Microglia depletion and alcohol: Transcriptome and behavioral profiles

Abstract

Alcohol abuse induces changes in microglia morphology and immune function, but whether microglia initiate or simply amplify the harmful effects of alcohol exposure is still a matter of debate. Here, we determine microglia function in acute and voluntary drinking behaviors using a colony‐stimulating factor 1 receptor inhibitor (PLX5622). We show that microglia depletion does not alter the sedative or hypnotic effects of acute intoxication. Microglia depletion also does not change the escalation or maintenance of chronic voluntary alcohol consumption. Transcriptomic analysis revealed that although many immune genes have been implicated in alcohol abuse, downregulation of microglia genes does not necessitate changes in alcohol intake. Instead, microglia depletion and chronic alcohol result in compensatory upregulation of alcohol‐responsive, reactive astrocyte genes, indicating astrocytes may play a role in regulation of these alcohol behaviors. Taken together, our behavioral and transcriptional data indicate that microglia are not the primary effector cell responsible for regulation of acute and voluntary alcohol behaviors. Because microglia depletion did not regulate acute or voluntary alcohol behaviors, we hypothesized that these doses were insufficient to activate microglia and recruit them to an effector phenotype. Therefore, we used a model of repeated immune activation using polyinosinic:polycytidylic acid (poly(I:C)) to activate microglia. Microglia depletion blocked poly(I:C)‐induced escalations in alcohol intake, indicating microglia regulate drinking behaviors with sufficient immune activation. By testing the functional role of microglia in alcohol behaviors, we provide insight into when microglia are causal and when they are consequential for the transition from alcohol use to dependence.

Increased Toll‐like Receptor‐MyD88‐NFκB‐Proinflammatory neuroimmune signaling in the orbitofrontal cortex of humans with alcohol use disorder

“…However, in a recent study, media transfer from ethanol-treated organotypic hippocampal slice cultures (OHSCs) containing microglial microvesicles to naïve OHSCs induced TNFA and other proinflammatory cytokines that was blunted in microglialdepleted ethanol-treated media consistent with microglial vesicular signaling contributing to some aspects of alcohol-induced neuroimmune activation (Crews et al, 2021). Further, while microglia depletion prevents escalations voluntary alcohol intake and concomitant anxiety-like behavior in alcohol dependent mice, it does not affect voluntary ethanol intake in nondependent mice supporting a role for microglia in alcohol dependence (Warden et al, 2021;Warden et al, 2020). The observation that numerous proinflammatory neuroimmune genes are unaltered following microglial depletion in vivo suggests that astrocytes and neurons express higher levels of neuroimmune mediators than previously known.…”

Neural Perturbations Associated With Recurrent Binge Alcohol in Male and Female Rats

“…Indeed, the increased microglia in the present study were observed in the absence of reactive astrogliosis, upholding the idea that microglial activation in the binge‐exposed brain is neuroprotective (Melbourne et al, 2019). The progressive increase with ongoing binge exposure is especially interesting in light of recent evidence that microglia may be causal in the escalation of drinking behavior (Warden et al, 2020), potentially contributing to the link between binge drinking and future AUD (Gowin et al, 2017).…”

Microglia Dystrophy Following Binge-Like Alcohol Exposure in Adolescent and Adult Male Rats

“…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, however, has been less clear (Walter and Crews, 2017 ; Warden et al, 2020 ).…”