Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany.
Department of Anatomical Sciences, Faculty of Medicine, Giulan University of Medical Sciences, Rasht, Iran.
Mol Neurobiol. 2018 May;55(5):4240-4252. doi: 10.1007/s12035-017-0637-9. Epub 2017 Jun 14.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of midbrain dopaminergic neurons, resulting in motor and non-motor symptoms. The underlying pathology of non-motor symptoms is poorly understood. Discussed are pathological changes of extrastriatal brain structures. In this study, we characterized histopathological alterations of extrastriatal brain structures in the 6-hydroxydopamine (6-OHDA) PD animal model. Lesions were induced by unilateral stereotactic injections of 6-OHDA into the striatum or medial forebrain bundle of adult male mice. Loss of tyrosine hydroxylase positive (TH) fibers as well as glia activation was quantified following stereological principles. Loss of dopaminergic innervation was further investigated by western-blotting. As expected, 6-OHDA injection into the nigrostriatal route induced retrograde degeneration of dopaminergic neurons within the substantia nigra pars compacta (SNpc), less so within the ventral tegmental area. Furthermore, we observed a region-specific drop of TH projection fiber density in distinct cortical regions. This pathology was most pronounced in the cingulate- and motor cortex, whereas the piriform cortex was just modestly affected. Loss of cortical TH fibers was not paralleled by microglia or astrocyte activation. Our results demonstrate that the loss of dopaminergic neurons within the substantia nigra pars compacta is paralleled by a cortical dopaminergic denervation in the 6-OHDA model. This model serves as a valuable tool to investigate mechanisms operant during cortical pathology in PD patients. Further studies are needed to understand why cortical dopaminergic innervation is lost in this model, and what functional consequence is associated with the observed denervation.
帕金森病（PD）是一种神经退行性疾病，其特征是中脑多巴胺能神经元进行性丧失，导致运动和非运动症状。非运动症状的潜在病理机制尚不清楚。本文探讨了纹状体外脑结构的病理学变化。在这项研究中，我们描述了 6-羟多巴胺（6-OHDA）PD 动物模型中纹状体外脑结构的组织病理学改变。通过立体定向单侧注射 6-OHDA 到纹状体或内侧前脑束诱导病变。根据体视学原理定量测量酪氨酸羟化酶阳性（TH）纤维和神经胶质细胞激活的丧失。通过 Western blot 进一步研究多巴胺能神经支配的丧失。正如预期的那样，6-OHDA 注射到黑质纹状体通路诱导黑质致密部（SNpc）内多巴胺能神经元的逆行性变性，腹侧被盖区的变性较少。此外，我们观察到特定皮质区域 TH 投射纤维密度的区域特异性下降。这种病理学在扣带回和运动皮质中最为明显，而梨状皮质则受到轻微影响。皮质 TH 纤维的丧失与小胶质细胞或星形胶质细胞的激活不平行。我们的结果表明，6-OHDA 模型中黑质致密部多巴胺能神经元的丧失伴随着皮质多巴胺能神经支配的丧失。该模型可作为研究 PD 患者皮质病理学相关机制的有用工具。需要进一步的研究来了解为什么在该模型中皮质多巴胺能神经支配丧失，以及与观察到的去神经支配相关的功能后果是什么。
