Molecular Ontology Predicts Output Connections From the Nucleus of the Solitary Tract

Understanding how the brain processes bodily signals requires mapping the circuits that transform interoceptive information into coordinated responses. Visceral signals converge in the nucleus of the solitary tract (NTS), which coordinates appetite, breathing, cardiovascular reflexes, and digestion. The NTS contains many intermingled subpopulations of neurons, and deciphering their functions requires understanding their connections. Here, we used cell-type-specific tracing to test whether molecularly distinct NTS neurons exhibit unique connectivity patterns. First, we found that Lmx1b-expressing excitatory neurons provide output to a broad array of NTS target regions in both the brainstem and forebrain, while inhibitory neurons in this region project predominantly within the brainstem. Next, we found that several genetically defined excitatory subpopulations-catecholaminergic (Th), neuropeptidergic (Cck, Npff, or Pdyn), and aldosterone-sensitive (Hsd11b2)-exhibit unique output patterns across multiple targets. As examples, the ventrolateral medulla receives moderate Th, Cck, and Pdyn, light Npff, and no Hsd11b2 input. The outer rim of the external lateral parabrachial subnucleus receives concentrated Th, Cck, and Npff input, contrasting a more uniform Pdyn input and a lack of Hsd11b2 input. The subcommissural bed nucleus of the stria terminalis receives broad Th, light Cck, sparse Pdyn, and virtually no Npff input, contrasting the focal Hsd11b2 input to its fusiform subnucleus. These divergent patterns demonstrate that molecular identity predicts connectivity and define the organizational logic by which interoceptive signals are transformed into coordinated autonomic and behavioral responses.