Grecco Gregory G, Huang Jui Yen, Muñoz Braulio, Doud Emma H, Hines Caliel D, Gao Yong, Rodriguez Brooke, Mosley Amber L, Lu Hui-Chen, Atwood Brady K
Department of Pharmacology and Toxicology, School of Medicine, Indiana University, Indianapolis, IN, United States.
Medical Scientist Training Program, School of Medicine, Indiana University, Indianapolis, IN, United States.
Adv Drug Alcohol Res. 2022 Apr;2. doi: 10.3389/adar.2022.10400. Epub 2022 Apr 25.
Rising opioid use among pregnant women has led to a growing population of neonates exposed to opioids during the prenatal period, but how opioids affect the developing brain remains to be fully understood. Animal models of prenatal opioid exposure have discovered deficits in somatosensory behavioral development that persist into adolescence suggesting opioid exposure induces long lasting neuroadaptations on somatosensory circuitry such as the primary somatosensory cortex (S1). Using a mouse model of prenatal methadone exposure (PME) that displays delays in somatosensory milestone development, we performed an un-biased multi-omics analysis and investigated synaptic functioning in the primary somatosensory cortex (S1), where touch and pain sensory inputs are received in the brain, of early adolescent PME offspring. PME was associated with numerous changes in protein and phosphopeptide abundances that differed considerably between sexes in the S1. Although prominent sex effects were discovered in the multi-omics assessment, functional enrichment analyses revealed the protein and phosphopeptide differences were associated with synapse-related cellular components and synaptic signaling-related biological processes, regardless of sex. Immunohistochemical analysis identified diminished GABAergic synapses in both layer 2/3 and 4 of PME offspring. These immunohistochemical and proteomic alterations were associated with functional consequences as layer 2/3 pyramidal neurons revealed reduced amplitudes and a lengthened decay constant of inhibitory postsynaptic currents. Lastly, in addition to reduced cortical thickness of the S1, cell-type marker analysis revealed reduced microglia density in the upper layer of the S1 that was primarily driven by PME females. Taken together, our studies show the lasting changes on synaptic function and microglia in S1 cortex caused by PME in a sex-dependent manner.
孕妇阿片类药物使用的增加导致了越来越多的新生儿在产前接触阿片类药物，但阿片类药物如何影响发育中的大脑仍有待充分了解。产前阿片类药物暴露的动物模型发现，体感行为发育存在缺陷，这种缺陷会持续到青春期，这表明阿片类药物暴露会在体感神经回路（如初级体感皮层（S1））上诱导持久的神经适应。我们使用产前美沙酮暴露（PME）的小鼠模型，该模型显示体感发育里程碑延迟，我们对青春期早期PME后代的初级体感皮层（S1）进行了无偏多组学分析，并研究了其突触功能，S1是大脑中接收触觉和疼痛感觉输入的区域。PME与S1中蛋白质和磷酸肽丰度的大量变化相关，这些变化在两性之间有很大差异。尽管在多组学评估中发现了显著的性别效应，但功能富集分析表明，无论性别如何，蛋白质和磷酸肽的差异都与突触相关的细胞成分和突触信号相关的生物学过程有关。免疫组织化学分析发现，PME后代的第2/3层和第4层的GABA能突触减少。这些免疫组织化学和蛋白质组学改变与功能后果相关，因为第2/3层锥体神经元的抑制性突触后电流幅度降低，衰减常数延长。最后，除了S1皮层厚度减小外，细胞类型标记分析显示，S1上层的小胶质细胞密度降低，这主要是由PME雌性小鼠驱动的。综上所述，我们的研究表明，PME以性别依赖的方式对S1皮层的突触功能和小胶质细胞产生持久变化。
