Neural network connectivity following opioid dependence is altered by a common genetic variant in the mu-opioid receptor,OPRM1A118G

Opioid use disorder is a chronic, relapsing disease associated with persistent changes in brain plasticity. A common single nucleotide polymorphism (SNP) in the mu-opioid receptor gene,OPRM1A118G, is associated with altered vulnerability to opioid addiction. Reconfiguration of neuronal connectivity may explain dependence risk in individuals with this SNP. Mice with the equivalentOprm1variant, A112G, demonstrate sex-specific alterations in the rewarding properties of morphine and heroin. To determine whether this SNP influences network-level changes in neuronal activity we compared FOS expression in male and female mice that were opioid-naïve or opioid-dependent. Network analyses identified significant differences between the AA and GGOprm1genotypes. Based on several graph theory metrics, including small-world analysis and degree centrality, we show that GG females in the opioid-dependent state exhibit distinct patterns of connectivity compared to other groups of the same genotype. Using a network control theory approach, we identified key cortical brain regions that drive the transition between opioid-naïve and opioid-dependent brain states; however, these regions are less influential in GG females leading to 6-fold higher average minimum energy needed to transition from the acute to the dependent state. In addition, we found that the opioid-dependent brain state is significantly less stable in GG females compared to other groups. Collectively, our findings demonstrate sex and genotype-specific modifications in local, mesoscale, and global properties of functional brain networks following opioid exposure and provide a framework for identifying genotype differences in specific brain regions that play a role in opioid dependence.Significance StatementOpioid use disorder is moderately heritable, and the common mu-opioid receptor variant (OPRM1A118G) has been repeatedly associated with this disease. Opioid use liability is often higher in individuals with a history of chronic exposure and can be moderated by this SNP. Using a mouse model of theOprm1SNP, our work revealed opioid-induced differences in network connectivity between sexes and opioid dependence states in AA and GGOprm1mice. We also identified six (predominantly cortical) brain regions that strongly influence the transition to an opioid-dependent brain state. These data suggest potential brain regions that may be targeted using non-invasive therapeutic approaches such as repetitive Transcranial Magnetic Stimulation (rTMS) and could be useful to inform personalized treatment.