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Binge Alcohol Exposure Causes Neurobehavioral Deficits and GSK3? Activation in the Hippocampus of Adolescent Rats.

ABSTRACT: Heavy alcohol exposure causes profound damage to the adolescent brain, particularly the hippocampus, which underlie some behavioral deficits. However, the underlying molecular mechanisms remain inconclusive. The current study sought to determine whether binge alcohol exposure affects the hippocampus-related behaviors and key signaling proteins that may mediate alcohol neurotoxicity in adolescent rats. Alcohol exposure reduced the number of both NeuN-positive and doublecortin-positive cells in the hippocampus. Alcohol also induced neurodegeneration which was confirmed by ultrastructural analysis by electronic microscopy and was accompanied with the activation of microglia. Binge alcohol exposure impaired spatial learning and memory which was evaluated by the Morris water maze. However, alcohol did not alter the spontaneous locomotor activity which was determined by the open field test. GSK3? is a multi-function serine/threonine protein kinase regulating both neuronal survival and neurogenesis and plays an important role in various neurodegenerative disorders. We have previously shown that GSK3? is a key mediator of alcohol-induced neuron apoptosis in the developing brain. We showed here binge alcohol exposure caused GSK3? activation by inducing dephosphorylation at Ser9 without affecting the phosphorylation of Tyr216 in the hippocampus. Thus, GSK3? may be involved in binge alcohol exposure-induced neuronal damage to the adolescent hippocampus.

SUBMITTER: Ji Z

PROVIDER: S-EPMC5814471 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Project description:Neurobehavioral consequences of heavy prenatal alcohol exposure are well documented; however, the role of age or sex in these effects has not been studied. The current study examined the effects of prenatal alcohol exposure, sex, and age on neurobehavioral functioning in children.Subjects were 407 youth with prenatal alcohol exposure (n = 192) and controls (n = 215). Two age groups (child [5 to 7 years] or adolescent [10 to 16 years]) and both sexes were included. All subjects completed standardized neuropsychological testing, and caregivers completed parent-report measures of psychopathology and adaptive behavior. Neuropsychological functioning, psychopathology, and adaptive behavior were analyzed with separate 2 (exposure history) × 2 (sex) × 2 (age) multivariate analyses of variance (MANOVAs). Significant effects were followed by univariate analyses.No 3-way or 2-way interactions were significant. The main effect of group was significant in all 3 MANOVAs, with the control group performing better than the alcohol-exposed group on all measures. The main effect of age was significant for neuropsychological performance and adaptive functioning across exposure groups with younger children performing better than older children on 3 measures (language, communication, socialization). Older children performed better than younger children on a different language measure. The main effect of sex was significant for neuropsychological performance and psychopathology; across exposure groups, males had stronger language and visual spatial scores and fewer somatic complaints than females.Prenatal alcohol exposure resulted in impaired neuropsychological and behavioral functioning. Although adolescents with prenatal alcohol exposure may perform more poorly than younger exposed children, the same was true for nonexposed children. Thus, these cross-sectional data indicate that the developmental trajectory for neuropsychological and behavioral performance is not altered by prenatal alcohol exposure, but rather, deficits are consistent across the 2 age groups tested. Similarly, observed sex differences on specific measures were consistent across the groups and do not support sexually dimorphic effects in these domains.

Project description:The objective of this study was to determine changes in gene expression within the extended amygdala following binge-like alcohol drinking by adolescent alcohol-preferring (P) rats. Starting at 28 days of age, P rats were given concurrent access to 15 and 30 % ethanol for 3 one-h sessions for 5 consecutive days each week until they were 49 days old. Rats were killed by decapitation 3 h after the first ethanol access session on the 15th day of drinking. RNA was prepared from micropunch samples of the nucleus accumbens shell (Acb-sh) and central nucleus of the amygdala (CeA). Ethanol intakes were 2.5 to 3.0 g/kg/session. There were 154 and 182 unique named genes that significantly differed (FDR = 0.2) between the water and ethanol group in the Acb-sh and CeA, respectively. Gene Ontology (GO) analyses indicated that adolescent binge drinking produced changes in the in biological processes involved in cell proliferation and regulation of cellular structure in the Acb-sh, and in neuron projection and positive regulation of cellular organization in the CeA. Ingenuity Pathway Analysis indicated that, in the Acb-sh, there were several major intracellular signaling pathways (e.g., cAMP-mediated and protein kinase A signaling pathways) altered by adolescent drinking, with 3-fold more genes up-regulated than down-regulated in the alcohol group. The cAMP-mediated signaling system was also up-regulated in the CeA of the alcohol group. Weighted gene co-expression network analysis (WGCNA) indicated significant G-protein coupled receptor signaling and transmembrane receptor protein kinase signaling categories in the Acb-sh and CeA, respectively. Overall, the results of this study indicated that binge-like alcohol drinking by adolescent P rats is differentially altering the expression of genes in the Acb-sh and CeA, some of which are involved in intracellular signaling pathways and may produce long-term changes in neuronal function. Differences in gene expression in the central nucleus of the amygdala (CeA) were compared in two groups of alcohol-preferring (P) rats, one given water only and the other given access to 15 & 30% ethanol during adolescence.

Project description:The objective of this study was to determine changes in gene expression within the extended amygdala following binge-like alcohol drinking by adolescent alcohol-preferring (P) rats. Starting at 28 days of age, P rats were given concurrent access to 15 and 30 % ethanol for 3 one-h sessions for 5 consecutive days each week until they were 49 days old. Rats were killed by decapitation 3 h after the first ethanol access session on the 15th day of drinking. RNA was prepared from micropunch samples of the nucleus accumbens shell (Acb-sh) and central nucleus of the amygdala (CeA). Ethanol intakes were 2.5 ‚Äì 3.0 g/kg/session. There were 154 and 182 unique named genes that significantly differed (FDR = 0.2) between the water and ethanol group in the Acb-sh and CeA, respectively. Gene Ontology (GO) analyses indicated that adolescent binge drinking produced changes in the in biological processes involved in cell proliferation and regulation of cellular structure in the Acb-sh, and in neuron projection and positive regulation of cellular organization in the CeA. Ingenuity Pathway Analysis indicated that, in the Acb-sh, there were several major intracellular signaling pathways (e.g., cAMP-mediated and protein kinase A signaling pathways) altered by adolescent drinking, with 3-fold more genes up-regulated than down-regulated in the alcohol group. The cAMP-mediated signaling system was also up-regulated in the CeA of the alcohol group. Weighted gene co-expression network analysis (WGCNA) indicated significant G-protein coupled receptor signaling and transmembrane receptor protein kinase signaling categories in the Acb-sh and CeA, respectively. Overall, the results of this study indicated that binge-like alcohol drinking by adolescent P rats is differentially altering the expression of genes in the Acb-sh and CeA, some of which are involved in intracellular signaling pathways and may produce long-term changes in neuronal function. Differences in gene expression in brain nucleus accumbens shell (Acb-sh) were compared in two groups of alcohol-preferring (P) rats, one given water only and the other given access to 15 & 30% ethanol during adolescence.

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Binge Alcohol Exposure Causes Neurobehavioral Deficits and GSK3? Activation in the Hippocampus of Adolescent Rats.

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