Adury R Z, Wilkes B J, Girdhar P, Li Y, Vaillancourt D E
Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA.
Department of Neurology, University of Florida, Gainesville, FL, USA.
Dystonia. 2025;4. doi: 10.3389/dyst.2025.13874. Epub 2025 Feb 12.
DYT1 dystonia is an early onset, generalized form of isolated dystonia characterized by sustained involuntary muscle co-contraction, leading to abnormal movements and postures. It is the most common hereditary form of primary dystonia, caused by a trinucleotide GAG deletion in the DYT1 gene, which encodes the TorsinA protein. Recent studies conceptualized dystonia as a functional network disorder involving basal ganglia, thalamus, cortex and cerebellum. However, how TorsinA dysfunction in specific cell types affects network connectivity and dystonia-related pathophysiology remains unclear. In this study, we aimed to elucidate the impact of the GAG TorsinA mutation present globally and when restricted to the cortical and hippocampal neurons. To accomplish this, we generated two distinct Dyt1 mouse models, one with Dyt1 dGAG knock-in throughout the body (dGAG) and another with a cerebral cortex-specific Dyt1 dGAG knock-in using Emx1 promoter (EMX). In both models, we performed neuroimaging at ultra-high field (11.1T). We employed functional magnetic resonance imaging (fMRI) to assess resting-state and sensory-evoked brain connectivity and activation, along with diffusion MRI (dMRI) to evaluate microstructural changes. We hypothesized that dGAG mice would exhibit widespread network disruptions compared to the cortex-specific EMX mice, due to broader TorsinA dysfunction across the basal ganglia and cerebellum. We also hypothesized that EMX mice would exhibit altered functional connectivity and activation patterns, supporting the idea that TorsinA dysfunction in the sensorimotor cortex alone can induce network abnormalities. In dGAG animals, we observed significantly lower functional connectivity between key sensorimotor nodes, such as the globus pallidus, somatosensory cortex, thalamus, and cerebellum. EMX mice, while showing less extensive network disruptions, exhibited increased functional connectivity between cerebellum and seeds in the striatum and brainstem. These functional connectivity alterations between nodes in the basal ganglia and the cerebellum in both dGAG, EMX models underscore the involvement of cerebellum in dystonia. No significant structural changes were observed in either model. Overall, these results strengthen the concept of dystonia as a network disorder where multiple nodes across the brain network contribute to pathophysiology, supporting the idea that therapeutic strategies in dystonia may benefit from consideration of network properties across multiple brain regions.
DYT1肌张力障碍是一种早发性、全身性的孤立性肌张力障碍，其特征为肌肉持续不自主协同收缩，导致异常运动和姿势。它是原发性肌张力障碍最常见的遗传形式，由DYT1基因中的三核苷酸GAG缺失引起，该基因编码TorsinA蛋白。最近的研究将肌张力障碍概念化为一种涉及基底神经节、丘脑、皮层和小脑的功能性网络障碍。然而，TorsinA在特定细胞类型中的功能障碍如何影响网络连接性和肌张力障碍相关的病理生理学仍不清楚。在本研究中，我们旨在阐明全局存在的GAG TorsinA突变以及仅限于皮质和海马神经元时的影响。为实现这一目标，我们构建了两种不同的Dyt1小鼠模型，一种是全身Dyt1 dGAG敲入模型（dGAG），另一种是使用Emx1启动子构建的大脑皮层特异性Dyt1 dGAG敲入模型（EMX）。在这两种模型中，我们在超高场（11.1T）下进行了神经成像。我们采用功能磁共振成像（fMRI）来评估静息态和感觉诱发的脑连接性及激活情况，同时使用扩散磁共振成像（dMRI）来评估微观结构变化。我们假设，与皮层特异性EMX小鼠相比，dGAG小鼠会表现出广泛的网络破坏，因为基底神经节和小脑中TorsinA功能障碍更为广泛。我们还假设，EMX小鼠会表现出功能连接性和激活模式的改变，这支持了仅感觉运动皮层中的TorsinA功能障碍就能诱发网络异常的观点。在dGAG动物中，我们观察到关键感觉运动节点之间的功能连接性显著降低，如苍白球、体感皮层、丘脑和小脑。EMX小鼠虽然表现出的网络破坏范围较小，但在小脑与纹状体和脑干中的种子区域之间表现出功能连接性增加。dGAG和EMX模型中基底神经节和小脑中节点之间的这些功能连接性改变强调了小脑参与肌张力障碍。在两种模型中均未观察到明显的结构变化。总体而言，这些结果强化了肌张力障碍是一种网络障碍的概念，即大脑网络中的多个节点都参与了病理生理学过程，支持了肌张力障碍的治疗策略可能受益于考虑多个脑区网络特性的观点。
