The Dynamic Relationship Between Peripheral and Central Nodose Ganglion Projections: Neurotrophin-4 Exerts Organ-Specific Regulation of Vagal Afferents

Vagal afferents form the primary gut-to-brain neural axis and are thought to communicate negative feedback signals to the central nervous system to attenuate consummatory behaviors by promoting satiation and possibly satiety. The expansive and fluid nature of the gastrointestinal organs has made it methodologically challenging to decipher the negative feedback signals, and how the signals are disseminated or converged within the central feeding systems. We sought to understand the anatomical relationship and organization between the terminal fields of the peripheral axonal projections and the central axonal projections of gastrointestinal (GI) vagal afferents for clues about what and how information is communicated along the gut-brain axis. Here, we quantified the density and distribution of peripheral and central GI vagal axonal projections in neurotrophin-4 deficient (KO) and control mice. KO mice exhibited a 75 and 55% reduction in small intestinal vagal mucosal afferents, proximally distally, and no significant reduction of mucosal vagal afferents in the stomach, compared to controls. Previous characterization, similarly, reported a >70% reduction in small intestinal vagal muscle afferents and no loss of muscle afferents in the stomach. Centrally, KO mice exhibited an increase in central terminal axonal projections in the medial nucleus tractus solitarius. Our findings support previous hypotheses that neurotrophin-4 exerts an organ-specific regulation of development of gastrointestinal vagal afferents innervation. Furthermore, our findings highlight the dynamic relationship between the peripheral and central axonal projections of vagal afferents.