It’s well known that alcohol has profound effects on brain function, and research shows that even low levels of the drug can damage your brain.
But how does alcohol actually cause brain damage at the cellular level?
In a surprising discovery reported in Immunityscientists have discovered that alcohol does not only interact with neurons.
New findings show that the drug also affects the brain’s immune cells called microglia, prompting them to dismantle the extracellular matrix that structurally supports brain cells.
“For years, the effects of alcohol on the brain have been largely observed through the prism of neurons, and for good reason: alcohol acts directly on neuronal receptors,” explains neuroscientist and lead author of the study Dimitrios Davalos of the Cleveland Clinic.
“By tracking microglia in real time, we were able to see that they don’t just respond to damage. They are behind the harmful changes caused by alcohol in the brain.”
Microglia are specialized immune cells that constantly monitor and maintain the brain by detecting threats, removing dead cells and damaged tissue, and eliminating neuronal connections.
To explore how microglial activity is affected by alcohol, the researchers studied a mouse model of heavy alcohol consumption, designed to mimic the effects of binge drinking and high-intensity drinking.
In experiments, mice were given an oral dose of ethanol or repeated doses over consecutive days, and researchers monitored the drug’s effects on microglia and neurons in live animals using two-photon microscopy and other imaging techniques.
The researchers found that microglia underwent significant changes in their shape and activity about an hour after alcohol administration, before the drug’s peak sedation.
The branches extending from their bodies decreased in number and length, and their surveillance territory shrank, with the effects becoming more pronounced after repeated exposure to alcohol.
Researchers also observed microglia damaging the extracellular matrix, a network of structural molecules that support brain cells and help enable stable communication between neurons.
In mice given alcohol, microglia began to engulf and digest components of the matrix, breaking it down and weakening the structure.
This leads to a loss of synaptic connections, researchers say, contributing to neuronal dysfunction and possibly some of the sedative effects of alcohol.
However, in a separate experiment using genetically modified mice, the researchers disabled a microglia protein called MyD88, which plays an important role in activating immune responses.
In animals that had their MyD88 silenced gene, alcohol exposure resulted in significantly less neuronal damage, reduced changes in microglial shape and activity, and less pronounced sedation.
In separate tests with these protected, genetically modified mice, the researchers degraded the animals’ extracellular matrix using an enzyme, which caused loss of synapses, motor disturbances and sedation when the animals were given alcohol.
According to the researchers, this shows that disruption of the extracellular matrix is a key causal process that directly produces some of the harmful effects of alcohol on the brain.
While the main findings were only shown in mouse experiments, a separate analysis of human brain tissue from six deceased people with alcohol use disorders showed evidence of extracellular matrix disruption compared to controls, suggesting that a similar type of microglial-based brain damage may occur in people who abuse alcohol.
This could make MyD88 a strong therapeutic target for future research, and perhaps beyond the effects of alcohol as well.
“We discovered a specific neuroimmune pathway activated by alcohol, but it is possible that other drugs also activate this pathway,” says Davalos.
“My lab is studying how to target microglia or protect the brain’s ECM to prevent or limit brain damage, from substance use and perhaps even other neurological diseases.”
The results are reported in Immunity.
This article was fact-checked by Fiona MacDonald and edited by Fiona MacDonald. Although we are proud of our process, we are only human. If you spot an error, please let us know.
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