Dataset Information

MicroRNA Expression Profiles in the Ventral Hippocampus during Pubertal Development and the Impact of Peri-Pubertal Binge Alcohol Exposure.

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.

SUBMITTER: Asimes A

PROVIDER: S-EPMC6468757 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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microRNA Expression Profiles in the Ventral Hippocampus during Pubertal Development and the Impact of Peri-Pubertal Binge Alcohol Exposure.

Asimes AnnaDorothea A Kim Chun K CK Rao Yathindar S YS Bartelt Kyle K Pak Toni R TR

Non-coding RNA 20190305 1

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 ...[more]

PMID: 30841593

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Project description:Adolescent binge alcohol exposure has been previously shown to have long-lasting effects on the expression of hypothalamic genes that regulate the stress response, even in the absence of subsequent adult alcohol exposure. Those data suggested that alcohol can induce permanent gene expression changes, potentially through epigenetic modifications. Importantly, epigenetic modifications can be transmitted to future generations therefore, in these studies we investigated the effects of adolescent binge alcohol exposure on hypothalamic gene expression patterns in the F1 generation offspring. It has been well documented that maternal alcohol exposure during fetal development can have devastating neurological consequences. However, less is known about the consequences of maternal and/or paternal alcohol exposure outside of the gestational time frame. Here, we exposed adolescent male and female rats to a repeated binge EtOH exposure paradigm and then mated them in adulthood. Hypothalamic samples were taken from the offspring of these animals at postnatal day (PND) 7 and subjected to a genome-wide microarray analysis followed by qRT-PCR for selected genes. Importantly, the parents were not intoxicated at the time of mating and were not exposed to EtOH at any time during gestation therefore, the offspring were never directly exposed to EtOH. Our results showed that the offspring of alcohol-exposed parents had significant differences in the expression of hypothalamic genes that mediate neurogenesis and synaptic plasticity during neurodevelopment, genes important for directing chromatin remodeling, posttranslational modifications or transcription regulation, as well as genes involved in regulation of obesity and reproductive function. These data demonstrate that repeated binge alcohol exposure during pubertal development can potentially have detrimental effects on future offspring even in the absence of direct fetal alcohol exposure. Male and female Wistar rats were purchased from Charles River Laboratories (Wilmington, MA) at weaning (postnatal day (PND) 23) and allowed to acclimate for 7 days after arrival. Animals were handled for 5 min./once/day beginning at PND 30. Pubertal EtOH exposure began on PND 37, which is defined as peri-puberty. Animals were undisturbed following the first exposure of our binge EtOH exposure paradigm until PND 68 (late puberty/early adult) at which time they received a second exposure to the same treatment paradigm. During the duration of the experiment, males and females were separately housed in pairs on a 12:12 light/dark cycle with lights on at 0700 h with food and water available ad libitum. Binge Exposure Paradigm and Treatment Design. Rats were handled 5min./once/day for 7 d prior to treatment to control for nonspecific stress responses. At 37 d, animals were given 3 g/kg EtOH (20% v/v in tap water; N = 3/sex), or tap water alone (N = 3/sex), once/day via oral gavage at 10:00 AM to avoid disrupting normal feeding patterns. This process was repeated according to the following schedule for a total duration of 8 consecutive days: 3 d EtOH, 2 d tap water, 3 d EtOH. Control animals were given tap water alone once/day for 8 consecutive days. Our previous studies showed that this repeated binge-pattern EtOH paradigm does not affect body weight/growth curves and consistently results in blood alcohol concentrations (BAC) of 150-180 mg/dl in males and 210-240 mg/dl in females. We and others have previously used this paradigm as a model for the pattern of binge alcohol consumption observed in adolescents and BAC achieved are similar to those observed in humans following a binge drinking episode . After peri-pubertal treatments, animals were left undisturbed in their home cage until PND 68 when each group was again exposed to their respective treatment (i.e. control or binge EtOH. We waited 24 hours after the last dose of EtOH to ensure that blood alcohol concentrations in the parents were undetectable at the time of mating (data not shown). Animals were grouped into mating pairs: binge male + binge female (N = 3 pairs); water male + water female (N = 3 pairs). All of the females gave birth to 12-16 pups approximately 28 d after being housed with a male, indicating that conception took place approximately 6 d after pairing; therefore, the pups were never directly exposed to alcohol at any time. At PND 7 pups were deeply anesthetized on ice and sacrificed. Brains were rapidly removed, the hypothalamus microdissected on ice, and then stored in -80ºC until further processing for a genome-wide analysis on hypothalamic total RNA samples using a chip-based microarray (Southern California Genotyping Consortium, SCGC, Illumina Rat Ref-12). The PND 7 time point was chosen because the extent of rat neurodevelopment at PND 7 is roughly equivalent to that of a human infant at birth

Project description:IntroductionAlcohol use disorders are major risk factors for the development of and susceptibility to acute respiratory distress syndrome. Although these risks of alcohol consumption on the lung are well described, mechanisms by which alcohol abuse promotes acute lung injury are poorly understood. These gaps in our understanding are due, at least in part, to limitations of animal models to recapitulate human alcohol consumption. Recently, a new model of chronic plus binge alcohol exposure was developed that is hypothesized to better model drinking patterns of individuals with alcohol use disorders. Specifically, this paradigm models chronic consumption coupled with periodic bouts of heavy drinking. The impacts of this alcohol-exposure regimen on the lung are uncharacterized. Therefore, the goal of this study was to examine lung injury and inflammation in a well-characterized experimental model of chronic + binge alcohol exposure.Methods10-week-old male C57Bl6/J mice were administered ethanol-containing (or isocaloric control) liquid diet for 10 days, followed by a single ethanol gavage (5 g/kg). Lung inflammation and pulmonary function were assessed.ResultsTen days of ethanol-containing liquid diet alone (chronic) did not detectably affect any variables measured. However, ethanol diet plus gavage (chronic + binge) caused neutrophils to accumulate in the lung tissue and in the bronchoalveolar lavage fluid 24 h post-binge. This inflammatory cell recruitment was associated with airway hyper-responsiveness to inhaled methacholine, as indicated by elevated resistance, Newtonian resistance, and respiratory resistance.ConclusionsTaken together, the novel findings reveal that ethanol alone, absent of any secondary inflammatory insult, is sufficient to produce inflammation in the lung. Although these changes were relatively mild, they were associated with functional changes in the central airways. This animal model may be useful in the future for identifying mechanisms by which alcohol abuse sensitizes at-risk individuals to lung injury.

Dataset Information

MicroRNA Expression Profiles in the Ventral Hippocampus during Pubertal Development and the Impact of Peri-Pubertal Binge Alcohol Exposure.

Publications

microRNA Expression Profiles in the Ventral Hippocampus during Pubertal Development and the Impact of Peri-Pubertal Binge Alcohol Exposure.

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