Signaling Connectomics: A Brain-wide Framework for Intercellular Communication

Understanding the brain requires mapping not only neuronal circuits but the full landscape of intercellular communication. Here we introduce "signaling connectomics", a systems framework for interpreting divergent signaling context. It charts brain-wide signaling across synaptic, neuromodulatory, immune, glial, and vascular pathways. By integrating targeted perturbations with multiplexed molecular and imaging readouts, this approach infers causal signaling networks that operate beyond conventional synapses. It challenges circuit-centric models by emphasizing how dynamic receptor landscapes, extracellular cues, and non-synaptic interactions collectively shape neural function and dysfunction. Combining cell-type-specific optogenetics, biosensors, and spatial transcriptomics, signaling connectomics enables systematic mapping of intercellular signaling dynamics and cross-talk in vivo, providing a multidimensional view of how the brain coordinates activity across diverse cell types. Ultimately, this framework provides conceptual and methodological foundations for linking multicellular signaling to circuit-level plasticity and behavior via explicit causal chains.