Protein linked to alcoholism relapse offers novel target for treatment

Studies have shown that withdrawal symptoms from alcohol include mounting anxiety, in part due to the release of stress molecules in the brain. One of these, known as corticotropin-releasing factor (CRF), is known to stimulate receptors on neurons in the prefrontal cortex along with the limbic system, brain structures that help process emotions.

Understanding which of these neurons are susceptible to CRF could therefore offer new ways to tackle this form of anxiety, and this is where the Scripps Research team has found some success. Through experiments on mice, the scientists identified a population of neurons in the medial pre-frontal cortex (mPFC) that expressed a receptor, dubbed CRF1, which makes them sensitive to CRF.

The experiments showed that these neurons played a role in shaping mood and behavior during alcohol exposure and withdrawal, and that deleting the CRF-sensitive neurons made the mice less anxious. Follow-up experiments showed these neurons were less excitable and less likely to send signals to other neurons during withdrawal among alcohol-dependent mice. Conversely, nearby neurons lacking the CRF receptors became more excitable.

Digging deeper into the mechanics at play, the scientists found that as alcohol withdrawal dampened the excitability of the CRF-sensitive neurons, it drove up gene expression associated with an immune protein called CSF1. Studies have shown that levels of CSF1 increase in mPFC neurons under conditions of chronic stress, and that it assists in disrupting connections between neurons, resulting in anxiety and depression.

“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,” said study senior author Marisa Roberto.