Abstract

Objectives To determine how selective optogenetic vagus nerve stimulation (VNS) of distinct axonal subpopulations modulates systemic inflammatory cytokines in an acute model of endotoxemia. Materials and Methods A silicone spiral nerve cuff with integrated custom probes including microscale light-emitting diodes (LEDs) was fabricated and implanted on the left cervical vagus nerve of anesthetized transgenic mice expressing ChR2 under cholinergic (ChAT) or glutamatergic (Vglut2) cell promoters. Lipopolysaccharide (3 mg/kg) was administered intraperitoneally to induce endotoxemia, and mice received optical VNS for 2 hours. Blood was collected 30 minutes after VNS termination and quantified via immunoassay for serum inflammatory cytokines (IL-6, IL-1{beta}, TNF-, IL-10) and C-reactive protein (CRP). Results ChAT-selective optical VNS significantly reduced IL-6 (p = 0.027) and IL-1{beta} (p = 0.026) relative to Cre-negative sham controls. Vglut2-targeted stimulation did not significantly reduce IL-6, IL-1{beta}, or TNF- versus sham. Cytokine levels were significantly reduced with ChAT VNS compared to Vglut2 VNS in all pro-inflammatory cytokines (IL-6: p=0.024, IL-1{beta}: p=0.011, TNF-: p=0.030). The anti-inflammatory cytokine IL-10 was significantly decreased with ChAT versus Vglut2 VNS (p=0.033). CRP levels were not statistically different between groups. Conclusions Optogenetic VNS targeting cholinergic neurons produced robust suppression of key pro-inflammatory cytokines IL-1{beta} and IL-6, whereas stimulation of glutamatergic neurons did not significantly alter inflammatory cytokine levels, highlighting the importance of pathway selectivity in the inflammatory effects of VNS. These findings highlight cell-type specific optogenetic neuromodulation as a valuable tool for assessing impact of vagal circuits and support preferential targeting of efferent cholinergic neurons in acute systemic inflammation.