What we study and how we do it.
Most organs are controlled by the brain and spinal cord from a distance. The intestine is different: it carries its own nervous system inside its wall. The enteric nervous system, the third division of the autonomic nervous system, can run much of digestion on its own, but it never works alone. Sensory neurons carry information from the gut inward, and autonomic neurons carry commands back out. Together these three lineages form the intestinal nervous system, and they make the gut an unusually good place to ask how peripheral neurons control an entire organ.
Genetic access
Enteric neurons were long grouped by broad functional categories rather than by molecular identity, which made it nearly impossible to test what any single cell type does. We have built more than thirty new mouse lines that label, silence, and activate transcriptionally defined neurons across all three lineages that innervate the gut: enteric, sensory, and autonomic. This gives us access to one cell type at a time in a living animal.
Development
Where does this diversity come from? Building a transcriptomic atlas of the sensory lineage, we found that neurons are born in a transcriptionally unspecialized state, co-expressing transcription factors that only later become restricted to particular subtypes. Signals from the neuron’s eventual target help drive that shift from generic to specific. We are now asking how the same problem is solved in the enteric and autonomic lineages.
Physiology
Knowing what a cell type is matters only if you can say what it does. We combine chemogenetics, in vivo multiphoton imaging, and quantitative measures of gut function to test each subtype directly. Enteric subtypes turn out to be far from redundant, individually shaping fecal output, hydration, and food intake, and some cannot control intestinal transit at all without extrinsic input. Colon-innervating sensory neurons, meanwhile, set the threshold at which distension becomes pain.