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Chronic alcohol use reshapes brain’s immune landscape, driving anxiety and addiction

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In their quest to understand how the immune system is implicated in alcohol use disorder, Scripps Research scientists in the United States have found a potential path for treatment. Their study has just been published in the journal Progress in Neurobiology.

Deep within the brain, a small almond-shaped region called the amygdala plays a vital role in how we exhibit emotion, behaviour and motivation. Understandably, it is also strongly implicated in alcohol abuse, making it a long-running focus of Dr Marisa Roberto, a professor in Scripps Research’s Department of Molecular Medicine.

Now, for the first time, Roberto and her team have identified important changes to anti-inflammatory mechanisms and cellular activity in the amygdala that drive alcohol addiction, Scripps Research reported on 16 November 2020.

By countering this process in mice, they were able to stop excessive alcohol consumption – revealing a potential treatment path for alcohol use disorder.

“We found that chronic alcohol exposure compromises brain immune cells, which are important for maintaining healthy neurons,” says Dr Reesha Patel, a postdoctoral fellow in Roberto’s lab and first author of the study. “The resulting damage fuels anxiety and alcohol drinking that may lead to alcohol use disorder.”

Roberto’s study looked specifically at an immune protein called Interleukin 10, or IL-10, which is prevalent in the brain. IL-10 is known to have potent anti-inflammatory properties, which ensures that the immune system doesn’t respond too powerfully to disease threats.

In the brain, IL-10 helps to limit inflammation from injury or disease, such as stroke or Alzheimer’s. But it also appears to influence key behaviors associated with chronic alcohol use.

New framework for therapeutic intervention

In mice with chronic alcohol use, IL-10 was significantly reduced in the amygdala and didn’t signal properly to neurons, contributing to increased alcohol intake. By boosting IL-10 signalling in the brain, however, the scientists could reverse the aberrant effects. Notably, they observed a stark reduction in anxiety-like behaviours and motivation to drink alcohol.

“We’ve shown that inflammatory immune responses in the brain are very much at play in the development and maintenance of alcohol use disorder,” Roberto says. “But perhaps more importantly, we provided a new framework for therapeutic intervention, pointing to anti-inflammatory mechanisms.”

Alcohol use disorder is widespread, affecting some 15 million people in the United States, and few effective treatments exist. By examining how brain cells change with prolonged exposure to alcohol, Roberto’s lab has uncovered many possible new therapeutic approaches for those with alcohol addiction.

In the latest study, Roberto’s lab collaborated with Dr Silke Paust, associate professor in the Department of Immunology and Microbiology. Paust and her team determined the precise immune cells throughout the whole brain that are affected by chronic alcohol use.

The findings revealed a large shift in the brain immune landscape, with increased levels of immune cells known as microglia and T-regulatory cells, which produce IL-10.

Despite a higher number of IL-10-producing cells in the whole brain of mice with prolonged alcohol use, the amygdala told a different story. In that region, levels of IL-10 were lower and their signalling function was compromised – suggesting that the immune system in the amygdala responds uniquely to chronic alcohol use.

This study complements recent findings by the Roberto lab demonstrating a causal role for microglia in the development of alcohol dependence.

Future studies will build on these findings to identify exactly how and when IL-10 signals to neurons in the amygdala and other addition-related brain circuits to alter behavior.

 

IL-10 normalizes aberrant amygdala GABA transmission and reverses anxiety-like behavior and dependence-induced escalation of alcohol intake

The journal Progress in Neurobiology. Published on 13 November 2020

Authors

Reesha Patel, Sarah Wolfe, Michal Bajo, Shawn Abeynaike, Amanda Pahng, Vittoria Borgonetti, Shannon D’Ambrosio, Rana Nikzad, Scott Edwards, Silke Paust, Amanda Roberts and Marisa Roberto 

Affiliations: The Scripps Research Institute, Louisana State University Health Sciences Center and the Southeast Louisiana Veterans Health Care System, United States.

Abstract

Alcohol elicits a neuroimmune response in the brain, contributing to the development and maintenance of alcohol use disorder (AUD). While pro-inflammatory mediators initiate and drive the neuroimmune response, anti-inflammatory mediators provide an important homeostatic mechanism to limit inflammation and prevent pathological damage.

However, our understanding of the role of anti-inflammatory signaling on neuronal physiology in critical addiction-related brain regions and pathological alcohol-dependence induced behaviours is limited, precluding our ability to identify promising therapeutic targets.

Here, we hypothesised that chronic alcohol exposure compromises anti-inflammatory signalling in the central amygdala, a brain region implicated in anxiety and addiction, consequently perpetuating a pro-inflammatory state driving aberrant neuronal activity underlying pathological behaviours.

We found that alcohol dependence alters the global brain immune landscape increasing IL-10 producing microglia and T-regulatory cells but decreasing local amygdala IL-10 levels. Amygdala IL-10 overexpression decreases anxiety-like behaviours, suggesting its local role in regulating amygdala-mediated behaviours.

Mechanistically, amygdala IL-10 signalling through PI3K and p38 MAPK modulates GABA transmission directly at presynaptic terminals and indirectly through alterations in spontaneous firing.

Alcohol dependence-induces neuroadaptations in IL-10 signalling leading to an overall IL-10-induced decrease in GABA transmission, which normalizes dependence-induced elevated amygdala GABA transmission.

Notably, amygdala IL-10 overexpression abolishes escalation of alcohol intake, a diagnostic criterion of AUD, in dependent mice. This highlights the importance of amygdala IL-10 signalling in modulating neuronal activity and underlying anxiety-like behavior and aberrant alcohol intake, providing a new framework for therapeutic intervention.

 

Scripps Research story – Chronic alcohol use reshapes the brain’s immune landscape, driving anxiety and addiction

 

The journal Progress in Neurobiology – IL-10 normalizes aberrant amygdala GABA transmission and reverses anxiety-like behavior and dependence-induced escalation of alcohol intake

 


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