Klengel, T. | bioRxiv Science

bioRxiv2018

microRNA regulation of persistent stress-enhanced memory

Disruption of persistent, stress-associated memories is relevant for treating posttraumatic stress disorder (PTSD) and related syndromes, which develop in a subset of individuals following a traumatic event. Using a stress-enhanced fear learning protocol that results in differential susceptibility in inbred mice, we integrated small-RNA sequencing with quantitative proteomics on basolateral amygdala tissue collected one month after training. We identified persistently changed microRNAs, including mir-135b-5p, and predicted target proteins associated with PTSD-like heightened fear expression. Functional manipulations of mir-135b-5p bidirectionally modulated stress-associated memory. mir-135b-5p is expressed in human amygdala and its passenger strand was elevated in serum from a well-characterized military PTSD cohort. miR-135b-5p is a therapeutic target for dampening persistent, stress-enhanced memory and its passenger strand a potential biomarker for responsivity to a mir-135-based therapeutic.\n\nOne Sentence Summarymir-135 can be manipulated to weaken persistent, stress-associated memory and serve as a biomarker of PTSD.

neuroscience↗

bioRxiv2018

Sensitive periods for the effect of childhood adversity on DNA methylation: Results from a prospective, longitudinal study

BackgroundExposure to \"early life\" adversity is known to predict DNA methylation (DNAm) patterns that may be related to prolonged psychiatric risk. However, few studies have investigated whether adversity has time-dependent effects based on the age at exposure.\n\nMethodsUsing a two-stage structured life course modeling approach (SLCMA), we tested the hypothesis that there are sensitive periods when adversity induced greater DNAm changes. We tested this hypothesis in relation to two alternative explanations: an accumulation hypothesis, in which the effect of adversity on DNAm increases with the number of occasions exposed, regardless of timing, and a recency model, in which the effect of adversity is stronger for more proximal events. Data came from the Accessible Resource for Integrated Epigenomics Studies (ARIES), a subsample of mother-child pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC; n=670-776).\n\nResultsAfter covariate adjustment and multiple testing correction, we identified 40 CpG sites that were differentially methylated at age 7 following exposure to adversity. Most loci (n=32) were predicted by the timing of adversity, namely exposures during infancy. Neither the accumulation nor recency of the adversity explained considerable variability in DNAm. A standard EWAS of lifetime exposure (vs. no exposure) failed to detect these associations.\n\nConclusionsThe developmental timing of adversity explains more variability in DNAm than the accumulation or recency of exposure. Infancy appears to be a sensitive period when exposure to adversity predicts differential DNAm patterns. Classification of individuals as exposed vs. unexposed to \"early life\" adversity may dilute observed effects.

genetics↗