Shahid Syed Salman, Grecco Gregory G, Atwood Brady K, Wu Yu-Chien
bioRxiv. 2023 Feb 23:2023.02.23.529659. doi: 10.1101/2023.02.23.529659.
Methadone-based treatment for pregnant women with opioid use disorder is quite prevalent in the clinical environment. A number of clinical and animal model-based studies have reported cognitive deficits in infants prenatally exposed to methadone-based opioid treatments. However, the long-term impact of prenatal opioid exposure (POE) on pathophysiological mechanisms that govern neurodevelopmental impairment is not well understood. Using a translationally relevant mouse model of prenatal methadone exposure (PME), the aim of this study is to investigate the role of cerebral biochemistry and its possible association with regional microstructural organization in PME offspring. To understand these effects, 8- week-old male offspring with PME (n=7) and prenatal saline exposure (PSE) (n=7) were scanned in vivo on 9.4 Tesla small animal scanner. Single voxel proton magnetic resonance spectroscopy ( H-MRS) was performed in the right dorsal striatum (RDS) region using a short echo time (TE) Stimulated Echo Acquisition Method (STEAM) sequence. Neurometabolite spectra from the RDS was first corrected for tissue T1 relaxation and then absolute quantification was performed using the unsuppressed water spectra. High-resolution in vivo diffusion MRI (dMRI) for region of interest (ROI) based microstructural quantification was also performed using a multi-shell dMRI sequence. Cerebral microstructure was characterized using diffusion tensor imaging (DTI) and Bingham-neurite orientation dispersion and density imaging (Bingham-NODDI). MRS results in the RDS showed significant decrease in N-acetyl aspartate (NAA), taurine (tau), glutathione (GSH), total creatine (tCr) and glutamate (Glu) concentration levels in PME, compared to PSE group. In the same RDS region, mean orientation dispersion index (ODI) and intracellular volume fraction (VF ) demonstrated positive associations with tCr in PME group. ODI also exhibited significant positive association with Glu levels in PME offspring. Significant reduction in major neurotransmitter metabolites and energy metabolism along with strong association between the neurometabolites and perturbed regional microstructural complexity suggest a possible impaired neuroadaptation trajectory in PME offspring which could be persistent even into late adolescence and early adulthood.
基于美沙酮的阿片类药物使用障碍孕妇治疗方法在临床环境中相当普遍。一些基于临床和动物模型的研究报告称，产前暴露于基于美沙酮的阿片类药物治疗的婴儿存在认知缺陷。然而，产前阿片类药物暴露（POE）对控制神经发育障碍的病理生理机制的长期影响尚未得到充分了解。本研究旨在利用与产前美沙酮暴露（PME）相关的转化小鼠模型，研究脑生物化学的作用及其与PME后代区域微观结构组织的可能关联。为了解这些影响，对8周龄的PME雄性后代（n = 7）和产前生理盐水暴露（PSE）雄性后代（n = 7）在9.4特斯拉小动物扫描仪上进行了活体扫描。使用短回波时间（TE）刺激回波采集方法（STEAM）序列，在右侧背侧纹状体（RDS）区域进行单体素质子磁共振波谱（ H-MRS）分析。首先对RDS的神经代谢物谱进行组织T1弛豫校正，然后使用未抑制的水谱进行绝对定量。还使用多壳扩散磁共振成像（dMRI）序列对感兴趣区域（ROI）进行基于微观结构定量的高分辨率活体扩散磁共振成像（dMRI）分析。使用扩散张量成像（DTI）和宾厄姆神经突方向分散和密度成像（Bingham-NODDI）对脑微观结构进行表征。与PSE组相比，RDS区域的MRS结果显示PME组中N-乙酰天门冬氨酸（NAA）、牛磺酸（tau）、谷胱甘肽（GSH）、总肌酸（tCr）和谷氨酸（Glu）浓度水平显著降低。在同一RDS区域，PME组的平均方向分散指数（ODI）和细胞内体积分数（VF ）与tCr呈正相关。ODI在PME后代中也与Glu水平呈显著正相关。主要神经递质代谢物和能量代谢的显著降低，以及神经代谢物与受干扰的区域微观结构复杂性之间的强关联，表明PME后代可能存在神经适应轨迹受损的情况，这种情况甚至可能持续到青春期晚期和成年早期。
