Combined lesions of direct and indirect basal ganglia pathways but not changes in dopamine levels explain learning deficits in patients with Huntington's disease
Combined lesions of direct and indirect basal ganglia pathways but not changes in dopamine levels explain learning deficits in patients with Huntington's disease
复制标题
DOI：
10.1111/ejn.12868
复制
发表时间：
2015-05
影响因子：
3.4
通讯作者：
H. Schroll;C. Beste;F. Hamker
中科院分区：
文献类型：
--
作者：
H. Schroll;C. Beste;F. Hamker
亨廷顿舞蹈症 (HD) 是一种遗传性基底神经节神经退行性疾病，会导致严重的运动、认知和情绪功能障碍。在人类基底神经节中，这些功能障碍伴随着纹状体中棘神经元的丧失、丘脑底核和苍白球的功能障碍以及多巴胺受体结合的变化。在这里，我们使用神经计算模型来研究这些基底神经节功能障碍中的哪些可以解释患者在不同刺激反应学习范式中的缺陷。我们表明，这些范例特别适合审查多巴胺信号传导的潜在变化和潜在的基底神经节病变对 HD 明显行为的影响。我们发现直接和间接基底神经节通路的组合损伤，但这些损伤中没有一个单独损伤，会重现患者的学习障碍。直接通路的中型多棘神经元的变性解释了患者在促进正确反应方面的缺陷，而间接通路的中型多棘神经元的变性解释了它们在抑制主导但不正确的反应方面的缺陷。经验结果不能用丘脑底核（超直接通路的一部分）的病变或多巴胺水平的变化来解释。总体而言，我们的模拟表明，直接和间接途径的联合损伤是 HD 患者学习障碍的主要根源，并且暂时也是其一般运动和认知缺陷的主要根源，而多巴胺水平的变化被认为与患者的障碍没有因果关系。
Huntington's disease (HD) is a hereditary neurodegenerative disease of the basal ganglia that causes severe motor, cognitive and emotional dysfunctions. In the human basal ganglia, these dysfunctions are accompanied by a loss of striatal medium spiny neurons, dysfunctions of the subthalamic nucleus and globus pallidus, and changes in dopamine receptor binding. Here, we used a neuro‐computational model to investigate which of these basal ganglia dysfunctions can explain patients’ deficits in different stimulus–response learning paradigms. We show that these paradigms are particularly suitable for scrutinising the effects of potential changes in dopamine signaling and of potential basal ganglia lesions on overt behavior in HD. We find that combined lesions of direct and indirect basal ganglia pathways, but none of these lesions alone, reproduce patients’ learning impairments. Degeneration of medium spiny neurons of the direct pathway accounts for patients’ deficits in facilitating correct responses, whereas degeneration of indirect pathway medium spiny neurons explains their impairments in inhibiting dominant but incorrect responses. The empirical results cannot be explained by lesions of the subthalamic nucleus, which is part of the hyperdirect pathway, or by changes in dopamine levels. Overall, our simulations suggest combined lesions of direct and indirect pathways as a major source of HD patients’ learning impairments and, tentatively, also their motor and cognitive deficits in general, whereas changes in dopamine levels are suggested to not be causally related to patients’ impairments.