The anxiety that occurs during withdrawal from excessive alcohol consumption and which contributes to relapse may be due in part to the release of an immune protein in the brain, according to a new study by scientists at Scripps Research. .
The discovery, reported online June 6, 2022, in Molecular Psychiatrysheds light on the molecular details of the brain’s response to alcohol withdrawal and suggests that the immune protein colony-stimulating factor 1 (CSF1) may be a target for future treatments for alcohol use disorder (AUD) .
“Alcohol withdrawal activates the stress system in the brain, which contributes to relapse, and in this study, we have linked this stress response to CSF1, a neuroimmune mediator, opening new opportunities for therapeutic intervention” , says the study’s lead author, Marisa Roberto, PhD. , Professor and Schimmel Family Chair in the Department of Molecular Medicine at Scripps Research.
The study’s first author, who performed numerous experiments, is Reesha R. Patel, PhD, a former postdoctoral researcher at the Roberto Lab.
Alcohol is by far the most abused and abused recreational drug. According to the 2019 National Drug Use and Health Survey, nine million men and more than five million women in the United States have alcohol use disorder (AUD), which is defines as an inability to control alcohol consumption despite its negative impact on the user’s health, social life and/or employment. Drug treatments, talk therapies, and support group-based treatments are available, but relapses are common, primarily due to limited understanding of the brain circuitry dysfunctions underlying AUD.
Relapse-promoting symptoms of alcohol withdrawal include increasing feelings of anxiety, caused at least in part by the release of stress molecules such as corticotropin-releasing factor (CRF) in the brain, scientists know. CRF stimulates receptors on neurons in the prefrontal cortex and the limbic system, a set of more primitive brain structures that process emotions. If scientists could fully identify and characterize these CRF-responsive neuronal populations, they could better understand how anxiety occurs during withdrawal and potentially design effective treatments to block it.
To that end, Roberto and his team, in the new study, identified a population of neurons in the medial prefrontal cortex (mPFC) of mice that are sensitive to CRF because they express a CRF receptor called CRF1. Scientists have shown that these neurons are involved in modifying mood and behavior during alcohol exposure and withdrawal.
The team’s early experiments revealed that suppressing these CRF-responsive neurons makes mice less anxious, suggesting that the neurons normally mediate anxious behaviors.
The researchers then found that these CRF-responsive mPFC neurons became less excitable — less likely to send signals to other neurons when stimulated — in alcohol-dependent mice in alcohol withdrawal. In contrast, nearby mPFC neurons lacking CRF receptors become more excitable.
“These CRF-responsive mPFC neurons appear to constitute a unique neuronal population that undergoes profound neuroadaptations with chronic alcohol exposure,” says study co-author Pauravi Gandhi, PhD, postdoctoral research associate in the Roberto lab.
Curiously, the researchers found that alcohol withdrawal, while reducing the excitability of CRF-sensitive neurons, also induced large increases in CSF1 gene expression in these neurons. CSF1 is an immune protein best known for its role in stimulating the maturation of stem cells into large white blood cells called macrophages. In the brain, CSF1 is thought to play a similar role in maintaining brain-resident immune cells called microglia. Additionally, previous research in mice has suggested that under conditions of chronic stress, CSF1 production increases in the mPFC, leading microglia to prune the connections between neurons, which in turn causes signs of anxiety. and depression.
Looking more closely at the role of CSF1 in alcohol withdrawal, Roberto and colleagues artificially increased CSF1 production in CRF-responsive mPFC neurons in mice, and observed that the animals exhibited many of the same neural changes and behavioral than those observed during alcohol withdrawal, suggesting that elevated CSF1 mPFC levels may be a key factor in the signs and symptoms of alcohol withdrawal.
“Targeting CSF1 can therefore be a good strategy for trading AUD, and we are now looking forward to testing this in our preclinical models,” says Patel.