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

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.

Subventricular zone neural precursor cell responses after traumatic brain injury and binge alcohol in male rats

“…We found that binge alcohol alone elicited a bilateral proliferative response in the SVZ, as alcohol only treated animals exhibited up to a fourfold increase in BrdU + cells at 24 hr compared to controls, similar to the magnitude observed after TBI alone. This is in contrast with previous studies using different alcohol intoxication models in rodents which reported that alcohol caused significant depression in SVZ and subgranular zone (SGZ) proliferation as examined at various time points (5 hr up to 41 days) post alcohol exposure (Anderson, Nokia, Govindaraju, & Shors, ; Liu & Crews, ; Nixon & Crews, ). However, one report found that discontinuing chronic alcohol administration led to an increase in SGZ cell number at day 2 and 7 after cessation (Anderson et al, ).…”

Hippocampal TNF-death receptors, caspase cell death cascades, and IL-8 in alcohol use disorder

“…Humans with AUD suffer from global subtle neurodegeneration and reduced hippocampal volumes associated with deficits in cognition and increased negative affect [4,5]. Preclinical studies in rats find alcohol exposure decrease hippocampal dentate gyrus (DG) neurogenesis [6] and increase markers of DG-induced neuronal death including: classic H&E, TUNEL, silver stain, Fluoro Jade B staining, and electron microscopyidentified necrotic morphology as well as immunohistochemistry (IHC) for active (cleaved) caspase-3+IR (CC3+IR) [7][8][9][10]. Alcohol exposure also increases brain neuroimmune gene expression, which mimics that found in postmortem human AUD brain and is hypothesized to contribute to alcohol-induced neurodegeneration [3,11] and the development of AUD [12][13][14].…”

Oxytocin and vasopressin modulation of social anxiety following adolescent intermittent ethanol exposure

“…during adolescence producing average peak blood ethanol concentrations (BECs) in the range of 130–200 mg/dL (see Kim et al, in press), similar to those estimated for binge drinking in early adolescents (Donovan, 2009). Adolescent exposure to ethanol in this range in rats has been shown to induce long-lasting behavioral and neural alterations that are not evident in controls receiving water i.g (Broadwater & Spear, 2014; Liu & Crews, 2017; Vetreno et al, 2017; Risher et al, 2015a,b; Swartzwelder et al, 2017). For instance, we have shown long-lasting and sex-dependent detrimental consequences of repeated intermittent i.g.…”