Department of Systems Pharmacology and Translational Therapeutics and Perelman School of Medicine, University of Pennsylvania, Philadelphia 19104, Pennsylvania.
Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia 19104, Pennsylvania.
J Neurosci. 2024 Feb 7;44(6):e1492232023. doi: 10.1523/JNEUROSCI.1492-23.2023.
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, 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 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 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.
阿片类药物使用障碍是一种与大脑可塑性持续变化相关的慢性、复发性疾病。µ-阿片受体基因中的一个常见单核苷酸多态性 (SNP)，A118G，与阿片类药物成瘾的易感性改变有关。神经元连接的重新配置可能解释了具有这种 SNP 的个体的依赖风险。具有等效变体 A112G 的小鼠表现出吗啡和海洛因奖赏特性的性别特异性改变。为了确定该 SNP 是否影响神经元活动的网络水平变化，我们比较了阿片类药物未使用或依赖的雄性和雌性小鼠中的 FOS 表达。网络分析在 AA 和 GG 基因型之间确定了显著差异。基于几种图论度量，包括小世界分析和度中心性，我们表明 GG 雌性在阿片类药物依赖状态下表现出与其他同基因型组不同的连接模式。使用网络控制理论方法，我们确定了关键的皮质脑区，这些脑区驱动了从阿片类药物未使用状态到依赖状态的转变；然而，在 GG 雌性中，这些区域的影响较小，导致从急性状态到依赖状态的平均最小能量增加了六倍。此外，我们发现 GG 雌性的阿片类药物依赖大脑状态明显不如其他组稳定。总的来说，我们的研究结果表明，在阿片类药物暴露后，功能性大脑网络的局部、中尺度和全局特性存在性别和基因型特异性改变，并为确定在特定大脑区域中发挥作用的基因型差异提供了框架在阿片类药物依赖中。
