Abstract
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.
Highlights
Alcohol misuse during pregnancy causes significant neurodevelopmental abnormalities including microcephaly, cerebellar hypoplasia, motor deficits, and neuro-cognitive impairments ranging from attention deficit hyperactivity disorder to mental retardation
Binge 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 insulin-like growth factor (IGF) signaling, including impaired receptor binding, reduced Akt, and increased glycogen synthase kinase 3β (GSK-3β) activation
fetal alcohol spectrum disorder (FASD)-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
Summary
Alcohol misuse during pregnancy causes significant neurodevelopmental abnormalities including microcephaly, cerebellar hypoplasia, motor deficits, and neuro-cognitive impairments ranging from attention deficit hyperactivity disorder to mental retardation. This pathology, combined with various stereotypical craniofacial defects is termed, ‘fetal alcohol spectrum disorders’ (FASD) [1,2]. Previous studies showed that perinatal neurodevelopmental defects in FASD are associated with inhibition of brain insulin and insulin-like growth factor (IGF) signaling It is not known whether sustained abnormalities in adolescent brain structure and function are mediated by the same phenomena. Aims—Using 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
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