Flawed epigenetic measurements of behavioral experiences

This 2018 New York rodent study not only wasted resources but also speciously attempted to extrapolate animal study findings to humans:

“While it is clear that behavioral experience modulates epigenetic profiles, it is less evident how the nature of that experience influences outcomes and whether epigenetic/genetic “biomarkers” could be extracted to classify different types of behavioral experience.

Male and female mice were subjected to either:

  • a Fixed Interval (FI) schedule of food reward, or
  • a single episode of forced swim followed by restraint stress, or
  • no explicit behavioral experience

after which global expression levels of two activating (H3K9ac and H3K4me3) and two repressive (H3K9me2 and H3k27me3) post-translational histone modifications (PTHMs), were measured in hippocampus (HIPP) and frontal cortex (FC).

A random subset of 5 of the 12 animals from each sex/behavioral experience group were used for these analyses. FC and HIPP were dissected from each of those 5 brains and homogenized for subsequent analyses. Thus, sample size for PTHM expression levels was n = 5 for each region/sex/behavioral treatment group and all PTHM expression level analyses utilized the homogenized tissue.

The specific nature of the behavioral experience differentiated profiles of PTHMs in a sex- and brain region-dependent manner, with all 4 PTHMs changing in parallel in response to different behavioral experiences. Global PTHMs may provide a higher-order pattern recognition function.”

The researchers knew or should have known that measuring “global expression levels” in “homogenized tissue” of “n = 5” subjects was flawed, and they did it anyway. They acknowledged some of the numerous study design defects with qualifiers such as:

“Even though these were global levels of histone modifications (and thus not indicative of changes at specific genes or sites on genes)..

As FS-RS behavioral experience was completed before FI behavioral experience, a longer overall post-behavior experience time (approximately 1 week) elapsed for this group, resulting in some differences in overall timing between these experiences and global PTHM assessment. However, extending the duration of the FS-RS experience (i.e., repeated exposures) would also have led to habituation..”

Did they purposely make these mistakes because of the “biomarkers” paradigm?

What would they have found if they had followed their judgments and training to design a better study? Experience-dependent histone modifications that differed by gender and brain region was certainly a promising research opportunity.

As for extrapolating the cited animal study findings to humans? Ummm..NO!

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060276/ “Different Behavioral Experiences Produce Distinctive Parallel Changes in, and Correlate With, Frontal Cortex and Hippocampal Global Post-translational Histone Levels”


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