Summary
Three main theories of the neurobiology of addiction have been proposed: (1) incentive salience mediated by a brainstem-striatal network, (2) habit mediated by a cortico-striato-thalamic network, and (3) hedonic allostasis mediated by an extended amygdala network. Efforts have been made to reconcile these theories within a three-stage model, but the relevance of each theory remains controversial. We tested the validity of each theory with a single dataset using unbiased single-cell whole-brain imaging and data-driven analyses of neuronal activity in a mouse model of alcohol use disorder. Abstinence in alcohol dependent mice decreased brain modularity and resulted in clustering of brain regions that correspond to each stage of the three-stage theory of addiction. Furthermore, we identified several brain regions whose activity highly predicted addiction-like behaviors and “hub” regions that may drive neural activation during abstinence. These results validate the three-stage theory of addiction and identify potential target regions for future study.
Footnotes
This work was supported by the National Institutes of Health (grant no. AA006420, AA026081, AA022977, AA026685, AA024198, NS79698, AA027301, and AA007456), the Pearson Center for Alcoholism and Addiction Research, and the Arnold and Mabel Beckman Foundation.