According to a new study by scientists from Scripps Research, anxiety that occurs during withdrawal from excessive alcohol consumption and contributes to relapse may be motivated in part by the release of an immune protein in the brain.
The finding, 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 immune protein, the colony-stimulating factor 1 (CSF1), could 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 linked this stress response to CSF1, a neuroimmune mediator, opening up new opportunities for therapeutic intervention.
Marisa Roberto, PhD, author and senior professor of the study and president of the Schimmel family, Department of Molecular Medicine, Scripps Research
The first author of the study, who conducted many of the experiments, is Reesha R. Patel, PhD, a former postdoctoral researcher at Roberto’s Laboratory.
Alcohol is by far the most widely used and abused recreational drug. According to the 2019 National Drug and Health Survey, nine million men and more than five million women in the United States have an alcohol disorder (AUD), which is defined as an inability to control alcohol consumption despite its negative impact on the health, social and / or working life of the user. There are drug treatments, conversation therapy, and support group-based treatments, but relapse is common, mainly due to the limited understanding of the brain circuit dysfunctions underlying AUD.
Scientists know that the symptoms of alcohol withdrawal that promote relapse include an increase in feelings of anxiety, caused at least in part by the release of stress molecules such as corticotropin-releasing factor (CRF) within the body. brain. CRF stimulates receptors on prefrontal cortex and limbic system neurons, a set 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 abstinence and potentially devise effective treatments to block it.
To this 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 altered mood and behavior during alcohol exposure and withdrawal.
Initial team experiments revealed that suppression of these CRF-sensitive neurons makes mice less anxious, suggesting that neurons typically mediate anxiety-like behaviors.
Subsequently, the researchers found that these CRF-sensitive mPFC neurons become less excitable; less likely to trigger signals to other neurons when stimulated; in alcohol-dependent mice experiencing alcohol abstinence. In contrast, nearby mPFC neurons that lack CRF receptors become more excitable.
“These CRF-sensitive mPFC neurons appear to constitute a single neuronal population that undergoes profound neuroadaptations with chronic alcohol exposure,” says study co-author Pauravi Gandhi, PhD, a postdoctoral research associate at Roberto Laboratory.
Interestingly, the researchers found that alcohol withdrawal, while reducing the excitability of CRF-sensitive neurons, also induced large increases 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 maintaining brain-resident immune cells called microglia. In addition, previous research in mice has suggested that under conditions of chronic stress, CSF1 production increases in mPFC, driving microglia to prune connections between neurons, which in turn causes signs of anxiety and depression.
Looking more closely at the role of CSF1 in alcohol abstinence, Roberto and colleagues artificially increased the production of CSF1 in CRF-sensitive mPFC neurons in mice and observed that the animals exhibited many of the same neuronal changes. and behavioral observed in alcohol withdrawal, suggesting that CSF1 increased. MPFC levels can be a key factor in the signs and symptoms of alcohol withdrawal.
“Therefore, targeting CSF1 may be a good strategy for treating AUD, and we are now looking forward to testing it in our preclinical models,” says Patel.
Reesha Patel, Sarah Wolfe, Vittoria Borgonetti, Pauravi Gandhi, Larry Rodriguez, Angela Snyder, Shannon D co-wrote anxiety and the conditioned rewarding effects of ethanol. ” Ambrosio, Michal Bajo, Alain Domissy, Steven Head, Candice Contet, R. Dayne Mayfield, Amanda Roberts and Marisa Roberto.
Source:
Scripps Research Institute
Magazine reference:
Patel, RR, et al. (2022) Ethanol withdrawal-induced adaptations to neurons expressing prefrontal corticotropin-releasing factor 1 receptor regulate anxiety and the conditioned rewarding effects of ethanol. Molecular Psychiatry. doi.org/10.1038/s41380-022-01642-3