Brain Network Allostasis after Chronic Alcohol Drinking Is Characterized by Functional Dedifferentiation and Narrowing

Abstract

Alcohol use disorder (AUD) causes complex alterations in the brain that are poorly understood. The heterogeneity of drinking patterns and the high incidence of comorbid factors compromise mechanistic investigations in AUD patients. Here we used male Marchigian Sardinian alcohol-preferring (msP) rats, a well established animal model of chronic alcohol drinking, and a combination of longitudinal resting-state fMRI and manganese-enhanced MRI to provide objective measurements of brain connectivity and activity, respectively. We found that 1 month of chronic alcohol drinking changed the correlation between resting-state networks. The change was not homogeneous, resulting in the reorganization of pairwise interactions and a shift in the equilibrium of functional connections. We identified two fundamentally different forms of network reorganization. First is functional dedifferentiation, which is defined as a regional increase in neuronal activity and overall correlation, with a concomitant decrease in preferential connectivity between specific networks. Through this mechanism, occipital cortical areas lost their specific interaction with sensory-insular cortex, striatal, and sensorimotor networks. Second is functional narrowing, which is defined as an increase in neuronal activity and preferential connectivity between specific brain networks. Functional narrowing strengthened the interaction between striatal and prefrontocortical networks, involving the anterior insular, cingulate, orbitofrontal, prelimbic, and infralimbic cortices. Importantly, these two types of alterations persisted after alcohol discontinuation, suggesting that dedifferentiation and functional narrowing rendered persistent network states. Our results support the idea that chronic alcohol drinking, albeit at moderate intoxicating levels, induces an allostatic change in the brain functional connectivity that propagates into early abstinence.

SIGNIFICANCE STATEMENT Excessive consumption of alcohol is positioned among the top five risk factors for disease and disability. Despite this priority, the transformations that the nervous system undergoes from an alcohol-naive state to a pathologic alcohol drinking are not well understood. In our study, we use an animal model with proven translational validity to study this transformation longitudinally. The results show that shortly after chronic alcohol consumption there is an increase in redundant activity shared by brain structures, and the specific communication shrinks to a set of pathways. This functional dedifferentiation and narrowing are not reversed immediately after alcohol withdrawal but persist during early abstinence. We causally link chronic alcohol drinking with an early and abstinence-persistent retuning of the functional equilibrium of the brain.