Alcohol relapse is linked to immune protein?
Scientists at the Scripps Research Institute have found that the immune protein CSF1 may cause anxiety during alcohol withdrawal. Some nuclei have the corticotropin-releasing factor receptor 1 crhr1 gene, and the glutamate transporter slc17a7 gene, but the glutamate decarboxylase gene gad2 does not, suggesting that they mainly constitute an excitatory population in the medial prefrontal cortex. Alcohol withdrawal leads to an increase in CSF1 in these neurons, mimics synaptic changes in glutamate transmission after alcohol withdrawal, and results in increased anxiety.
A new study by scientists at Scripps Research shows that the anxiety that develops during abstinence from excessive drinking can lead to relapse, and that anxiety may be caused in part by the release of immune proteins in the brain.
The findings, published online recently in Molecular Psychiatry, shed light on the molecular details of the brain's response to alcohol addicts and suggest that the immune protein, population-stimulating factor 1 (CSF1), may be a target for future treatment of alcohol use disorders (AUD).
'Abstinence from alcohol activates the stress system in the brain, which leads to recurrence, and in this study, we linked this stress response to CSF1 (a neuroimmune mediator), providing new opportunities for therapeutic intervention,' said senior author Marissa Roberto, PhD, professor in the Department of Molecular Medicine at the Scripps Research Center and chairman of the Schimmel family.
Dr. Reesha R. Patel, first author of the study, performed many experiments.
So far, alcohol is the most used and abused recreational drug. According to the 2019 National Survey on Drug Use and Health, 9 million men and more than 5 million women in the United States have an alcohol use disorder (AUD), defined as uncontrolled alcohol use despite its negative impact on users' health, social life, and/or employment. Pharmacotherapy, talk therapy, and support group-based therapy are feasible, but relapse is common, mainly due to limited knowledge of brain circuit dysfunction behind AUD.
Scientists know that promoting the relapse of alcohol withdrawal symptoms, including a rise in anxiety, is caused at least in part by the release of stress molecules in the brain, such as corticotropin-releasing factor (CRF). CRF stimulates receptors on neurons in the prefrontal cortex and the limbic system, a group of more primitive brain structures that process emotions. If scientists can fully identify and characterize these CRF-sensitive neuronal populations, they can better understand how anxiety occurs during withdrawal and potentially design effective treatments to stop it.
To that end, in the new study, Roberto and her team identified a population of CRF-sensitive neurons in the medial prefrontal cortex (mPFC) of mice because they express a CRF called CRF1 receptor. The scientists showed that these neurons are involved in changes in mood and behavior during alcohol exposure and withdrawal.
The team's initial experiments showed that deleting these CRF-sensitive neurons made the mice less anxious, suggesting that the neurons normally regulate anxiety-like behaviors.
The researchers then found that these CRF-sensitive mPFC neurons became less excitable, less likely to signal to other neurons when stimulated, and in alcohol-dependent mice, these mice experienced alcohol withdrawal. In contrast, mPFC neurons lacking CRF receptors become more excitable.
'These CRF-sensitive mPFC neurons appear to constitute a distinct neuronal population that has undergone profound neural adaptations under prolonged alcohol exposure,' said study co-author Dr. Pauravi Gandhi, a postdoctoral researcher in Roberto's lab.
Interestingly, the researchers found that even when alcohol abstinence reduced the excitability of CRF-sensitive neurons, it led to a large increase in CSF1 gene expression in these neurons. CSF1 is an immune protein best known for stimulating stem cells to mature into large white blood cells called macrophages. In the brain, CSF1 is thought to have a similar role in maintaining brain-resident immune cells called microglia. In addition, previous studies in mice have shown that under chronic stress conditions, increased production of CSF1 in the mPFC drives microglia to prune connections between neurons, which in turn leads to signs of anxiety and depression.
After further investigating the role of CSF1 in alcohol withdrawal, Roberto and colleagues artificially increased CSF1 production in CRF-sensitive mPFC neurons in mice, and observed that these animals exhibited many of the same effects seen in alcohol withdrawal of neuronal and behavioral changes, suggesting that elevated levels of CSF1 in the mPFC may be a key driver of alcohol withdrawal symptoms and signs.
'Targeting CSF1 may therefore be a good strategy for the treatment of AUD, and we are now eager to test this in our preclinical models,' Patel said.
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