Nietz Angela K, Popa Laurentiu S, Carter Russell E, Gerhart Morgan L, Manikonda Keerthi, Ranum Laura P W, Ebner Timothy J
Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
Center for Neurogenetics, Department of Molecular Genetics & Microbiology, College of Medicine, McKnight Brain Institute, Genetics Institute and Fixel Institute, University of Florida, Gainesville, FL 32610, USA.
Neurobiol Dis. 2025 Mar;206:106795. doi: 10.1016/j.nbd.2025.106795. Epub 2025 Jan 7.
Spinocerebellar Ataxia Type 8 (SCA8) is an inherited neurodegenerative disease caused by a bidirectionally expressed CTG•CAG expansion mutation in the ATXN8 and ATXN8OS genes. While SCA8 patients have motor abnormalities, patients may also exhibit psychiatric symptoms and cognitive dysfunction. It is difficult to elucidate how the disease alters brain function in areas with little or no degeneration producing both motor and cognitive symptoms. Using transparent polymer skulls and CNS-wide GCaMP6f expression, we studied neocortical networks throughout SCA8 progression using wide-field Ca imaging in a transgenic mouse model of SCA8. Compared to wild-type controls, neocortical networks in SCA8+ mice were hyperconnected globally, which leads to network configurations with increased global efficiency and centrality. At the regional level, significant network changes occurred in nearly all cortical regions, however mainly involved sensory and association cortices. Changes in functional connectivity in anterior motor regions worsened later in the disease. Near perfect decoding of animal genotype was obtained using a generalized linear model based on canonical correlation strengths between activity in cortical regions. The major contributors to decoding were concentrated in the somatosensory, higher visual and retrosplenial cortices and occasionally extended into the motor regions, demonstrating that the areas with the largest network changes are predictive of disease state.
8型脊髓小脑共济失调（SCA8）是一种遗传性神经退行性疾病，由ATXN8和ATXN8OS基因中双向表达的CTG•CAG扩增突变引起。虽然SCA8患者有运动异常，但患者也可能出现精神症状和认知功能障碍。很难阐明这种疾病如何在几乎没有或没有退化的区域改变脑功能，从而产生运动和认知症状。利用透明聚合物颅骨和全中枢神经系统的GCaMP6f表达，我们在SCA8转基因小鼠模型中使用宽视野钙成像研究了整个SCA8病程中的新皮质网络。与野生型对照相比，SCA8+小鼠的新皮质网络在整体上连接过度，这导致网络配置的全局效率和中心性增加。在区域水平上，几乎所有皮质区域都发生了显著的网络变化，但主要涉及感觉皮质和联合皮质。疾病后期，前运动区域的功能连接变化恶化。使用基于皮质区域活动之间典型相关强度的广义线性模型，几乎可以完美解码动物基因型。解码的主要贡献区域集中在体感皮质、高级视觉皮质和压后皮质，偶尔也会延伸到运动区域，这表明网络变化最大的区域可预测疾病状态。
