Abstract
Microglia are dynamic cells that have roles in neuronal plasticity as well as in recovery responses following neuronal injury. Although many hypothesize that hyperactivation of microglia contributes to alcohol-induced neuropathology, in other neurodegenerative conditions disruption of normal microglial processes also contributes to neuronal loss, particularly as microglia become dystrophic or dysfunctional. Based on the observation of a striking, abnormal morphology in microglia during binge-like ethanol exposure, the present study investigated the impact of excessive ethanol exposure on microglia number and dystrophic morphology in a model of alcohol dependence that includes neurodegeneration in both adult and adolescent rats. Following 2- and 4-day binge ethanol exposure, the number of microglia was decreased in the hippocampus and the perirhinal and entorhinal cortices of both adult and adolescent rats. Furthermore, a significant number of microglia with a dystrophic morphology were observed in ethanol-exposed tissue, accompanied by a significant decrease in brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Together these findings suggest another means by which microglia may contribute to alcohol-induced neurodegeneration, specifically dystrophic microglia and/or loss of microglia may disrupt homeostatic and recovery mechanisms. These results demonstrate that microglia also degenerate with excessive alcohol exposure, which has important implications for understanding the role of microglia—and specifically their contributions to plasticity and neuronal survival—in neurodegenerative disease.
Highlights
Excessive alcohol intake, a hallmark of alcohol use disorders (AUDs), produces neurodegeneration which may result in significant cognitive and behavioral impairments that contribute to the downward spiral from social alcohol drinking to addiction (Crews and Nixon, 2009)
We report that excessive alcohol exposure results in dystrophic microglia in the hippocampus, an effect that was coupled with a loss of Iba1+ cells in the hippocampus as well as the peri-entorhinal cortex of adolescent and adult rats
This reduction in Iba1+ cells combined with the observation of a dystrophic morphology with two independent markers of microglia (Figure 3) supports that a loss of microglia occurs with binge-like alcohol exposure, which aligns with previous work in various models (Marshall et al, 2016; Barton et al, 2017; Grifasi et al, 2019; Hu et al, 2020)
Summary
A hallmark of alcohol use disorders (AUDs), produces neurodegeneration which may result in significant cognitive and behavioral impairments that contribute to the downward spiral from social alcohol drinking to addiction (Crews and Nixon, 2009). The contribution of the neuroimmune system has been inferred from gene expression studies in human tissues and increased expression of microglial markers and chemokines in the brains of post-mortem alcoholics (e.g., Liu et al, 2004; He and Crews, 2008; Crews et al, 2013) In both adolescent and adult animal models of AUDs, microglia are activated by excessive ethanol consumption (McClain et al, 2011; Crews et al, 2013; Marshall et al, 2013; Peng et al, 2017; for review see Crews et al, 2016; Melbourne et al, 2019) and manipulating neuroimmune signaling drives alcohol consumption in some models (Agrawal et al, 2011; Blednov et al, 2011). The specific role of microglia, has been less clear (Walter and Crews, 2017; Warden et al, 2020)
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