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The content provided examines the effect of a common genetic variant in the µ-opioid receptor gene, known as OPRM1 A118G, on neural network connectivity following opioid dependence. The study finds that mice with the equivalent variant show sex-specific alterations in the rewarding properties of opioids. Network analyses reveal significant differences in connectivity patterns between different genotypes. Using graph theory metrics, it is shown that female mice with the GG genotype in the opioid-dependent state exhibit distinct patterns of connectivity. Key cortical brain regions that drive the transition from opioid-naive to opioid-dependent states are less influential in GG females, leading to a higher energy requirement for the transition. Furthermore, the opioid-dependent brain state is less stable in GG females compared to other groups. These findings demonstrate sex- and genotype-specific modifications in brain networks following opioid exposure and provide insights into the role of specific brain regions in opioid dependence.
Opioid use disorder is a chronic, relapsing disease associated with persistent changes in brain plasticity. A common single nucleotide polymorphism (SNP) in the µ-opioid receptor gene, OPRM1 A118G, is associated with altered vulnerability to opioid addiction. Reconfiguration of neuronal connectivity may explain dependence risk in individuals with this SNP. Mice with the equivalent Oprm1 variant, 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-naive or opioid-dependent. Network analyses identified significant differences between the AA and GG Oprm1 genotypes. 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-naive and opioid-dependent brain states; however, these regions are less influential in GG females leading to sixfold 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.