Increase IL-10 Signaling in Brain can restrict Alcohol Use

The amygdala plays a crucial role deep inside the brain in how we exhibit emotion, actions, and motivation. It is also deeply involved in substance misuse, making it a long-running subject of Marisa Roberto, PhD, a professor in the molecular medicine department of Scripps Science.

Now, improvements to anti-inflammatory pathways and cellular activity in the amygdala that drive alcohol addiction have been identified by Roberto and her team. They were able to avoid excessive alcohol intake by combating this mechanism in mice, revealing a prospective therapeutic route for alcohol use disorder.

This study was publish in Progress in Neurobiology, under title "IL-10 normalizes aberrant amygdala GABA transmission and reverses anxiety-like behavior and dependence-induced escalation of alcohol intake"

Alcohol causes a brain neuroimmune response that leads to alcohol use disorder (AUD) creation and maintenance. While the neuroimmune response is triggered and guided by pro-inflammatory mediators, anti-inflammatory mediators provide a significant homeostatic mechanism for limiting inflammation and preventing pathological damage, the researchers write.

"However in essential addiction-related brain regions and pathological alcohol-dependence-induced behaviours, our understanding of the role of anti-inflammatory signalling in neuronal physiology is limited, preventing our ability to recognise promising therapeutic targets. Here, we hypothesised that chronic alcohol exposure in the central amygdala compromises anti-inflammatory signalling. thereby perpetuating a pro-inflammatory condition driving aberrant pathological behaviours underlying neuronal activity.

The team found that alcohol dependency changes the immune landscape of the global brain, increasing the development of microglia and T-regulatory cells by IL-10, but decreasing the levels of local amygdala IL-10. Overexpression of Amygdala IL-10 reduces anxiety-like behaviours, indicating its local role in the regulation of amygdala-mediated behaviours. Mechanistically, PI3K and p38 MAPK amygdala IL-10 signalling modulates GABA transmission directly to presynaptic terminals and indirectly through random firing alterations.

'Alcohol dependence-induces IL-10 signalling neuroadaptations, leading to an overall decrease in GABA transmission caused by IL-10, normalising dependency-induced elevated GABA amygdala transmission. Notably, amygdala IL-10 overexpression in dependent mice prevents alcohol consumption escalation, a diagnostic criterion of AUD.

In modulating neuronal activity and underlying anxiety-like behaviour and aberrant alcohol consumption, this illustrates the importance of amygdala IL-10 signalling, offering a new mechanism for therapeutic intervention.

"We have found that chronic exposure to alcohol involves brain immune cells, which are important for maintaining healthy neurons," says Reesha Patel, PhD, a Roberto lab postdoctoral fellow and first study author. "The resulting harm fuels anxiety and drinking alcohol, which can lead to alcohol use disorder."

Specifically, Roberto's research looked at an immune protein called Interleukin 10, or IL-10, which is abundant in the brain. It is known that IL-10 has potent anti-inflammatory properties, ensuring that the immune system does not respond to disease threats too strongly. In the brain, IL-10 tends to minimise inflammation, such as stroke or Alzheimer's, from injury or illness. Yet key habits associated with recurrent use of alcohol often tend to be affected.

IL-10 was significantly decreased in the amygdala in mice with chronic alcohol use and did not signal correctly to neurons, leading to increased alcohol consumption. However, scientists could reverse the aberrant effects by improving IL-10 signalling in the brain. In particular, they found a sharp decline in anxiety-like habits and desire to consume alcohol.

"We have shown that the development and maintenance of alcohol use disorder is very much at play in inflammatory immune responses in the brain," Roberto says. "But perhaps more importantly, we have provided a new therapeutic intervention framework that points to anti-inflammatory mechanisms."

Roberto's lab has discovered potential new treatment options for those with alcohol abuse by studying how brain cells change with repeated exposure to alcohol.

Roberto's laboratory collaborated with Silke Paust, PhD, an associate professor in the Department of Immunology and Microbiology, in the most recent research. Paust and her team determined the specific immune cells that are impacted by excessive alcohol consumption in the entire brain. The results showed a significant change in the brain immune landscape, with increased immune cell levels known as microglia and T-regulatory cells generating IL-10.

The amygdala revealed a different storey, considering a higher number of IL-10-producing cells in the whole brain of mice with prolonged alcohol use. IL-10 levels were lower in that area and their signalling role was impaired, indicating that the amygdala immune system responds uniquely to repeated use of alcohol.

This research complements recent Roberto lab results showing that microglia plays a casual role in the production of alcohol dependency. In order to determine precisely how and when IL-10 communicates to amygdala neurons and other addition-related brain circuits to modify actions, future research will build on these results.