Department of Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA.
Neuropsychopharmacology. 2023 Nov;48(12):1724-1734. doi: 10.1038/s41386-023-01639-8. Epub 2023 Jul 3.
Use of the synthetic opioid fentanyl increased ~300% in the last decade, including among women of reproductive ages. Adverse neonatal outcomes and long-term behavioral disruptions are associated with perinatal opioid exposure. Our previous work demonstrated that perinatal fentanyl exposed mice displayed enhanced negative affect and somatosensory circuit and behavioral disruptions during adolescence. However, little is known about molecular adaptations across brain regions that underlie these outcomes. We performed RNA sequencing across three reward and two sensory brain areas to study transcriptional programs in perinatal fentanyl exposed juvenile mice. Pregnant dams received 10 μg/ml fentanyl in the drinking water from embryonic day 0 (E0) through gestational periods until weaning at postnatal day 21 (P21). RNA was extracted from nucleus accumbens (NAc), prelimbic cortex (PrL), ventral tegmental area (VTA), somatosensory cortex (S1) and ventrobasal thalamus (VBT) from perinatal fentanyl exposed mice of both sexes at P35. RNA sequencing was performed, followed by analysis of differentially expressed genes (DEGs) and gene co-expression networks. Transcriptome analysis revealed DEGs and gene modules significantly associated with exposure to perinatal fentanyl in a sex-wise manner. The VTA had the most DEGs, while robust gene enrichment occurred in NAc. Genes enriched in mitochondrial respiration were pronounced in NAc and VTA of perinatal fentanyl exposed males, extracellular matrix (ECM) and neuronal migration enrichment were pronounced in NAc and VTA of perinatal fentanyl exposed males, while genes associated with vesicular cycling and synaptic signaling were markedly altered in NAc of perinatal fentanyl exposed female mice. In sensory areas from perinatal fentanyl exposed females, we found alterations in mitochondrial respiration, synaptic and ciliary organization processes. Our findings demonstrate distinct transcriptomes across reward and sensory brain regions, with some showing discordance between sexes. These transcriptome adaptations may underlie structural, functional, and behavioral changes observed in perinatal fentanyl exposed mice.
在过去十年中，合成阿片类药物芬太尼的使用增加了约 300%，包括在育龄妇女中。围产期阿片类药物暴露与不良新生儿结局和长期行为障碍有关。我们之前的工作表明，围产期芬太尼暴露的小鼠在青春期表现出增强的消极情绪和躯体感觉回路以及行为障碍。然而，对于这些结果背后的大脑区域的分子适应知之甚少。我们对三个奖励和两个感觉脑区进行了 RNA 测序，以研究围产期芬太尼暴露的幼年小鼠中的转录程序。从胚胎期 0 天（E0）到妊娠期，怀孕的母鼠通过饮用水摄入 10μg/ml 的芬太尼，直到产后第 21 天（P21）断奶。从围产期芬太尼暴露的雄性和雌性幼年小鼠的伏隔核（NAc）、额前皮质（PrL）、腹侧被盖区（VTA）、躯体感觉皮层（S1）和腹侧基底节（VBT）中提取 RNA。进行 RNA 测序，然后分析差异表达基因（DEGs）和基因共表达网络。转录组分析显示，DEGs 和基因模块以性别特异性的方式与围产期芬太尼暴露显著相关。VTA 中 DEGs 最多，而 NAc 中基因富集显著。围产期芬太尼暴露雄性的 NAc 和 VTA 中富集的基因与线粒体呼吸有关，围产期芬太尼暴露雄性的 NAc 和 VTA 中富集的基因与细胞外基质（ECM）和神经元迁移有关，而与囊泡循环和突触信号有关的基因在围产期芬太尼暴露的雌性小鼠的 NAc 中明显改变。在围产期芬太尼暴露雌性的感觉区，我们发现线粒体呼吸、突触和纤毛组织过程发生改变。我们的研究结果表明，在奖励和感觉脑区之间存在不同的转录组，其中一些表现出性别之间的差异。这些转录组适应可能是围产期芬太尼暴露的小鼠中观察到的结构、功能和行为变化的基础。
