this, but I am finding to difficult to articulate the value of the Holly et al paper. First, I want to fully acknowledge that the quantifications in the paper do show me convincing evidence that there is an interaction between sex and stress on cross-sensitization to cocaine. Figure 2 shows that the effects of stress on females is greater than in males (a and b), Figure 4 shows there is a greater effect of stress on DA concentration in females, and Figure 5 shows there is more infusions and longer “binge” durations in stressed females. Importantly, these do not seem to be just additive effects of stress on top of already existing sex differences because in all three experiments they show/state that the data for the non-stressed males and females is not significantly different. However, I still take issue with the paper because it does not seem to add anything to the existing body of knowledge that they themselves cite in the introduction. They establish from the beginning that people have already shown “females are more sensitive to the reinforcing effects of cocaine,” that “females subjected to social defeat stress self-administer significantly more cocaine than similarly stressed males,” and “ovariectomized females outperform males in every phase of self administration...and all these effects are potentiated with estradiol treatment.” In light of these previous studies, the experiments in these papers seem to be something you would find in the supplements of these cited works, if not simply redundant, but this would have been forgivable if they had explored the effects of the estrous cycle on these sex differences, as they proposed. Unfortunately, they try but fail to do so. Figure 2 shows that there is a difference in female response to endogenous changes in cycling hormones, (even though this should be the case based on the ovariectomy and estradiol replacement paper they already reference), but this branch of investigation ceases from here on because their sample size in the microdialysis experiments was too low to do statistical comparison (see discussion). The authors already state that their cocaine “binge” data is “expected” based on the existing studies, so perhaps Figure 4 could be the novel part of the paper as it potentially provides a biochemical basis for the enhanced reinforcing effects of cocaine in females (cited in the introduction), but this feels like such a minor advance since I would expect this to constitute one panel in one figure or a supplemental figure in another major journal.

I was surprised to see that the results of the Vassoler et al paper showed the opposite trend of epigenetic inheritance seen in humans--cocaine exposure in male sired rats resulted in a drug-resistance phenotype in the offspring. The results seem very clean in my opinion and, as the authors state, leaves the open question as to how to consolidate these results with the data from human studies. The use of paternal exposure, rather than the usual maternal exposure, was an interesting choice that I had not considered, but it is useful in that it isolated the effects of exposure to epigenetic influences, as opposed to in utero condition etc. that could have been encountered in a maternal exposure model. On a somewhat tangential note, I think it is increasingly valuable to have studies like this that look at male epigenetic contributions to offspring because the majority of papers I have seen disproportionately focus on female influences. Without getting too deep into the social debates, I think that this imbalance has implications regarding the social perception of motherhood and childbearing responsibilities, particularly the social consequences for having children later in life, lifestyle choices (i.e. diet, physical activity, breastfeeding), overall health (obesity, etc.)--basically anything you can think of--and how that adds risk for autism, schizophrenia, and a thousand other disorders despite the fact that there also studies that show paternal contributions to these same risk factors, though these studies are considerably fewer in number. To give a rough sense of how disproportionately maternal contributions are covered, a quick search for the keywords “paternal” and “epigenetic” yield a little less that 50,000 results, whereas “maternal” and “epigenetic” produce around 124,000 results. Add “contributions” and you get around 24,000 hits regarding paternal epigenetic influences and around 54,000 for maternal epigenetic influences.

Week 8

While this week’s papers didn’t capture my interest like the previous week’s papers on the gut-microbiome, I still enjoyed learning more about the behavioral effects of cocaine administration and sex differences in a cocaine-resistant phenotype. I’m excited to finally see some research using both female and male animals, as laboratory research has mainly used male animals until very recently. I personally preferred reading the Vassoler et. al paper; I found it is be particularly interesting because I’ve never encountered a paper examining the paternal line and its resulting behavioral effects on offspring. The results were a bit surprising; to my knowledge, human males are more susceptible to drug and alcohol addiction than women. Furthermore, severe exposure to drugs before or during pregnancy seems to produce a variety of behavioral effects in offspring and increase susceptibility to addiction. Therefore, the finding that cocaine-experienced male offspring (CocSired) had a protective advantage to cocaine self-administration was unexpected. The authors did acknowledge that the results are at odds with human data, which leads me to question the translatability of these experiments to human research. However, the fact that the researchers found the specific mechanism behind this increased protection (increased BNDF promoter acetylation in the sperm) was impressive and convincing.


I was underwhelmed by the results of the Holly et. al paper. I appreciate that the researchers were able to find a sex difference in socially stressed females and males when exposed to cocaine. However, I wish the researchers had elaborated on the different phases on the estrus cycle in regards to their results; I was not entirely convinced that estradiol was only involved in social-defeat behavioral sensitization and not the binge duration. Overall, I think this paper provides a promising foundation for further research regarding sex differences, cocaine exposure, and the estrogen/dopamine relationship.

Week 8

I found both papers this week to be highly intriguing. I do public health research on addiction and we spend a lot of time discussing the complex nature of this disease and the variety of factors that can affect the development and outcome of an addiction. I found these two papers to pair together well but I had a slight preference for Vassoler's. I found the sex differences to be an interesting find, especially as they mentioned how the bed nucleus of the stria terminalis, is larger in males than females and additionally how progesterone detracts from the effects of cocaine. Its also interesting how their results oppose the notion that addiction to cocaine is heritable. If this finding is based in fact and is applicable in humans, it would mean that the epidemiological studies that show a higher rate of addiction in offspring of addicts, are engaging in this behavior because of non-genetic factors.
Holly's paper also explores the sex differences in cocaine addiction and utilizes the same social defeat model we have seen before. The two papers results aren't exactly contradictory but Holly's does explore the female susceptibility to stress and the resulting longer binges of cocaine that Vassoler did not consider. I find this to be evidence against their assumption that it is brain region size, or hormone changes that make their male mice more effected. These clearly play a role in the sexes relationship with cocaine but the evidence of specific binging behavior and susceptibility to stress being higher in females in Hollys paper certainly raises questions about the conclusions made in Vassolers. 

Week 8 Papers

          Both the Holly et al and Vassoler et al paper had clear hypotheses that were backed up by a decade of previous research. Both groups went into their studies knowing the specific question they were asking and expecting a very specific answer. That made these papers informative but not exciting at all. The entire groundwork of these papers was laid in the introduction and the results were just a retelling of everything that had been hypothesized and backed up with research in the introduction. I thought that Holly et al had the more interesting of the two papers even though their experimental manipulations seemed brief. The fact that the group found a specific sex x stress x time interaction when looking at basal DA levels was interesting. There were no cross interactions besides this three way interaction and I found that curious that it took all of these conditions in order to see the interplay and effect. Overall the results that females had a heightened predisposition to cocaine and its effects was sort of already known as they mentioned and the estrous cycle affecting these crossover sensitizations had been hinted at before.

            The Vassoler paper was interesting due to its excessive drug paradigm. A 60d self administration where the dosage was essentially controlled by the animal must have caused a lot of effects in the F0 generation rodent. This drug riddled rodent paradigm allowed for the sperm to become altered by cocaine’s affects and that was the key. The idea that a drug addicted father could cause a less drug sensitive male offspring was an interesting finding. The fact that previous research had been done into the mechanism and they were able to find the proteins and transcriptional processes behind this desensitization was impressive as well. I do fail to see the translatability of these findings however and even in the paper they mention that it cannot translate to the human condition. Without the information gained from the experiment being able to help in the understanding of a problem in the human condition then was the experiment really worth completing?