Imaging cellular activity across all organs reveals body-wide circuits

Abstract An animal’s ability to survive and thrive—whether fleeing from danger, eating a meal, or fighting an infection—arises from the collective moment-to-moment activity of many interacting cell types throughout the body. Physiology seeks to elucidate these cellular interactions that span organs, cell types and timescales, but has been limited by the inability to record this time-varying cellular activity simultaneously throughout the entire body. Here we develop WHOLISTIC (WHole-Organism Live-Imaging System for recording Tissue and IntraCellular activity), a method to image second-timescale activity of cells across the entire vertebrate body at cellular resolution. WHOLISTIC advances and integrates volumetric fluorescence microscopy, machine learning, and pancellular transgenic expression of calcium sensors 1 , demonstrated in larval zebrafish, with proof of concept in adult Danionella cerebrum . To access information about the molecular and ultrastructural substrates for the measured dynamics, we advanced whole-body expansion microscopy 2 . At the cellular scale, body-wide screening revealed unexpected responses, including chondrocyte reactions to cold and meningeal responses to ketamine. At the organ scale, WHOLISTIC identified rhythmic travelling waves along the renal nephron. At the multi-organ scale, it revealed unknown muscle synergies and muscle–organ interactions. At the whole-organism scale, the method captured brainstem-controlled redistribution of body-wide blood flow. Combining optogenetics with WHOLISTIC enabled all-optical causal dissection of brain–body interactions. These advances establish a paradigm for systems biology that bridges cellular and organismal physiology, enabling comprehensive discovery across scales—from fundamental mechanisms to therapeutic targets.