Abstract
Adolescence is hallmarked by two parallel processes of sexual maturation and adult patterning of the brain. Therefore, adolescence represents a vulnerable postnatal period for neurodevelopment where exogenous factors can negatively impact adult brain function. For example, alcohol exposure during pubertal development can lead to long-term and widespread neurobiological dysfunction and these effects have been shown to persist even in the absence of future alcohol exposure. However, the molecular mechanisms mediating the persistent effects of alcohol are unclear. We propose that dysregulation of microRNAs (miR) could be a unifying epigenetic mechanism underlying these widespread long-term changes. We tested the hypothesis that repeated alcohol exposure during pubertal development would cause disruption of normal miR expression profiles during puberty and, subsequently, their downstream mRNA target genes in the ventral hippocampus using an established rat model of adolescent binge drinking. We found 6 alcohol-sensitive miRs that were all downregulated following alcohol exposure and we also investigated the normal age-dependent changes in those miRs throughout the pubertal period. Interestingly, these miRs were normally decreased throughout the process of puberty, but alcohol prematurely exacerbated the normal decline in miR expression levels. The work presented herein provides foundational knowledge about the expression patterns of miRs during this critical period of neurodevelopment. Further, this regulation of miR and mRNA expression by alcohol exposure presents a complex regulatory mechanism by which perturbation in this time-sensitive period could lead to long-term neurological consequences.
Highlights
Adolescence is an important period of human brain development, where the neural circuitry governing executive function and adult-like responses to stressors is still being shaped
The data show a strong correlation between alcohol-induced changes in these miRs at peri-puberty and the expression levels of their mRNA targets, many of which are directly implicated in the regulation of sexual maturation and/or neuronal development. miRs have the ability to regulate hundreds of mRNA gene targets, which in turn can be regulated by multiple miRs; this work provides fundamental groundwork towards uncovering potentially broad cellular regulatory programs that can be disrupted by the extremely popular teenage behavior of binge drinking
The expression of miR-19a/b-3p, miR-34a, and miR-488-3p all progressively decreased from Post-Natal Day (PND) 30 to PND 74 in the ventral hippocampus of untreated animals, suggesting that their target genes would be increased and are likely important mediators of neurodevelopmental processes
Summary
Adolescence is an important period of human brain development, where the neural circuitry governing executive function and adult-like responses to stressors is still being shaped. These characteristics, make this a well-fit rodent model to investigate the underlying molecular mechanisms that contribute to the negative effects of teenage binge-pattern alcohol consumption on brain and sexual development We have used this model to study the long-term effects of adolescent binge alcohol consumption in the hypothalamus and found persistent changes in the adult male stress response, even in the absence of further alcohol exposure [7,9,12]. Non-Coding RNA 2019, 5, x hypothesized that repeated adolescent binge alcohol exposure would alter the expression of genes relatNeodn-tcoodinngeuRNroAd2e01v9e, 5lo, 2p1ment by dysregulating the normal temporal pattern of miR express3ioonf 16in the ventral hippocampus We investigated these questions using our well-established animal treatment paraWdieghmypoofthreespizeeadtethdatbrienpgeeateadlcaodhoolelsecexnptobsiunrgee adlcuorhinogl exppuobseurrteawl oduelvdealoltpermtheenetxipnremssaiolne oWf gisetnaers rats. E2.xRpeersiumletsnt 1: Hormone Levels and Spermatogenesis in Untreated Male Wistar Rats at Post-Natal Day (PND) 30, 44, and 74
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