According to a new research, anxiety incurred during withdrawal from excessive alcohol use and contributes to relapse may be triggered in part by the release of an immune protein in the brain.
The discovery, published online June 6, 2022, in Molecular Psychiatry, reveals the molecular properties of the brains'' response to alcohol withdrawal, and suggests that the immune protein, colony stimulating factor 1 (CSF1), might be a target of future therapy for alcohol use disorder (AUD).
According to the study, alcohol withdrawal activates the brain''s stress system, which causes relapse, and this stress response was linked to CSF1, a neuroimmune mediator, bringing up new possibilities for therapeutic therapy, according to a senior author. Marisa Roberto, PhD, and the Schimmel Family Chair at Scripps Research.
Reesha R. Patel, a former postdoctoral researcher in the Roberto lab, is the first author of the study.
According to the 2019 National Drug Use and Health Survey, nine million people 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 their health, social life, and/or employment. Drug therapy, talk-therapy, and therapy groups are also available, but relapse is common because to the limited understanding of the brain-circuit disorders.
The rise in anxiety is caused at least partly by the release of stress molecules such as the corticotropin-releasing factor (CRF) within the brain. CRF stimulates receptors in the prefrontal cortex, and in the limbic system, a set of more primitive brain structures that process emotions. If scientists could fully identify and characterize these CRF-sensitive neuronal populations, they might develop effective therapies to prevent it.
Roberto and her team, in a new study, identified a group of neurons in the medial prefrontal cortex (mPFC) of mice that are sensitive to CRF because they form a CRF receptor called CRF1. These neurons are involved in altering mood and behavior during alcohol exposure and withdrawal.
Initial experiments with teams revealed that the deletion of these CRF-sensitive neurons makes mice less anxious, implying that these neurons normally mediate anxiety-like behaviors.
These CRF-sensitive mPFC neurons became less excitableless likely to send signals to other neurons when stimulatedin alcohol-dependent mice experienced alcohol withdrawal. In contrast, nearby mPFC neurons with CRF receptors became more excitable.
These CRF-sensitive mPFC neurons appear to be a unique neuronal group that is subject to profound neuroadaptations due to chronic alcohol exposure, according to Pauravi Gandhi, a postdoctoral research associate.
Alcohol withdrawal, even as it reduced the excitability of the CRF-sensitive neurons, induced significant increases in CSF1 gene expression within these neurons. CSF1 is a well-known immune protein used to stimulate stem cells to mature into large white blood cells called macrophages. In the brain, CSF1 is thought to play a similar role in sustaining brain-resident immune cells called microglia, thus causing depression and anxiety.
Roberto and his colleagues examined CSF1''s role in alcohol withdrawal artificially increased CSF1 production in CRF-sensitive mPFC neurons in mice, and found that these animals showed many of the same neuronal and behavioral changes seen in alcohol withdrawalsuggesting that increased CSF1 levels in mPFC may be a major driver of alcohol withdrawal symptoms.
CSF1 is therefore considered a good strategy for treating AUD, and we are now eager to do so in our preclinical experiments, according to Patel.
