Bursting Parameters Alter Excitatory Postsynaptic Currents in Nucleus Tractus Solitarius Neurons: Implications for Clinical Vagus Nerve Stimulation.

Vagus nerve stimulation (VNS) is an approved therapy for multiple neurological and autonomic disorders; however, the mechanisms underlying its therapeutic effects and optimal stimulation parameters remain poorly understood. Vagal afferents activated by VNS terminate within the nucleus tractus solitarius (NTS), where sensory information is integrated and propagated throughout central autonomic networks. Although conventional VNS paradigms are used therapeutically, previous studies have demonstrated high rates of synaptic transmission failure within NTS circuits, suggesting that alternative stimulation strategies could enhance neural activity. Bursting VNS has emerged as a promising alternative to standard stimulation patterns, but its effects on NTS neuronal processing remain unclear. The present study used voltage-clamp recordings in rat brainstem slices to study NTS neurons, with solitary tract (ST) stimulation delivered using single-pulse or bursting parameters to evoke excitatory postsynaptic currents (EPSCs). Bursting paradigms varying in frequency (150-350 Hz) and pulse number (2-4 pulses per burst) were compared with single-pulse stimulation. EPSC amplitude and total area under the curve (AUC) were used to quantify stimulation responses. In NTS neurons monosynaptically connected to ST afferents, bursting paradigms significantly reduced the amplitude of the first EPSC relative to single-pulse stimulation, whereas no differences in overall AUC were observed. In contrast, polysynaptic neurons exhibited burst-dependent differences in excitatory transmission, with differences observed relative to baseline and across pulse conditions. Specifically, AUC was significantly greater during lower-frequency (150-250 Hz) 3- and/or 4-pulse bursts compared with single-pulse stimulation. Across all frequencies tested, 3- and/or 4-pulse bursts also produced significantly greater AUC than the corresponding 2-pulse paradigm. These findings indicate that bursting stimulation differentially modulates excitatory transmission in monosynaptic and polysynaptic NTS neurons, with specific pulse and frequency combinations preferentially influencing higher-order NTS circuitry and providing insight into stimulation strategies that may improve central network engagement during clinical VNS.