Morin, E. L. | bioRxiv Science

bioRxiv2023

RNA in extracellular vesicles during adolescence reveal immune, energetic and microbial imprints of early life adversity.

Exposure to early life adversity (ELA), including childhood maltreatment, is one of the most significant risk factors for the emergence of neuropsychiatric disorders in adolescence and adulthood. Despite this relationship being well established, the underlying mechanisms remain unclear. One way to achieve this understanding is to identify molecular pathways and processes that are perturbed as a consequence of childhood maltreatment. Ideally, these perturbations would be evident as changes in DNA, RNA or protein profiles in easily accessible biological samples collected in the shadow of childhood maltreatment. In this study, we isolated circulating extracellular vesicles (EVs) from plasma collected from adolescent rhesus macaques that had either experienced nurturing maternal care (CONT) or maternal maltreatment (MALT) in infancy. RNA sequencing of RNA in plasma EVs and gene enrichment analysis revealed that genes related to translation, ATP synthesis, mitochondrial function and immune response were downregulated in MALT samples, while genes involved in ion transport, metabolism and cell differentiation were upregulated. Interestingly, we found that a significant proportion of EV RNA aligned to the microbiome and that MALT altered the diversity of microbiome-associated RNA signatures found in EVs. Part of this altered diversity suggested differences in prevalence of bacterial species in CONT and MALT animals noted in the RNA signatures of the circulating EVs. Our findings provide evidence that immune function, cellular energetics and the microbiome may be important conduits via which infant maltreatment exerts effects on physiology and behavior in adolescence and adulthood. As a corollary, perturbations of RNA profiles related to immune function, cellular energetics and the microbiome may serve as biomarkers of responsiveness to ELA. Our results demonstrate that RNA profiles in EVs can serve as a powerful proxy to identify biological processes that might be perturbed by ELA and that may contribute to the etiology of neuropsychiatric disorders in the aftermath of ELA.

zoology↗

bioRxiv2019

Molecular and Behavioral Effects of Infant Maltreatment across Generations in Rhesus Monkeys

Childhood maltreatment is among the most robust risk factors for subsequent psychiatric and medical disorders, and data in humans and rodents suggest that effects of adverse childhood experiences may be transmitted across generations. Recent indications for biological processes underlying this transfer of experiential effects are intriguing; yet, their relevance in primates is inconclusive due to limitations of current studies. In this study, we bridge research in rodent models and humans with a natural non-human primate model on intergenerational effects of childhood maltreatment. Using a unique, well-controlled, randomized cross-fostering design in rhesus monkeys, we test the influence of ancestral maltreatment on molecular, neuroendocrine and behavioral outcomes in offspring, and show that childhood maltreatment results in transmission of information to the subsequent generation independent of behavioral transmission. We further demonstrate differences in the offspring longitudinal DNA methylation profile of the FKBP5 gene, an important regulator of the hypothalamus-pituitary-adrenal axis in offspring of the maltreatment lineage compared to the control lineage. Finally, we show that differences in FKBP5 methylation have functional effects on molecular, neuroendocrine and behavioral outcomes in offspring of the maltreatment ancestral line, even if the infants were never exposed to maltreatment nor interacted with their exposed ancestors. Although the molecular mechanism underlying our observations remains unknown, our data point to a potential germline-dependent effect. In summary, our data suggest that history of maltreatment in primates can induce molecular and behavioral changes in a subsequent generation independent of behavioral transmission that may influence risk for mental and physical diseases across generations.

neuroscience↗