Connectivity webs mediate the unique biology of the mammalian brain. Yet, while cell circuit maps are increasingly available, knowledge of their underlying molecular networks remains limited. Here, we applied multi-dimensional biochemical fractionation with mass spectrometry and machine learning to survey endogenous macromolecules across the adult mouse brain. We defined a global “interactome” comprising over one thousand multi-protein complexes. These include hundreds of brain-selective assemblies that have distinct physical and functional attributes, show regional and cell-type specificity, and have links to core neurological processes and disorders. Using reciprocal pull-downs and a transgenic model, we validated a putative 28-member RNA-binding protein complex associated with amyotrophic lateral sclerosis, suggesting a coordinated function in alternative splicing in disease progression. This brain interaction map (BraInMap) resource facilitates mechanistic exploration of the unique molecular machinery driving core cellular processes of the central nervous system. It is publicly available and can be explored here https://www.bu.edu/dbin/cnsb/mousebrain/.

连接网络介导了哺乳动物大脑的独特生物学。然而，尽管细胞电路图越来越多，但对其底层分子网络的了解仍然有限。在这里，我们应用多维生化分级分离与质谱和机器学习来调查成年小鼠大脑中的内源性大分子。我们定义了一个由一千多个多蛋白复合物组成的全局“相互作用组”。其中包括数百个具有独特物理和功能属性的大脑选择性组合，显示区域和细胞类型特异性，并与核心神经过程和疾病有关。使用相互下拉和转基因模型，我们验证了与肌萎缩侧索硬化症相关的假定的 28 成员 RNA 结合蛋白复合物，表明选择性剪接在疾病进展中具有协调功能。该大脑交互图 (BraInMap) 资源有助于对驱动中枢神经系统核心细胞过程的独特分子机制进行机械探索。它是公开可用的，可以在此处进行探索：https://www.bu.edu/dbin/cnsb/mousebrain/。