Effects of Acute Prenatal Exposure to Ethanol on microRNA Expression are Ameliorated by Social Enrichment

Abstract

Fetal alcohol spectrum disorders (FASDs) are associated with abnormal social behavior. These behavioral changes may resemble those seen in autism. Rats acutely exposed to ethanol on gestational day 12 show decreased social motivation at postnatal day 42. We previously showed that housing these ethanol-exposed rats with non-exposed controls normalized this deficit. The amygdala is critical for social behavior and regulates it, in part, through connections with the basal ganglia, particularly the ventral striatum. MicroRNAs (miRNAs) are short, hairpin-derived RNAs that repress mRNA expression. Many brain disorders, including FASD, show dysregulation of miRNAs. In this study, we tested if miRNA and mRNA networks are altered in the amygdala and ventral striatum as a consequence of prenatal ethanol exposure and show any evidence of reversal as a result of social enrichment. RNA samples from two different brain regions in 72 male and female adolescent rats were analyzed by RNA-Seq and microarray analysis. Several miRNAs showed significant changes due to prenatal ethanol exposure and/or social enrichment in one or both brain regions. The top predicted gene targets of these miRNAs were mapped and subjected to pathway enrichment analysis. Several miRNA changes caused by ethanol were reversed by social enrichment, including mir-204, mir-299a, miR-384-5p, miR-222-3p, miR-301b-3p, and mir-6239. Moreover, enriched gene networks incorporating the targets of these miRNAs also showed reversal. We also extended our previously published mRNA expression analysis by directly examining all annotated brain-related canonical pathways. The additional pathways that were most strongly affected at the mRNA level included p53, CREB, glutamate, and GABA signaling. Together, our data suggest a number of novel epigenetic mechanisms for social enrichment to reverse the effects of ethanol exposure through widespread influences on gene expression.

Plasma miRNA Profiles in Pregnant Women Predict Infant Outcomes following Prenatal Alcohol Exposure

“…Moreover, stress has also been show to alter circulating miRNA expression profiles [66], and consequently, socioeconomic status may also contribute to the alterations in miRNA expression observed in the current study. It is encouraging to note that interventions such as social enrichment, which may be expected to mitigate effects of socioeconomic status, have recently been shown to reverse effects of prenatal ethanol exposure on miRNA expression profiles [67]. Both socioeconomic status and current smoking have been identified as risk factors for FASD in other populations as well [68].…”

Downregulation of miR-384-5p attenuates rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through inhibiting endoplasmic reticulum stress

“…Cells were exposed to rotenone (Sigma, St. Louis, MO) at various concentrations (1,5,10,20, and 50 M) (28) for the indicated times before being harvested for analysis. For miRNA transfection, cells were transfected with miR-384-5p mimics or inhibitors using Lipofectamine 2000 (Invitrogen) at a final concentration of 50 nM for 24 h prior to rotenone (20 M) exposure.…”

“…In recent years, miR-384-5p has been reported to play an important role for cell survival in response to different insults. Ethanol exposure causes expression changes of miR-384-5p in rat brain (20). Spinal cord injury significantly increases the expression of miR-384-5p in the serum (13).…”

Maternal alcohol consumption and altered miRNAs in the developing fetus: Context and future perspectives

“…The finding suggests that the effect of ethanol is reversed by social enrichment, and they have also reported the down‐regulation of miR‐204, miR‐299a, miR‐384‐5p, miR‐222‐3p, miR‐301b‐3p and miR‐6239 expression (Ignacio et al . , ).…”