Binge ethanol exposure during adolescence leads to a persistent loss of neurogenesis in the dorsal and ventral hippocampus that is associated with impaired adult cognitive functioning.

Ryan P Vetreno,Fulton T Crews

doi:10.3389/fnins.2015.00035

Ryan P Vetreno, Fulton T Crews

Open Access

https://doi.org/10.3389/fnins.2015.00035

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Abstract

Adolescence is a developmental period that coincides with the maturation of adult cognitive faculties. Binge drinking is common during adolescence and can impact brain maturation. Using a rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 20% EtOH w/v; 2 days on/2 days off from postnatal day [P]25 to P55), we discovered that AIE treatment reduced neurogenesis (i.e., doublecortin-immunoreactive [DCX + IR] cells) in both the dorsal and ventral hippocampal dentate gyrus of late adolescent (P56) male Wistar rats that persisted during abstinence into adulthood (P220). This reduction in neurogenesis was accompanied by a concomitant reduction in proliferating cells (Ki-67) and an increase in cell death (cleaved caspase-3). In the hippocampus, AIE treatment induced a long-term upregulation of neuroimmune genes, including Toll-like receptor 4 (TLR4) and its endogenous agonist high-mobility group box 1 as well as several proinflammatory signaling molecules. Administration of lipopolysaccharide, a gram-negative endotoxin agonist at TLR4, to young adult rats (P70) produced a similar reduction of DCX + IR cells that was observed in AIE-treated animals. Behaviorally, AIE treatment impaired object recognition on the novel object recognition task when assessed from P163 to P165. Interestingly, object recognition memory was positively correlated with DCX + IR in both the dorsal and ventral hippocampal dentate gyrus while latency to enter the center of the apparatus was negatively correlated with DCX + IR in the ventral dentate gyrus. Together, these data reveal that adolescent binge ethanol exposure persistently inhibits neurogenesis throughout the hippocampus, possibly through neuroimmune mechanisms, which might contribute to altered adult cognitive and emotive function.

Highlights

Adolescence is a conserved neurodevelopmental period in humans and other mammalian species characterized by a surge in cortical and limbic system plasticity that parallels increased social interactions and engagement in risky behaviors
Similar to the dorsal hippocampus, adolescent intermittent ethanol (AIE) treatment led to a 42% (±7%) decrease in DCX + IR in the adolescent (P56) ventral hippocampal dentate gyrus that persisted from young adulthood (P80 [46 ± 9%]) into adulthood (P220 [63 ± 7%]), relative to CONs [main effect of Treatment: F(1,39) = 25.3, p < 0.01; see Figure 2B]
These data reveal that adolescent binge ethanol exposure reduces DCX expression in the dorsal and ventral hippocampal dentate gyrus of the adolescent brain (P56) that follows the age-related decline in neurogenesis with AIE-induced deficits persisting into adulthood (P220), the age-associated decline in DCX + IR obscures the AIEinduced differences, within the dorsal hippocampal dentate gyrus, where it is largely diminished by 220 days of age

Summary

Introduction

Adolescence is a conserved neurodevelopmental period in humans and other mammalian species characterized by a surge in cortical and limbic system plasticity that parallels increased social interactions and engagement in risky behaviors (i.e., novelty- and sensation-seeking). Neurogenesis is restricted to the subgranular zone of the hippocampal dentate gyrus, which contains a mitotically active microenvironment that permits neurogenesis to occur throughout life (Abrous et al, 2005). It is a highly dynamic process modulated by many intrinsic and extrinsic factors, including neurotransmitters [e.g., acetylcholine (Cooper-Kuhn et al, 2004)], environmental enrichment (Cotman and Berchtold, 2002), pathological insults (Richardson et al, 2007), and drugs of abuse (He et al, 2005). Adolescent binge ethanol exposure has been shown to cause a persistent loss of neurogenesis in primates (Taffe et al, 2010) that in rats is unique to adolescence (Broadwater et al, 2014), the long-term consequences of alcohol exposure during adolescence on adult neurogenesis in the dorsal and ventral hippocampal dentate gyrus is unknown

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