Santoro Matteo, Lam Rachel K, Blumenfeld Sarah E, Tan Weiqi, Ciari Peter, Chu Emily K, Saw Nay L, Rijsketic Daniel Ryskamp, Lin Jennifer S, Heifets Boris D, Shamloo Mehrdad
Stanford University School of Medicine.
Res Sq. 2024 Oct 16:rs.3.rs-5206046. doi: 10.21203/rs.3.rs-5206046/v1.
Efforts to develop disease-modifying treatments for Parkinson's disease (PD) have been hindered by the lack of animal models replicating all hallmarks of PD and the insufficient attention to extra-nigrostriatal regions pathologically critical for the prodromal appearance of non-motor symptoms. Among PD models, 6-hydroxydopamine (6-OHDA) infusion in mice has gained prominence since 2012, primarily focusing on the nigrostriatal region. This study characterized widespread tyrosine hydroxylase-positive neuron and fiber loss across the brain following a unilateral 6-OHDA (20 μg) infusion into the dorsal striatum. Our analysis integrates immunolabeling, brain clearing (iDISCO+), light sheet microscopy, and computational methods, including fMRI and machine learning tools. We also examined sex differences, disease progression, neuroinflammatory responses, and pro-apoptotic signaling in nigrostriatal regions of C57BL/6 mice exposed to varying 6-OHDA dosages (5, 10, or 20 μg). This comprehensive, spatiotemporal analysis of 6-OHDA-induced pathology may guide the future design of experimental PD studies and neurotherapeutic development.
开发帕金森病（PD）疾病修饰疗法的努力受到了阻碍，原因在于缺乏能够复制PD所有特征的动物模型，以及对非运动症状前驱期出现至关重要的黑质纹状体以外区域在病理上未得到足够重视。在PD模型中，自2012年以来，向小鼠脑内注射6-羟基多巴胺（6-OHDA）受到了广泛关注，主要聚焦于黑质纹状体区域。本研究描述了向背侧纹状体单侧注射20μg 6-OHDA后，全脑广泛的酪氨酸羟化酶阳性神经元和纤维丢失情况。我们的分析整合了免疫标记、脑透明化技术（iDISCO+）、光片显微镜检查以及包括功能磁共振成像（fMRI）和机器学习工具在内的计算方法。我们还研究了暴露于不同剂量（5、10或20μg）6-OHDA的C57BL/6小鼠黑质纹状体区域的性别差异、疾病进展、神经炎症反应和促凋亡信号。这种对6-OHDA诱导病理的全面时空分析可能会为未来实验性PD研究的设计和神经治疗开发提供指导。
