Vagal subcircuits differentially regulate sepsis-induced sickness and anxiety-related behaviors

The brain monitors peripheral immune activity via vagus nerve sensory neurons, whose cell bodies lie in the nodose ganglia and project to the brainstem dorsal vagal complex. This relay activates neural circuits mediating infection-related behavioral changes, such as sickness behavior. In severe inflammation like sepsis, this signaling can contribute to brain dysfunction, including persistent anxiety. Using the rodent sepsis model of cecal ligation and puncture, we investigated how vagal subcircuits contribute to these effects, by integrating surgical and chemogenetic gain- and loss-of-function approaches. Activating dorsal vagal complex neurons exacerbated sickness behavior and promoted lasting anxiety-related behavior, while activating upstream nodose neurons did not. Nodose or brainstem transient inhibition had no effect. However, subdiaphragmatic vagotomy reduced acute brain activation and partly attenuated anxiety symptoms in sepsis survivors. These results highlight the complex vagal-immune-brain interplay and emphasize the importance of mechanistic insights to guide the development of targeted therapies.