Haggerty David L, Grecco Gregory G, Huang Jui-Yen, Doud Emma H, Mosley Amber L, Lu Hui-Chen, Atwood Brady K
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States.
Indiana University School of Medicine, Medical Scientist Training Program, Indianapolis, IN, United States.
Front Pharmacol. 2023 Feb 1;14:1124108. doi: 10.3389/fphar.2023.1124108. eCollection 2023.
As problematic opioid use has reached epidemic levels over the past 2 decades, the annual prevalence of opioid use disorder (OUD) in pregnant women has also increased 333%. Yet, how opioids affect the developing brain of offspring from mothers experiencing OUD remains understudied and not fully understood. Animal models of prenatal opioid exposure have discovered many deficits in the offspring of prenatal opioid exposed mothers, such as delays in the development of sensorimotor function and long-term locomotive hyperactivity. In attempt to further understand these deficits and link them with protein changes driven by prenatal opioid exposure, we used a mouse model of prenatal methadone exposure (PME) and preformed an unbiased multi-omic analysis across many sensoriomotor brain regions known to interact with opioid exposure. The effects of PME exposure on the primary motor cortex (M1), primary somatosensory cortex (S1), the dorsomedial striatum (DMS), and dorsolateral striatum (DLS) were assessed using quantitative proteomics and phosphoproteomics. PME drove many changes in protein and phosphopeptide abundance across all brain regions sampled. Gene and gene ontology enrichments were used to assess how protein and phosphopeptide changes in each brain region were altered. Our findings showed that M1 was uniquely affected by PME in comparison to other brain regions. PME uniquely drove changes in M1 glutamatergic synapses and synaptic function. Immunohistochemical analysis also identified anatomical differences in M1 for upregulating the density of glutamatergic and downregulating the density of GABAergic synapses due to PME. Lastly, comparisons between M1 and non-M1 multi-omics revealed conserved brain wide changes in phosphopeptides associated with synaptic activity and assembly, but only specific protein changes in synapse activity and assembly were represented in M1. Together, our studies show that lasting changes in synaptic function driven by PME are largely represented by protein and anatomical changes in M1, which may serve as a starting point for future experimental and translational interventions that aim to reverse the adverse effects of PME on offspring.
在过去20年里，问题性阿片类药物使用已达到流行程度，孕妇中阿片类药物使用障碍（OUD）的年患病率也增加了333%。然而，阿片类药物如何影响患有OUD的母亲所生后代的发育中的大脑，仍未得到充分研究且尚未完全了解。产前阿片类药物暴露的动物模型已发现产前暴露于阿片类药物的母亲的后代存在许多缺陷，例如感觉运动功能发育延迟和长期运动亢进。为了进一步了解这些缺陷并将它们与产前阿片类药物暴露所驱动的蛋白质变化联系起来，我们使用了产前美沙酮暴露（PME）的小鼠模型，并对许多已知与阿片类药物暴露相互作用的感觉运动脑区进行了无偏倚的多组学分析。使用定量蛋白质组学和磷酸化蛋白质组学评估了PME暴露对初级运动皮层（M1）、初级体感皮层（S1）、背内侧纹状体（DMS）和背外侧纹状体（DLS）的影响。PME在所有采样的脑区中驱动了蛋白质和磷酸肽丰度的许多变化。基因和基因本体富集用于评估每个脑区中蛋白质和磷酸肽变化是如何改变的。我们的研究结果表明，与其他脑区相比，M1受PME的影响具有独特性。PME独特地驱动了M1谷氨酸能突触和突触功能的变化。免疫组织化学分析还确定了由于PME导致M1中谷氨酸能突触密度上调和GABA能突触密度下调的解剖学差异。最后，M1与非M1多组学之间的比较揭示了与突触活动和组装相关的磷酸肽在全脑范围内的保守变化，但M1中仅表现出突触活动和组装方面的特定蛋白质变化。总之，我们的研究表明，PME驱动的突触功能的持久变化在很大程度上表现为M1中的蛋白质和解剖学变化，这可能作为未来旨在逆转PME对后代不利影响的实验和转化干预的起点。
