PDF(Pubmed)
Abstract：
The striatum plays a central role in directing many complex behaviors ranging from motor control to action choice and reward learning. In our study, we used 55 male CFW mice with rapid decay linkage disequilibrium to systematically mine the striatum-related behavioral functional genes by analyzing their striatal transcriptomes and 79 measured behavioral phenotypic data. By constructing a gene coexpression network, we clustered the genes into 13 modules, with most of them being positively correlated with motor traits. Based on functional annotations as well as Fisher\'s exact and hypergeometric distribution tests, brown and magenta modules were identified as core modules. They were significantly enriched for striatal-related functional genes. Subsequent Mendelian randomization analysis verified the causal relationship between the core modules and dyskinesia. Through the intramodular gene connectivity analysis, Adcy5 and Kcnma1 were identified as brown and magenta module hub genes, respectively. Knock outs of both Adcy5 and Kcnma1 lead to motor dysfunction in mice, and KCNMA1 acts as a risk gene for schizophrenia and smoking addiction in humans. We also evaluated the cellular composition of each module and identified oligodendrocytes in the striatum to have a positive role in motor regulation.
摘要：
纹状体在指导从运动控制到动作选择和奖励学习的许多复杂行为中起着核心作用。在我们的研究中,我们使用了55只具有快速衰变连锁不平衡的CFW小鼠，通过分析其纹状体转录组和79个测量的行为表型数据，系统地挖掘了纹状体相关的行为功能基因。通过构建基因共表达网络,我们把基因分成13个模块，其中大多数与运动性状呈正相关。基于功能注释以及Fisher的精确和超几何分布检验，棕色和洋红色模块被确定为核心模块。它们显着富集了纹状体相关的功能基因。随后的孟德尔随机化分析验证了核心模块与运动障碍之间的因果关系。通过模块内基因连接分析，Adcy5和Kcnma1被鉴定为棕色和洋红色模块集线器基因，分别。基因敲除Adcy5和Kcnma1导致小鼠运动功能障碍，KCNMA1是人类精神分裂症和吸烟成瘾的风险基因。我们还评估了每个模块的细胞组成，并确定了纹状体中的少突胶质细胞在运动调节中具有积极作用。意义声明纹状体在指导从运动控制到动作选择和奖励学习的许多复杂行为中起着核心作用。临床上,纹状体功能障碍导致多种神经退行性疾病,包括众所周知的阿尔茨海默病和亨廷顿病。在我们的研究中,我们使用55只CFW小鼠系统地挖掘了纹状体相关的行为功能基因。我们以多种方式验证了我们的发现。我们发现小鼠中的Adcy5和Kcnma1敲除导致小鼠运动功能障碍，并且Kcnma1与精神分裂症有关，这个发现对人类来说是正确的。最后,我们还评估了不同细胞在纹状体行为调节中的作用，发现纹状体中的少突胶质细胞在运动调节中起着积极的作用。
