The application of epiphenotyping approaches to DNA methylation array studies of the human placenta.

Background : Genome-wide DNA methylation (DNAme) profiling of the placenta with Illumina Infinium Methylation bead arrays is often used to explore the connections between in utero exposures, placental pathology, and fetal development. However, many technical and biological factors can lead to signals of DNAme variation between samples and between cohorts, and understanding and accounting for these factors is essential to ensure meaningful and replicable data analysis. Recently, "epiphenotyping" approaches have been developed whereby DNAme data can be used to impute information about phenotypic variables such as gestational age, sex, cell composition, and ancestry. These epiphenotypes offer avenues to compare phenotypic data across cohorts, and to understand how phenotypic variables relate to DNAme variability. However, the relationships between placental epiphenotyping variables and other technical and biological variables, and their application to downstream epigenome analyses, have not been well studied. Results : Using DNAme data from 204 placentas across three cohorts, we applied the PlaNET R package to estimate epiphenotypes gestational age, ancestry, and cell composition in these samples. PlaNET ancestry estimates were highly correlated with independent polymorphic ancestry informative markers, and epigenetic gestational age, on average, was estimated within 4 days of reported gestational age, underscoring the accuracy of these tools. Cell composition estimates varied both within and between cohorts, but reassuringly were robust to placental processing time. Interestingly, the ratio of cytotrophoblast to syncytiotrophoblast proportion decreased with increasing gestational age, and differed slightly by both maternal ethnicity (lower in white vs. non-white) and genetic ancestry (lower in higher probability European ancestry). The cohort of origin and cytotrophoblast proportion were the largest drivers of DNAme variation in this dataset, based on their associations with the first principal component. Conclusions : This work confirms that cohort, array (technical) batch, cell type proportion, self-reported ethnicity, genetic ancestry, and biological sex are important variables to consider in any analyses of Illumina DNAme data. Further, we demonstrate that estimating epiphenotype variables from the DNAme data itself, when possible, provides both an independent check of clinically-obtained data and can provide a robust approach to compare variables across different datasets.

Anodal transcranial direct current stimulation with monopolar pulses improves limb use after stroke by enhancing inter-hemispheric coherence.

Post-stroke neurological deficits, such as sensorimotor impairments, are often permanent and a leading cause of disability. Stroke is also associated with changes in neuronal synchrony among different brain areas. Multiple studies demonstrated that non-invasive brain stimulation, such as transcranial direct current stimulation (tDCS), enhances the efficacy of existing rehabilitative therapies. We hypothesized that the therapeutic effects of tDCS could be due to its influence on neuronal synchrony. To study this, we recorded local field potentials in rats treated with anodal tDCS (a-tDCS) after unilateral ischemic motor cortex lesion. To enhance the effect of a-tDCS on neuronal synchrony, we added monopolar pulses (a-tDCSmp) during a treatment. We found that ischemic lesions reduced interhemispheric coherence in the low gamma frequency range. By contrast, a-tDCSmp treatment increased interhemispheric coherence along with motor improvement in a skilled reaching task. These observations indicate that increased neuronal coherence is a likely mechanism by which tDCS improves stroke recovery. Moreover, this work adds to previous evidence that measures of brain coherence could be used as a biomarker of stroke recovery, which may help in the design of more effective tDCS protocols for stroke rehabilitation.

Oxytocin-mediated social enrichment promotes longer telomeres and novelty seeking.

The quality of social relationships is a powerful determinant of lifetime health. Here, we explored the impact of social experiences on circulating oxytocin (OT) concentration, telomere length (TL), and novelty-seeking behaviour in male and female rats. Prolonged social housing raised circulating OT levels in both sexes while elongating TL only in females. Novelty-seeking behaviour in females was more responsive to social housing and increased OT levels than males. The OT antagonist (OT ANT) L-366,509 blocked the benefits of social housing in all conditions along with female-specific TL erosion and novelty-seeking deficit. Thus, females seem more susceptible than males to genetic and behavioural changes when the secretion of endogenous OT in response to social life is interrupted. Social enrichment may, therefore, provide a therapeutic avenue to promote stress resiliency and chances of healthy aging across generations.