Sex Differences in Neural Networks Recruited by Frontloaded Binge Alcohol Drinking.

Area of Science:

• Neuroscience
• Behavioral Neuroscience
• Systems Neuroscience

Background:

• Frontloading, characterized by skewed alcohol intake towards the beginning of access, is a significant drinking pattern.
• Understanding the neural underpinnings of frontloading is crucial for developing targeted interventions.
• Previous research has not fully elucidated the specific brain regions and network dynamics associated with this behavior.

Approach:

• This study utilized the drinking-in-the-dark (DID) model in C57Bl/6J mice (n=63) to investigate brain activity during alcohol frontloading.
• Fos protein expression, a marker of neural activity, was measured using advanced imaging techniques (iDISCO+, light sheet imaging) and analyzed with ClearMap2.1.
• Change-point analysis differentiated frontloaders from non-frontloaders, enabling comparative brain network analyses based on functional correlation matrices and hierarchical clustering.

Key Points:

• In male mice, alcohol access decreased brain network modularity compared to water controls, with frontloaders exhibiting distinct connector and provincial hubs, particularly in hindbrain regions.
• Female mice showed an opposite effect, with alcohol access increasing modularity, and frontloaders displaying unique hubs across multiple modules.
• Only the nucleus raphe pontis served as a common connector hub in both sexes, indicating sex-specific neural recruitment in alcohol frontloading.

Conclusions:

• Alcohol frontloading significantly reorganizes functional brain architecture in a sex-dependent manner.
• Male frontloading is associated with reduced network efficiency and distinct hindbrain-striatal/cortical pathway recruitment.
• Female frontloading involves widespread network alterations with unique hub recruitment, suggesting divergent neural mechanisms underlying this drinking pattern in males and females.