Persistent Decreases in Adult Subventricular and Hippocampal Neurogenesis Following Adolescent Intermittent Ethanol Exposure.

Wen Liu,Fulton T Crews

doi:10.3389/fnbeh.2017.00151

Abstract

Neurogenesis in hippocampal dentate gyrus (DG) and subventricular zone (SVZ) matures during adolescence to adult levels. Binge drinking is prevalent in adolescent humans, and could alter brain neurogenesis and maturation in a manner that persists into adulthood. To determine the impact of adolescent binge drinking on adult neurogenesis, Wistar rats received adolescent intermittent ethanol (AIE) exposure (5.0 g/kg/day, i.g., 2 days on/2 days off from postnatal day, P25–P54) and sacrificed on P57 or P95. Neural progenitor cell proliferation, differentiation, survival and maturation using immunohistochemistry was determined in the DG and SVZ. We found that AIE exposure decreased neurogenesis in both brain regions in adulthood (P95). In the DG at P57, AIE exposure resulted in a significant reduction of SOX2+, Tbr2+, Prox1+ and parvalbumin (PV)+IR expression, and at P95 decreased DCX+ and PV+IR expression. AIE exposure also reduced the expression of two cell proliferation markers (Ki67+ and BrdU+IR with 300 mg/kg, 2 h) at P95. The immune signaling molecule β-2 microglobulin+ and the cell death marker activated caspase-3+IR were significantly increased in the DG by AIE exposure. In the SVZ, AIE exposure decreased SOX2+, Mash1+, DCX+ and Dlx2+IR expression at P95, but not at P57. Thus, in adulthood both brain regions have reduced neurogenesis following AIE exposure. To assess progenitor cell survival and maturation, rats were treated with BrdU (150 mg/kg/day, 14 days) to label proliferating cells and were sacrificed weeks later on P95. In the hippocampus DG, AIE exposure increased survival BrdU+ cells which differentiated into Iba1+ microglia. In contrast, SVZ had decreased BrdU+ cells similar to decreased DCX+ neurogenesis. These data indicate that AIE exposure causes a lasting decrease in both adult hippocampal DG and forebrain SVZ neurogenesis with brain regional differences in the AIE response that persist into adulthood.

Highlights

Adult neurogenesis involves the formation of new brain neurons that alter neurocircuits and contribute to neuroplasticity
In the dentate gyrus (DG), markers of neuroprogenitor cells (NPCs) that distinguish stages of neurogenesis, including sex determining regions Y-box 2 (SOX2) which is expressed in non-radial and horizontal type-1 cells, and T-box brain protein 2 (Tbr2), a T-box transcription factor expressed by type-2a and -2b intermediate NPCs that persist to maturation into neuroblasts
We report here that adolescent intermittent ethanol (AIE) causes a persistent loss of both subventricular zone (SVZ) and DG neurogenesis, and that the AIE-induced changes in markers of NPC stages and cell death suggest that the mechanisms of the AIE-induced loss of new neuron formation in DG and SVZ is different for each brain region

Summary

INTRODUCTION

Adult neurogenesis involves the formation of new brain neurons that alter neurocircuits and contribute to neuroplasticity. A binge model of alcohol dependence found reduced adult hippocampal DG neurogenesis following ethanol treatment (Nixon and Crews, 2004; Hansson et al, 2010). Acute adolescent binge ethanol exposure has been found to reduce both DG and SVZ neurogenesis (Crews et al, 2006), to our knowledge the impact of AIE on proliferation and maturation of NPC in SVZ neurogenesis has not been determined. We report here that AIE causes a persistent loss of both SVZ and DG neurogenesis, and that the AIE-induced changes in markers of NPC stages and cell death suggest that the mechanisms of the AIE-induced loss of new neuron formation in DG and SVZ is different for each brain region

MATERIALS AND METHODS

RESULTS

DISCUSSION