Biologist, Know Thy Cells - A Colorful Barcoding Method to ID Cell Types, their Fate, and Decode Brainwide Communication

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A major challenge in biological imaging is resolving cell identities. These are necessary for determining cell-specific protein expression and function, the effect of transcription factors on cell fate, and the contribution of individual neurons to brainwide activity and behavior. Present methods are limited to a piecemeal approach, using multiple strains to identify a few cell types at a time. I introduce a new method and software that can identify many cell types, and in some cases all neurons, in vivo using a single strain. My method combines cell reporters with five distinguishable fluorescent proteins to create unique, stereotyped color codes that identify cell types. I illustrate this in C. elegans, engineering a multicolor transgene called NeuroPAL (a Neuronal Polychromatic Atlas of Landmarks), to create an identical colormap in all worms that uniquely identifies every neuron, showcasing three applications. First, I identify the neuronal expression patterns of all metabotropic receptors for acetylcholine, GABA, and glutamate, thus completing a map of this communication network. My findings indicate that second-messenger systems are the primary means of GABA communication in worm, and further suggest widespread extrasynaptic GABA signaling. Second, I analyze the conserved transcription factor EOR-1/PLZF and, despite its ubiquitous expression, uncover a precise role in neuronal fate. Third, I identify brainwide codes for gustatory and olfactory stimuli. My findings show a complex code that challenges the present view that global neuronal activity is simply low dimensional. To facilitate the workflow, I present semi-automated cell identification software and optimal-coloring software to apply the same method in other tissues and organisms. Lastly, I discuss future applications: investigating how whole-nervous-system activity is remodeled to change behavior during early development, sexual maturation, in response to environmental stress, and even across 15+ million years of evolutionary divergence.