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Week 7: Sex Differences in Drug Abuse

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As I started reading Vassoler et al 2013, I first assumed that the behavioral results were in opposition to each other. As I thought more about the difference between their statistical analysis, I realized that Holly et al 2012 did something more to analyze sex differences. In addition to look at within sex differences, Holly et al looked at between sex differences of the same conditions. This is something that Vassoler appeared to not do. They have the data for both sex cohorts in their research, but I don’t think they compared the different sexes of the same conditions, only within sex. I’d be curious to see if they did a statistical analysis between sexes on their paper. Specifically, I noticed that for their first experiment on cocaine intake it looked as though the cocaine infusions for CocSired females increased over time while the males didn’t. It looks as though they could be statistically significant and might indicate a variable effect between males and females. Similarly, in their PR protocol, the initial breakpoints for low dose cocaine self-administration were way higher than males at a lower dose. And Holly et al did their entire research using a low dose of cocaine and saw a similar effect of females having increased levels of cocaine administration.

In general, I feel that Vassoler could enrich their analysis of sex differences by comparing conditions between sexes and not just within and determine if Cocaine sired offspring produces some sort of distinguishable difference between males and females, not just between SalSired and CocSired. I do think that Vassoler did a better job of taking into consideration the effect of developmental endocrinology by mentioning that sex differences could be emerging from gestational and neonatal hormone levels affect organizational patterns that matter more in the developed animal. I wish that Holly et al would look into the effect of sex hormone manipulation in development to see if the observed behavioral differences originate from varied organizational patterns set-up in gestational, neonatal, or pre-adolescent periods from circulating sex hormones.  

Additionally, I found it fascinating the look into the chromatin configuration differences of this intergenerational effect of drug use. I do wish they would have used an alternative method to analyze chromatin changes. Given that they used ChIP-qPCR, this limits the breadth of their analysis. Because it’s qPCR, they can only quantify differences in specific gene targets with selected primers. This inherently limits the scope of the understanding of epigenetic changes that cocaine usage of Sires imparts of their offspring. It would be more ideal to utilize ChIP-seq, which was around at the time of the study though it may not have been as widely accessible or financially feasible. This would allow Vassoler to combine Chromatin immunoprecipitation with genome-wide analysis and circumvents the restriction of prior probe knowledge. It would be fascinating to see other locations where DNA/protein interactions vary. Even though ChIP-seq would be more expansive in characterizing the animal model they’ve created, ChIP-seq, is still limited to antibody usage and effectiveness because it’s based on chromatin immunoprecipitation. In general, I want to analyze this animal model utilizing ATAC-seq. This method would allow for the genome-wide breadth but would capture chromatin accessibility without the bias of probes or antibodies. Granted, the greatest limiting factor for this method is cost as next-generation sequencing tools are not cheap for a lab to purchase, the data could then point out genetics landmarks that vary between the two populations of CocSired and SalSired. Removing the bias of probe selection and antibody limitations would allow the researchers to find unique peaks in chromatin accessibility to determine what other factors beyond BDNF in the PFC could be influencing the observed delay in administration and reduced maintenance of self-administration in these rats.

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