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Published on: August 4, 2022
Microglia Control Escalation of Drinking in Alcohol-Dependent Mice: Genomic and Synaptic Drivers
Anna S Warden1, Sarah A Wolfe2, Sophia Khom2
1Waggoner Center for Alcoholism and Addiction Research, University of Texas at Austin, Austin, Texas; Institute for Neuroscience, University of Texas at Austin, Austin, Texas.
Background:
Microglia, the primary immune cells of the brain, are implicated in alcohol use disorder. However, it is not known if microglial activation contributes to the transition from alcohol use to alcohol use disorder or is a consequence of alcohol intake.
Methods:
We investigated the role of microglia in a mouse model of alcohol dependence using a colony stimulating factor 1 receptor inhibitor (PLX5622) to deplete microglia and a chronic intermittent ethanol vapor two-bottle choice drinking procedure. Additionally, we examined anxiety-like behavior during withdrawal. We then analyzed synaptic neuroadaptations in the central nucleus of the amygdala (CeA) and gene expression changes in the medial prefrontal cortex and CeA from the same animals used for behavioral studies.
Results:
PLX5622 prevented escalations in voluntary alcohol intake and decreased anxiety-like behavior associated with alcohol dependence. PLX5622 also reversed expression changes in inflammatory-related genes and glutamatergic and GABAergic (gamma-aminobutyric acidergic) genes in the medial prefrontal cortex and CeA. At the cellular level in these animals, microglia depletion reduced inhibitory GABAA and excitatory glutamate receptor-mediated synaptic transmission in the CeA, supporting the hypothesis that microglia regulate dependence-induced changes in neuronal function.
Conclusions:
Our multifaceted approach is the first to link microglia to the molecular, cellular, and behavioral changes associated with the development of alcohol dependence, suggesting that microglia may also be critical for the development and progression of alcohol use disorder.
Insights
Depleting brain immune cells called microglia prevented increased alcohol intake and anxiety in mice. This suggests microglia play a key role in alcohol dependence development and progression.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Microglia, the brain's immune cells, are linked to alcohol use disorder (AUD).
- It remains unclear whether microglial activation drives AUD development or results from alcohol consumption.
Purpose of the Study:
- To investigate the role of microglia in the development of alcohol dependence.
- To determine if targeting microglia can alter alcohol intake and related behaviors.
Main Methods:
- Utilized a colony stimulating factor 1 receptor inhibitor (PLX5622) to deplete microglia in a mouse model.
- Employed a chronic intermittent ethanol vapor two-bottle choice procedure to induce alcohol dependence.
- Assessed anxiety-like behavior during withdrawal and analyzed synaptic neuroadaptations and gene expression in key brain regions (CeA, mPFC).
Main Results:
- Microglia depletion with PLX5622 prevented escalation of voluntary alcohol intake and reduced anxiety-like behaviors during withdrawal.
- Reversed expression of inflammatory, glutamatergic, and GABAergic genes in the medial prefrontal cortex and central nucleus of the amygdala (CeA).
- Reduced inhibitory GABAA and excitatory glutamate receptor-mediated synaptic transmission in the CeA.
Conclusions:
- This study provides the first evidence linking microglia to molecular, cellular, and behavioral changes in alcohol dependence.
- Microglia are critical regulators of synaptic plasticity and neuronal function in the context of alcohol dependence.
- Targeting microglia may represent a novel therapeutic strategy for alcohol use disorder.
