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Persistent Adult Neuroimmune Activation and Loss of Hippocampal Neurogenesis Following Adolescent Ethanol Exposure: Blockade by Exercise and the Anti-inflammatory Drug Indomethacin.

ABSTRACT: Alcohol abuse and binge drinking are common during adolescence, a developmental period characterized by heightened neuroplasticity. Animal studies reveal that adolescent ethanol exposure decreases hippocampal neurogenesis that persists into adulthood, but the mechanism remains to be fully elucidated. Using a rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-days on/2-days off from postnatal day [P]25 to P55), we tested the hypothesis that AIE-induced upregulation of neuroimmune signaling contributes to the loss of hippocampal neurogenesis in adulthood. We found that AIE caused upregulation of multiple proinflammatory Toll-like receptors (TLRs), increased expression of phosphorylated NF-?B p65 (pNF-?B p65) and the cell death marker cleaved caspase 3, and reduced markers of neurogenesis in the adult (P80) hippocampus, which is consistent with persistently increased neuroimmune signaling reducing neurogenesis. We observed a similar increase of pNF-?B p65-immunoreactive cells in the post-mortem human alcoholic hippocampus, an effect that was negatively correlated with age of drinking onset. Voluntary wheel running from P24 to P80 prevented the AIE-induced loss of neurogenesis markers (i.e., nestin and doublecortin) in the adult hippocampus that was paralleled by blockade of increased expression of the cell death marker cleaved caspase 3. Wheel running also prevented the AIE-induced increase of hippocampal pNF-?B p65 and induction of neuroimmune NF-?B target genes, including TNF? and I?B? in the adult brain. Administration of the anti-inflammatory drug indomethacin during AIE prevented the loss of neurogenesis markers (i.e., nestin and doublecortin) and the concomitant increase of cleaved caspase 3, an effect that was accompanied by blockade of the increase of pNF-?B p65. Similarly, administration of the proinflammatory TLR4 activator lipopolysaccharide resulted in a loss of doublecortin that was paralleled by increased expression of cleaved caspase 3 and pNF-?B p65 in the hippocampal dentate gyrus of CON animals that mimicked the AIE-induced loss of neurogenesis. Taken together, these data suggest that exercise and anti-inflammatory drugs protect against adolescent binge ethanol-induced brain neuroimmune signaling and the loss of neurogenesis in the adult hippocampus.

SUBMITTER: Vetreno RP

PROVIDER: S-EPMC5882830 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Persistent Adult Neuroimmune Activation and Loss of Hippocampal Neurogenesis Following Adolescent Ethanol Exposure: Blockade by Exercise and the Anti-inflammatory Drug Indomethacin.

Vetreno Ryan P RP Lawrimore Colleen J CJ Rowsey Pamela J PJ Crews Fulton T FT

Frontiers in neuroscience 20180328

Alcohol abuse and binge drinking are common during adolescence, a developmental period characterized by heightened neuroplasticity. Animal studies reveal that adolescent ethanol exposure decreases hippocampal neurogenesis that persists into adulthood, but the mechanism remains to be fully elucidated. Using a rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-days on/2-days off from postnatal day [P]25 to P55), we tested the hypothesis that AIE-induced upregulation of neuroim ...[more]

PMID: 29643762

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Project description:BackgroundBinge ethanol exposure during adolescence reduces hippocampal neurogenesis, a reduction which persists throughout adulthood despite abstinence. This loss of neurogenesis, indicated by reduced doublecortin+ immunoreactivity (DCX+IR), is paralleled by an increase in hippocampal proinflammatory signaling cascades. As galantamine, a cholinesterase inhibitor, has anti-inflammatory actions, we tested the hypothesis that galantamine would prevent (study 1) or restore (study 2) AIE induction of proinflammatory signals within the hippocampus as well as AIE-induced loss of hippocampal neurogenesis.MethodsGalantamine (4 mg/kg) or vehicle (saline) was administered to Wistar rats during adolescent intermittent ethanol (AIE; 5.0 g/kg ethanol, 2 days on/2 days off, postnatal day [P] 25-54) (study 1, prevention) or after AIE during abstinent maturation to adulthood (study 2, restoration).ResultsResults indicate AIE reduced DCX+IR and induced cleaved caspase3 (Casp3) in DCX-expressing immature neurons. Excitingly, AIE induction of activated Casp3 in DCX-expressing neurons is both prevented and reversed by galantamine treatment, which also resulted in prevention and restoration of neurogenesis (DCX+IR). Similarly, galantamine prevented and/or reversed AIE induction of proinflammatory markers, including the chemokine (C-C motif) ligand 2 (CCL2), cyclooxygenase-2 (COX-2), and high mobility group box 1 (HMGB1) protein, suggesting that AIE induction of proinflammatory signaling mediates both cell death cascades and hippocampal neurogenesis. Interestingly, galantamine treatment increased Ki67+IR generally as well as increased pan-Trk expression specifically in AIE-treated rats but failed to reverse AIE induction of NADPH-oxidase (gp91phox).ConclusionsCollectively, our studies suggest that (1) loss of neurogenesis after AIE is mediated by persistent induction of proinflammatory cascades which drive activation of cell death machinery in immature neurons, and (2) galantamine can prevent and restore AIE disruptions in the hippocampal environmental milieu to then prevent and restore AIE-mediated loss of neurogenesis.

Project description:BackgroundAdolescent intermittent ethanol (AIE) exposure causes long-term changes in the brain and behavior of adult male rodents, including persistent induction of innate immune pathways, reductions in hippocampal neurogenic and forebrain cholinergic neuronal markers, and reversal learning deficits. The current study tests the hypothesis that proinflammatory induction mediates AIE-induced (1) loss of adult neurogenesis (i.e., doublecortin (DCX) expressing immature neurons), (2) reductions in forebrain and hippocampal cholinergic markers, and (3) reversal learning deficits.MethodsMale and female rats underwent AIE (5.0 g/kg/day ethanol or water, i.g., 2 day-on/2 day-off from postnatal day (PND) 25-54), followed by a 2-week regimen of the anti-inflammatory compound indomethacin (4.0 g/kg/day, PND 56-69) or vehicle, after which one cohort was euthanized for immunohistochemical markers (PND 70) and the second underwent the Morris water maze to assess reversal learning.ResultsAIE reduced adult (PND 70) DCX+ immunoreactivity (IR) and increased hippocampal expression of the innate immune signal's high-mobility group box protein 1 (HMGB1 + IR) and cyclooxygenase-2 (COX-2 + IR) in adult male and female rats. AIE also reduced choline acetyltransferase (ChAT+IR) in the basal forebrain and co-labeling of hippocampal vesicular acetylcholine transporter (VAChT+) cholinergic terminals on DCX + IR neurons. Indomethacin treatment after AIE restored molecular endpoints to control levels and rescued AIE-induced reversal learning deficits in the Morris water maze in both sexes. Of note, indomethacin produced several adverse effects selectively in control conditions, highlighting the uniquely beneficial effect of indomethacin in AIE rats.ConclusionsThese data suggest that in males and females, (1) AIE persistent neuroimmune induction mediates both the loss of adult hippocampal DCX and loss of basal forebrain cholinergic neurons and their innervation to hippocampal targets, and (2) anti-inflammatory indomethacin treatment following AIE that restores these persistent molecular pathologies also restores spatial reversal learning deficits.

Dataset Information

Persistent Adult Neuroimmune Activation and Loss of Hippocampal Neurogenesis Following Adolescent Ethanol Exposure: Blockade by Exercise and the Anti-inflammatory Drug Indomethacin.

Publications

Persistent Adult Neuroimmune Activation and Loss of Hippocampal Neurogenesis Following Adolescent Ethanol Exposure: Blockade by Exercise and the Anti-inflammatory Drug Indomethacin.

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