DYT1 dystonia is a debilitating movement disorder characterized by repetitive, unintentional movements and postures. The disorder has been linked to mutation of the TOR1A/DYT1 gene encoding torsinA. Convergent evidence from studies in humans and animal models suggest that striatal medium spiny neurons and cholinergic neurons are important in DYT1 dystonia. What is not known is how torsinA dysfunction in these specific cell types contributes to the pathophysiology of DYT1 dystonia. In this study we sought to determine whether torsinA dysfunction in cholinergic neurons alone is sufficient to generate the sensorimotor dysfunction and brain changes associated with dystonia, or if torsinA dysfunction in a broader subset of cell types is needed. We generated two genetically modified mouse models, one with selective Dyt1 knock-out from dopamine-2 receptor expressing neurons (D2KO) and one where only cholinergic neurons are impacted (Ch2KO). We assessed motor deficits and performed in vivo 11.1 T functional MRI to assess sensory-evoked brain activation and connectivity, along with diffusion MRI to assess brain microstructure. We found that D2KO mice showed greater impairment than Ch2KO mice, including reduced sensory-evoked brain activity in key regions of the sensorimotor network, and altered functional connectivity of the striatum that correlated with motor deficits. These findings suggest that (1) the added impact of torsinA dysfunction in medium spiny and dopaminergic neurons of the basal ganglia generate more profound deficits than the dysfunction of cholinergic neurons alone, and (2) that sensory network impairments are linked to motor deficits in DYT1 dystonia.

DYT1 肌张力障碍是一种使人衰弱的运动障碍，其特征是重复的、无意的运动和姿势。该疾病与编码torsinA的TOR1A/DYT1基因突变有关。来自人类和动物模型研究的趋同证据表明，纹状体中等棘神经元和胆碱能神经元在 DYT1 肌张力障碍中很重要。尚不清楚这些特定细胞类型中的 torsinA 功能障碍如何导致 DYT1 肌张力障碍的病理生理学。在这项研究中，我们试图确定仅胆碱能神经元中的 torsinA 功能障碍是否足以产生与肌张力障碍相关的感觉运动功能障碍和大脑变化，或者是否需要更广泛的细胞类型亚群中的 torsinA 功能障碍。我们生成了两种转基因小鼠模型，一种具有选择性Dyt1从表达多巴胺 2 受体的神经元 (D2KO) 和仅影响胆碱能神经元 (Ch2KO) 的神经元中敲除。我们评估了运动缺陷并在体内进行11.1 T 功能 MRI 评估感觉诱发的大脑激活和连通性，以及扩散 MRI 评估大脑微观结构。我们发现 D2KO 小鼠比 Ch2KO 小鼠表现出更大的损伤，包括感觉运动网络关键区域的感觉诱发大脑活动减少，以及与运动缺陷相关的纹状体功能连接性改变。这些发现表明（1）基底神经节的中型多刺神经元和多巴胺能神经元中 torsinA 功能障碍的额外影响比单独的胆碱能神经元功能障碍产生更严重的缺陷，以及（2）感觉网络损伤与 DYT1 中的运动缺陷有关肌张力障碍。