Alcoholism relapse may driven by release of immune protein in brain



ANI |
Updated:
08 June 2022 22:19 IST

Washington [US]June 8 (ANI): According to a new study from scientists at Scripps Research, the anxiety that occurs during quitting excessive alcohol consumption and that contributes to relapse may be caused in part by the release of an immune protein in the brain.
The discovery, reported online June 6, 2022, in Molecular Psychiatry, sheds light on the molecular details of the brain’s response to alcohol withdrawal, and suggests that the immune protein, colony-stimulating factor 1 (CSF1), could be a target of 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 linked this stress response to CSF1, a neuroimmune mediator, opening up new avenues for therapeutic intervention,” said senior author Marisa Roberto, PhD, professor and Schimmel Family Chair in the Department of Molecular Medicine at Scripps Research.
The lead author of the study, who conducted many of the experiments, is Reesha R. Patel, PhD, a former postdoctoral researcher in the Roberto lab.
Alcohol is by far the most commonly used and abused recreational drug. According to the 2019 National Survey on Drug Use and Health, nine million men and more than five million women in the United States have an alcohol use disorder (AUD), which is defined as the inability to control alcohol use despite its negative impact on the population. health, social life and/or work of the user. Drug treatments, talk therapy, and supportive group treatments are available, but relapse is common, primarily due to the limited understanding of the brain circuitry dysfunctions underlying AUD.
Scientists know that relapse-promoting alcohol withdrawal symptoms consist of increasing anxiety, which is at least in part caused by the release of stress molecules such as corticotropin-releasing factor (CRF) in the brain. CRF stimulates receptors on neurons in the prefrontal cortex and in the limbic system, a series of more primitive brain structures that process emotions. If scientists could fully identify and characterize these CRF-sensitive neuronal populations, they could better understand how anxiety occurs during withdrawal and potentially devise effective treatments to block it.

To that end, in the new study, Roberto and her team 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. The scientists showed that these neurons are involved in changing mood and behavior during alcohol exposure and withdrawal.
The team’s first experiments revealed that removing these CRF-sensitive neurons makes the mice less anxious, suggesting that the neurons mediate normal anxiety-like behavior.
The researchers then found that these CRF-sensitive mPFC neurons become less excitable — less likely to fire signals to other neurons when stimulated — in alcohol-dependent mice experiencing alcohol withdrawal. In contrast, nearby mPFC neurons without CRF receptors become more excitable.
“These CRF-sensitive mPFC neurons appear to form a unique neuronal population that undergo profound neuro-adaptations with chronic alcohol exposure,” said co-author Pauravi Gandhi, PhD, a postdoctoral research associate in the Roberto lab.
Intriguingly, the researchers found that alcohol withdrawal, even if it reduced the excitability of the CRF-sensitive neurons, also caused a large increase in CSF1 gene expression within these neurons. CSF1 is an immune protein best known for its role in stimulating stem cells to mature into large white blood cells called macrophages. In the brain, CSF1 is thought to play a similar role in supporting immune cells called microglia in the brain. In addition, previous research in mice has suggested that under conditions of chronic stress, CSF1 production in the mPFC increases, causing microglia to prune the connections between neurons, which in turn causes signs of anxiety and depression.
By looking more closely at the role of CSF1 in alcohol withdrawal, Roberto and colleagues artificially increased CSF1 production in CRF-sensitive mPFC neurons in mice, noting that the animals showed many of the same neuronal and behavioral changes seen in alcohol withdrawal — suggesting that elevated CSF1 levels in mPFC may be a major cause of signs and symptoms of alcohol withdrawal.
“Targeting CSF1 may therefore be a good strategy for the treatment of AUD, and we are now eager to test that in our preclinical models,” says Patel. (ANI)

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