The Multilayer Connectome of Caenorhabditis elegans

Connectomics has focused primarily on the mapping of synaptic links in the brain; yet it is well established that extrasynaptic volume transmission, especially via monoamines and neuropeptides, is also critical to brain function and occurs primarily outside the synaptic connectome. We have mapped the putative monoamine connections, as well as a subset of neuropeptide connections, in C. elegans based on new and published gene expression data. The monoamine and neuropeptide networks exhibit distinct topological properties, with the monoamine network displaying a highly disassortative star-like structure with a rich-club of interconnected broadcasting hubs, and the neuropeptide network showing a more recurrent, highly clustered topology. Despite the low degree of overlap between the extrasynaptic (or wireless) and synaptic (or wired) connectomes, we find highly significant multilink motifs of interaction, pinpointing locations in the network where aminergic and neuropeptide signalling modulate synaptic activity. Thus, the C. elegans connectome can be mapped as a multiplex network with synaptic, gap junction, and neuromodulator layers representing alternative modes of interaction between neurons. This provides a new topological plan for understanding how aminergic and peptidergic modulation of behaviour is achieved by specific motifs and loci of integration between hard-wired synaptic or junctional circuits and extrasynaptic signals wirelessly broadcast from a small number of modulatory neurons.连接组学（Connectomics）此前主要聚焦于大脑内突触连接的图谱绘制；但已有充分研究证实，突触外容积传递（extrasynaptic volume transmission）——尤其是通过单胺类物质（monoamines）和神经肽（neuropeptides）介导的传递——同样对大脑功能至关重要，且其主要发生于突触连接组（synaptic connectome）之外。我们基于新增及已发表的基因表达数据，绘制了秀丽隐杆线虫（C. elegans）中推定的单胺能连接，以及部分神经肽连接的图谱。单胺能与神经肽能网络展现出截然不同的拓扑特性：单胺能网络呈现高度异配的星型结构，并拥有由互联广播枢纽构成的富人俱乐部（rich-club）结构；而神经肽网络则表现出更具递归性、高度聚类的拓扑特征。尽管突触外（或称"无线"）连接组与突触（或称"有线"）连接组的重叠度极低，但我们仍发现了极具统计学显著性的多连接基序（multilink motifs）交互模式，精准定位到了胺能与神经肽能信号调控突触活动的网络位点。据此，秀丽隐杆线虫的连接组可被建模为包含突触连接、缝隙连接（gap junction）以及神经调节层（neuromodulator layers）的多路网络（multiplex network），各层代表神经元间不同的交互模式。这为理解行为的胺能与肽能调控机制提供了全新的拓扑框架：阐明了硬连接的突触或缝隙连接回路，与少量调节性神经元无线广播的突触外信号之间，如何通过特定基序与整合位点实现行为调控。