Brain-wide functional architecture remodeling by alcohol dependence and abstinence

Abstract

Alcohol abuse and alcohol dependence are key factors in the development of alcohol use disorder, which is a pervasive societal problem with substantial economic, medical, and psychiatric consequences. Although our understanding of the neurocircuitry that underlies alcohol use has improved, novel brain regions that are involved in alcohol use and novel biomarkers of alcohol use need to be identified. The present study used a single-cell whole-brain imaging approach to 1) assess whether abstinence from alcohol in an animal model of alcohol dependence alters the functional architecture of brain activity and modularity, 2) validate our current knowledge of the neurocircuitry of alcohol abstinence, and 3) discover brain regions that may be involved in alcohol use. Alcohol abstinence resulted in the whole-brain reorganization of functional architecture in mice and a pronounced decrease in modularity that was not observed in nondependent moderate drinkers. Structuring of the alcohol abstinence network revealed three major brain modules: 1) extended amygdala module, 2) midbrain striatal module, and 3) cortico-hippocampo-thalamic module, reminiscent of the three-stage theory. Many hub brain regions that control this network were identified, including several that have been previously overlooked in alcohol research. These results identify brain targets for future research and demonstrate that alcohol use and dependence remodel brain-wide functional architecture to decrease modularity. Further studies are needed to determine whether the changes in coactivation and modularity that are associated with alcohol abstinence are causal features of alcohol dependence or a consequence of excessive drinking and alcohol exposure.

Depletion of the Microbiome Alters the Recruitment of Neuronal Ensembles of Oxycodone Intoxication and Withdrawal

“…To further assess the impact of antibiotic treatment on brain networks, we evaluated the degree of associations between changes in neuronal activity (i.e., functional connectivity) in each brain region during oxycodone intoxication and withdrawal (Kimbrough et al, 2020). We found that antibiotic treatment was associated with dysregulation of the functional network that was produced by decorrelations between several brain regions compared with the control groups.…”

Leveraging Neural Networks in Preclinical Alcohol Research

“…A hub is defined as a node with high connectivity to other nodes in the same module (provincial hubs) or to other modules (connector hubs) [ 191 , 192 ]. Hub brain regions are critical to network function and represent the highest level of connectivity [ 99 , 129 , 171 , 190 , 193 ]. An example of hub identification and validation in brain-wide neural networks can be seen in a study by Vetere et al, in which in silico node deletion and in vivo chemogenetic silencing of the identified nodes confirmed the connection between a region’s node degree and role in memory consolidation [ 129 ].…”

“…This fear network was further examined using in vivo chemogenetic silencing of different network nodes to confirm the importance of the hubs predicted in network models [ 129 ]. Similarly, an unbiased brain-wide Fos protein approach, using the single-cell whole-brain imaging (iDISCO+) method, has been combined with functional connectivity and graph theory to identify changes to neural network structure and function caused by withdrawal from alcohol and psychostimulants [ 99 , 217 ].…”

“…Similarly, the unbiased single-cell whole-brain imaging and network analysis approach identified a massive increase in coactivation among brain regions and reduced modular structuring of the brain during abstinence from alcohol dependence when compared to control networks [ 99 ]. In the alcohol abstinence network, an overall structural simplification was observed, with three large modules identified that corresponded well to the classic three-stage theory of addiction [ 3 , 5 , 6 ]: an extended amygdala module, a midbrain striatal module, and a cortico-hippocampo-thalamic module.…”

“…To study excessive and compulsive-like drinking due to alcohol dependence, the intermittent ethanol (CIE) vapor exposure model has been heavily used in both rats and mice [ 16 , 55 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 ].…”