BackgroundChronic or binge ethanol exposures during development can cause fetal alcohol spectrum disorder (FASD) which consists of an array of neurobehavioral deficits, together with structural, molecular, biochemical, and neurotransmitter abnormalities in the brain. Previous studies showed that perinatal neurodevelopmental defects in FASD are associated with inhibition of brain insulin and insulin-like growth factor (IGF) signaling. However, it is not known whether sustained abnormalities in adolescent brain structure and function are mediated by the same phenomena.AimsUsing an early postnatal (3rd trimester equivalent) binge ethanol exposure model, we assessed neurobehavioral function, structure, and the integrity of insulin/IGF signaling in young adolescent cerebella.MethodsLong Evans male rats were treated with 50 µl of saline (vehicle) or 2 mg/kg of ethanol by i.p. injection on postnatal days (P) 2, 4, 6, and 8. On P19–20, rats were subjected to rotarod testing of motor function, and on P30, they were sacrificed to harvest cerebella for histological, molecular, and biochemical studies.ResultsBinge ethanol exposures impaired motor function, caused sustained cerebellar hypocellularity, and reduced neuronal and oligodendrocyte gene expression. These effects were associated with significant deficits in insulin and IGF signaling, including impaired receptor binding, reduced Akt, and increased GSK-3β activation.ConclusionsFASD-associated neurobehavioral, structural, and functional abnormalities in young adolescent brains may be mediated by sustained inhibition of insulin/IGF-1 signaling needed for cell survival, neuronal plasticity, and myelin maintenance.
Background. Neurodevelopmental abnormalities in fetal alcohol spectrum disorder (FASD) are associated with impaired insulin and IGF signaling, which is needed for neuronal growth, survival, and plasticity. We characterized effects of the L-165,041 PPAR-δ agonist insulin sensitizer on cerebellar structure and function in relation to insulin/IGF and neurotrophin signaling in an FASD model. Methods. On postnatal days (P) 2, 4, 6, and 8, rat pups were administered (i.p.) 2 g/kg of ethanol or saline; and on P5, P7, P9, and P11, they were treated with saline or L-165,041. Rotarod tests assessed motor function. Cerebella were studied biochemically. Results. Ethanol-impaired motor function and signaling through the insulin receptor and Akt were abrogated by PPAR-δ agonist treatments, whereas neurotrophin expression was unaffected. Conclusions: PPAR-δ agonists may help normalize cerebellar function in FASD by supporting insulin signaling through cell survival pathways, but additional approaches are needed to restore neurotrophin expression for neuronal plasticity.
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