Comparative analysis of functional network dynamics in high and low alcohol preference mice

Individual variability preference is a typical characteristic of alcohol drinking behaviors, with a higher risk for the development of alcohol use disorders (AUDs) in high alcohol preference (HP) populations. Here, we created a map of alcohol-related brain regions through c-Fos profiling, and comparatively investigated the differences of functional neural networks between the HP mice and low alcohol preference (LP) mice. We found that neuronal activity in some brain regions, such as ventral tegmental area (VTA), was altered in both HP and LP mice, indicating that these neurons were universally sensitive to alcohol. Most importantly, several brain regions, such as the prefrontal cortex and insular cortex, exhibited significantly higher c-Fos expression in HP mice than that in LP mice and displayed broader and stronger neural connections across brain networks, suggesting that these brain regions are the potential targets for individual alcohol preference. Graph theory-based analysis unraveled a decrease in brain modularity in HP networks, yet with more centralized connection patterns, and maintained higher communication efficiency and redundancy. Furthermore, LP mice switched the central network hubs, with the key differential network centered on nucleus accumbens shell (NAc Sh), nucleus accumbens core (NAc C), VTA, and anterior insular cortex (AIC), indicating that these brain regions and related neural circuits, such as NAc Sh-AIC may be involved in regulating individual alcohol preference. These results provide novel insights into the neural connections governing individual preferences to alcohol consumption, which may contribute to AUDs prediction and pharmacotherapy.