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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.

SUBMITTER: Ignacio C

PROVIDER: S-EPMC4173670 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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

Ignacio Cherry C Mooney Sandra M SM Middleton Frank A FA

Frontiers in pediatrics 20140924

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 ...[more]

PMID: 25309888

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Project description:BackgroundIndividuals with fetal alcohol spectrum disorders (FASD) often show processing deficits in all sensory modalities. Using an operant light reinforcement model, we tested whether prenatal ethanol exposure (PE) alters operant responding to elicit a contingent sensory stimulus-light onset (turning on the light) and habituation to this behavior in rats. We also explored whether postnatal environmental enrichment could ameliorate PE-induced deficits.MethodsPregnant Sprague Dawley rats were gavaged twice/day with 0 or 3 g/kg/treatment ethanol (15% w/v) during gestational days 8-20, mimicking second-trimester heavy PE in humans. The offspring were reared in a standard housing condition or an enriched condition. Adult male and female offspring underwent an operant light reinforcement experiment with either a short-access or a long-access procedure. A dishabituation test was also conducted to characterize the habituation process.ResultsIn the short-access procedure, PE led to increased operant responding to the contingent light onset in both sexes reared in the standard housing condition. Such an effect was not observed in rats reared in enriched conditions due to an overall decrease in responding. Moreover, rats reared in enriched conditions showed greater short-term habituation. In the long access procedure, PE rats showed increased responding and impaired long-term habituation. The long-access procedure facilitated both short-term and long-term habituation in control and PE rats.ConclusionPrenatal ethanol exposure increases responding to contingent light onset and impairs the long-term habituation process. The PE-induced deficits were ameliorated by rearing in the enriched environment and increasing the duration and frequency of exposure to light onset. The PE-induced effects are like increased sensation-seeking, a subtype of sensory-processing deficit that is often observed in individuals with FASD. Our findings could inform a suitable animal model for investigating the underlying mechanisms and possible intervention strategies for sensory deficits in FASD.

Project description:BackgroundAutism spectrum disorder (ASD) is characterized by impaired social interactions and repetitive patterns of behavior. Symptoms appear in early life and persist throughout adulthood. Early social stimulation can help reverse some of the symptoms, but the biological mechanisms of these therapies are unknown. By analyzing the effects of early social stimulation on ASD-related behavior in the mouse, we aimed to identify brain structures that contribute to these behaviors.MethodsWe injected pregnant mice with 600-mg/kg valproic acid (VPA) or saline (SAL) at gestational day 12.5 and evaluated the effect of weaning their offspring in cages containing only VPA animals, only SAL animals, or mixed. We analyzed juvenile play at PD21 and performed a battery of behavioral tests in adulthood. We then used preclinical PET imaging for an unbiased analysis of the whole brain of these mice and studied the function of the piriform cortex by c-Fos immunoreactivity and HPLC.ResultsCompared to control animals, VPA-exposed animals play less as juveniles and exhibit a lower frequency of social interaction in adulthood when reared with other VPA mice. In addition, these animals were less likely to investigate social odors in the habituation/dishabituation olfactory test. However, when VPA animals were weaned with control animals, these behavioral alterations were not observed. Interestingly, repetitive behaviors and depression-related behaviors were not affected by social enrichment. We also found that VPA animals present high levels of glucose metabolism bilaterally in the piriform cortex (Pir), a region known to be involved in social behaviors. Moreover, we found alterations in the somatosensory, motor, and insular cortices. Remarkably, these effects were mostly reversed after social stimulation. To evaluate if changes in glucose metabolism in the Pir correlated with changes in neuronal activity, we measured c-Fos immunoreactivity in the Pir and found it increased in animals prenatally exposed to VPA. We further found increased dopamine turnover in the Pir. Both alterations were largely reversed by social enrichment.ConclusionsWe show that early social enrichment can specifically rescue social deficits in a mouse model of ASD. Our results identified the Pir as a structure affected by VPA-exposure and social enrichment, suggesting that it could be a key component of the social brain circuitry.

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

Publications

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

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