The brain senses peripheral immune activity through sensory neurons of the vagus nerve, whose cell bodies reside in the nodose ganglia and that project centrally to the brainstem dorsal vagal complex. This visceral sensory relay engages neural circuits that drive infection-associated behavioral changes collectively described as sickness behavior. In settings of severe inflammation such as sepsis, this same signaling axis can contribute to deleterious brain outcomes, including sustained anxiety-related behaviors.
The investigators used the cecal ligation and puncture (CLP) model in rodents to study how distinct vagal subcircuits influence sepsis-induced behavioral and brain changes. They applied a combination of surgical manipulations and chemogenetic gain- and loss-of-function techniques to selectively modulate activity in upstream sensory neurons (nodose ganglia) and downstream brainstem targets (dorsal vagal complex). The abstract reports results from activating or transiently inhibiting these neuronal populations and from a subdiaphragmatic vagotomy intervention.
Chemogenetic activation of neurons within the dorsal vagal complex aggravated acute sickness behavior induced by sepsis and promoted lasting anxiety-related behavior in animals that survived the septic insult. These findings identify the dorsal vagal complex as a node whose increased activity can both exacerbate immediate illness behaviors and contribute to persistent affective symptoms after recovery from acute systemic inflammation.
By contrast, activating upstream nodose sensory neurons did not reproduce the behavioral effects seen with dorsal vagal complex stimulation, indicating functional dissociation between these segments of the vagal pathway. Additionally, transient inhibition of either nodose neurons or dorsal vagal complex neurons reportedly produced no effect on sepsis-induced behaviors, as described in the source. Together these observations suggest that acute activation of brainstem circuitry, rather than modulation of nodose sensory neurons alone, may be crucial for driving the behavioral sequelae observed in this model.
Surgically interrupting subdiaphragmatic vagal signaling (subdiaphragmatic vagotomy) reduced acute brain activation associated with sepsis and partly attenuated anxiety symptoms in sepsis survivors. This partial mitigation indicates that peripheral vagal inputs below the diaphragm contribute to sepsis-related brain activation and to the development of subsequent anxiety, but that other pathways or mechanisms likely also participate in producing persistent behavioral changes.
The study demonstrates that different components of the vagal pathway have distinct functional impacts during sepsis: dorsal vagal complex activation intensifies sickness and fosters persistent anxiety-related behavior, whereas manipulation of upstream nodose ganglia neurons did not yield comparable effects in the reported experiments. The partial benefit of subdiaphragmatic vagotomy implies a role for visceral afferents in transmitting immune signals that affect the brain, but also highlights the complexity of the vagal-immune-brain interplay.
Clinically, these findings emphasize that targeted interventions aiming to modify vagal signaling in sepsis-related brain dysfunction will require mechanistic precision. Approaches that globally modify vagal tone may produce heterogeneous effects depending on which subcircuits are engaged. The work supports further preclinical delineation of the specific neuronal populations and downstream networks that mediate acute and long-term neurobehavioral consequences of systemic inflammation.
The abstract summarizes experimental findings but does not provide detailed methodological parameters in this source: quantitative behavioral data, effect sizes, timing of interventions, animal numbers, exact chemogenetic constructs used, or histological and electrophysiological outcomes are not reported here. The absence of those specifics in the abstract limits assessment of experimental robustness and translational relevance from this source alone. For full experimental detail, results, and discussion, consult the complete article in Cell Reports (doi: 10.1016/j.celrep.2026.117896).
Overall, the reported results identify the dorsal vagal complex as a key modulator of sepsis-induced sickness and anxiety-related behaviors and indicate that selective interruption of subdiaphragmatic vagal input can partially diminish sepsis-associated brain activation and later anxiety, while underscoring the need for mechanistic clarity before therapeutic translation.