Neuro-Epigenetic Indications of Acute Stress Response in Humans: The Case of MicroRNA-29c

Abstract

Stress research has progressively become more integrative in nature, seeking to unfold crucial relations between the different phenotypic levels of stress manifestations. This study sought to unravel stress-induced variations in expression of human microRNAs sampled in peripheral blood mononuclear cells and further assess their relationship with neuronal and psychological indices.We obtained blood samples from 49 healthy male participants before and three hours after performing a social stress task, while undergoing functional magnetic resonance imaging (fMRI). A seed-based functional connectivity (FC) analysis was conducted for the ventro-medial prefrontal cortex (vmPFC), a key area of stress regulation. Out of hundreds of microRNAs, a specific increase was identified in microRNA-29c (miR-29c) expression, corresponding with both the experience of sustained stress via self-reports, and alterations in vmPFC functional connectivity. Explicitly, miR-29c expression levels corresponded with both increased connectivity of the vmPFC with the anterior insula (aIns), and decreased connectivity of the vmPFC with the left dorso-lateral prefrontal cortex (dlPFC). Our findings further revealed that miR-29c mediates an indirect path linking enhanced vmPFC-aIns connectivity during stress with subsequent experiences of sustained stress. The correlative patterns of miR-29c expression and vmPFC FC, along with the mediating effects on subjective stress sustainment and the presumed localization of miR-29c in astrocytes, together point to an intriguing assumption; miR-29c may serve as a biomarker in the blood for stress-induced functional neural alterations reflecting regulatory processes. Such a multi-level model may hold the key for future personalized intervention in stress psychopathology.

MicroRNAs in Psychological Stress Reactions and Their Use as Stress-Associated Biomarkers, Especially in Human Saliva

“…Two of these studies used experimental stress elicitation tasks - analyzing acute, not chronic stress reactions [21,22]. Three of these studies used stressors of everyday life, such as academic exams or tests as events to be expected and therefore functioning as chronic psychological stressors [13,23,24].…”

“…In 2016, Vaisvaser et al [21] investigated miRNA expression in peripheral blood, responding to an acute psychological stress elicitation task. They found an increase in the concentration levels of miR-29c in peripheral blood.…”

“…Changes in the miRNA concentration levels correlated with the subjective experience of perceived stress (measured by a 9 point Likert scale) and the activation of the ventromedial prefrontal cortex as a key area of stress regulation (measured in parallel by functional magnetic resonance imaging). They assumed that stress-induced changes in miRNA expression may occur very quickly - minutes after induction [21]. …”

Epigenetic programming of the neuroendocrine stress response by adult life stress

“…DNA methylation profiles within SCL6A4 were found to moderate the association of the 5-HTT linked polymorphic region (5-HTTLPR) and stress coping (van IJzendoorn et al 2010, Alexander et al 2014. High serum SCL6A4 methylation was associated with an increased risk of unresolved responses to loss or other trauma in carriers of the usually protective 5-HTTLPR long allelic variant, while low levels of methylated SCL6A4 predicted unresolved loss or trauma in short allele carriers.…”

“…miRNA expression levels in rodents and human cells have been found to be altered in response to various environmental factors, such as light, sound, nutrients, drugs and stress (Codocedo & Inestrosa 2016). Preliminary results have demonstrated the upregulation of several serum miRNAs directly after an acute social stress task in healthy participants (Vaisvaser et al 2016) and have associated transiently altered expression of serum miRNAs with chronic academic stress (Honda et al 2013). Abnormalities in miRNA expression have also been implicated in PTSD, with several miRNAs being significantly downregulated in PTSD cases vs age-matched healthy controls .…”