Department of Radiology, School of Medicine, Duke University, Durham, North Carolina, USA.
Department of Cell Biology, School of Medicine, Duke University, Durham, North Carolina, USA.
NMR Biomed. 2023 Feb;36(2):e4842. doi: 10.1002/nbm.4842. Epub 2022 Nov 23.
The United States is experiencing a dramatic increase in maternal opioid misuse and, consequently, the number of individuals exposed to opioids in utero. Prenatal opioid exposure has both acute and long-lasting effects on health and wellbeing. Effects on the brain, often identified at school age, manifest as cognitive impairment, attention deficit, and reduced scholastic achievement. The neurobiological basis for these effects is poorly understood. Here, we examine how in utero exposure to heroin affects brain development into early adolescence in a mouse model. Pregnant C57BL/6J mice received escalating doses of heroin twice daily on gestational days 4-18. The brains of offspring were assessed on postnatal day 28 using 9.4 T diffusion MRI of postmortem specimens at 36 μm resolution. Whole-brain volumes and the volumes of 166 bilateral regions were compared between heroin-exposed and control offspring. We identified a reduction in whole-brain volume in heroin-exposed offspring and heroin-associated volume changes in 29 regions after standardizing for whole-brain volume. Regions with bilaterally reduced standardized volumes in heroin-exposed offspring relative to controls include the ectorhinal and insular cortices. Regions with bilaterally increased standardized volumes in heroin-exposed offspring relative to controls include the periaqueductal gray, septal region, striatum, and hypothalamus. Leveraging microscopic resolution diffusion tensor imaging and precise regional parcellation, we generated whole-brain structural MRI diffusion connectomes. Using a dimension reduction approach with multivariate analysis of variance to assess group differences in the connectome, we found that in utero heroin exposure altered structure-based connectivity of the left septal region and the region that acts as a hub for limbic regulatory actions. Consistent with clinical evidence, our findings suggest that prenatal opioid exposure may have effects on brain morphology, connectivity, and, consequently, function that persist into adolescence. This work expands our understanding of the risks associated with opioid misuse during pregnancy and identifies biomarkers that may facilitate diagnosis and treatment.
美国正经历着产妇阿片类药物滥用的急剧增加，因此，暴露于子宫内阿片类药物的人数也在增加。产前阿片类药物暴露对健康和幸福既有急性影响，也有长期影响。对大脑的影响，通常在学龄期被识别，表现为认知障碍、注意力缺陷和学习成绩下降。这些影响的神经生物学基础尚未被很好地理解。在这里，我们在小鼠模型中研究了宫内暴露于海洛因如何影响大脑发育到青春期早期。怀孕的 C57BL/6J 小鼠在妊娠第 4-18 天每天两次接受递增剂量的海洛因。在产后第 28 天，通过对死后标本进行 9.4T 扩散 MRI 分析，在 36μm 分辨率下评估后代的大脑。在标准化全脑体积后，比较海洛因暴露组和对照组后代的全脑体积和 166 个双侧区域的体积。我们发现海洛因暴露组后代的全脑体积减少，并且在标准化全脑体积后，海洛因暴露组后代有 29 个区域的体积发生了变化。与对照组相比，海洛因暴露组后代双侧体积减少的区域包括外侧和岛叶皮质。与对照组相比，海洛因暴露组后代双侧体积增加的区域包括导水管周围灰质、隔区、纹状体和下丘脑。利用微观分辨率扩散张量成像和精确的区域分割，我们生成了全脑结构 MRI 扩散连接组。使用多维方差分析的降维方法来评估连接组中的组间差异，我们发现宫内海洛因暴露改变了左侧隔区和作为边缘调节作用枢纽的区域的结构连接。与临床证据一致，我们的研究结果表明，产前阿片类药物暴露可能对大脑形态、连接以及随后的功能产生持续到青春期的影响。这项工作扩展了我们对怀孕期间阿片类药物滥用相关风险的认识，并确定了可能有助于诊断和治疗的生物标志物。
