According to a recent study by Scripps Research scientists, the anxiety that occurs during withdrawal from excessive alcohol consumption and contributes to relapse may be triggered in part by the release of an immune protein in the brain.
The study, published online in Molecular Psychiatry on June 6, 2022, sheds light on the molecular aspects of the brain’s reaction to alcohol withdrawal and implies that the immunological protein colony-stimulating factor 1 (CSF1) might be a target of future therapies for alcohol consumption 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 opportunities for therapeutic intervention,” says study senior author Marisa Roberto, PhD, professor of psychiatry at the University of Texas at Austin.
“Alcohol withdrawal triggers the stress system in the brain, which leads to relapse,” explains research senior author Marisa Roberto, PhD, professor and Schimmel Family Chair in Scripps Research’s Department of Molecular Medicine.
Reesha R. Patel, PhD, a former postdoctoral researcher in the Roberto lab, is the study’s first author and performed several of the tests.
Alcohol is by far the most popular and misused recreational substance. 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 an inability to control alcohol use despite its negative impact on the user’s health, social life, and/or employment. There are drug therapies, talk therapy, and support group-based treatments available, but recurrence is prevalent, owing to a lack of understanding of the brain-circuit dysfunctions driving AUD.
Scientists know that relapse-promoting alcohol withdrawal symptoms include increased anxiety, which is generated, at least in part, by the production of stress molecules such as corticotropin-releasing factor (CRF) inside the brain.
CRF activates receptors on neurons in the prefrontal cortex as well as those in the limbic system, a group of more basic brain areas that process emotions. If scientists were able to thoroughly identify and define these CRF-sensitive neuronal groups, they would be able to better understand how anxiety develops during withdrawal and maybe develop effective therapies to alleviate it.
In the latest work, Roberto and her colleagues found a group of neurons in the medial prefrontal cortex (mPFC) of mice that are responsive to CRF because they express a CRF receptor known as CRF1. The researchers discovered that these neurons influence mood and behaviour during alcohol intake and withdrawal.
The team’s preliminary research demonstrated that removing these CRF-sensitive neurons reduces anxiety in mice, indicating that the neurons regularly influence anxiety-like behaviours.
The researchers discovered that when alcohol-dependent mice suffer alcohol withdrawal, these CRF-sensitive mPFC neurons become less excitable (less likely to fire messages to other neurons when stimulated). Nearby mPFC neurons lacking CRF receptors, on the other hand, become more excitable.
“These CRF-sensitive mPFC neurons appear to represent a distinct neuronal population that experiences dramatic neuroadaptations with persistent alcohol exposure,” explains study co-author and postdoctoral research fellow Pauravi Gandhi, PhD.
Surprisingly, the researchers discovered that, while alcohol withdrawal reduced the excitability of CRF-sensitive neurons, it simultaneously increased CSF1 gene expression inside these neurons. CSF1 is an immunological protein best recognised for its involvement in promoting the maturation of stem cells into giant white blood cells known as macrophages. CSF1 is expected to play a similar role in the brain in the maintenance of brain-resident immune cells known as microglia. Furthermore, previous study in mice suggests that under chronic stress, CSF1 synthesis increases in the mPFC, causing microglia to prune connections between neurons, resulting in anxiety and depression symptoms.
To investigate CSF1’s role in alcohol withdrawal further, Roberto and colleagues artificially increased CSF1 production in CRF-sensitive mPFC neurons in mice, and found that the animals displayed many of the same neuronal and behavioural changes seen in alcohol withdrawal, implying that elevated CSF1 levels in mPFC may be a key driver of alcohol-withdrawal signs and symptoms.
“Targeting CSF1 may therefore be a suitable method for treating AUD,” Patel adds, “and we’re now keen to test that in our preclinical models.”
