Vagus nerve stimulation drives selective circuit modulation through cholinergic reinforcement

• Published in: Neuron (Cambridge, Mass.) Vol. 110; no. 17; pp. 2867 - 2885.e7
• Main Authors: Bowles, Spencer, Hickman, Jordan, Peng, Xiaoyu, Williamson, W. Ryan, Huang, Rongchen, Washington, Kayden, Donegan, Dane, Welle, Cristin G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.09.2022
• Subjects: Animals; basal forebrain; Brain; cholinergic; Cholinergic Agents - pharmacology; learning; Mice; motor cortex; motor learning; Nervous System Diseases - therapy; neuromodulation; Neuronal Plasticity - physiology; outcome; plasticity; reinforcement; vagus nerve stimulation; Vagus Nerve Stimulation - methods; neuromodulation; motor cortex; motor learning; cholinergic; basal forebrain; plasticity; vagus nerve stimulation; learning; reinforcement; outcome
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2022.06.017

Vagus nerve stimulation (VNS) is a neuromodulation therapy for a broad and expanding set of neurologic conditions. However, the mechanism through which VNS influences central nervous system circuitry is not well described, limiting therapeutic optimization. VNS leads to widespread brain activation, but the effects on behavior are remarkably specific, indicating plasticity unique to behaviorally engaged neural circuits. To understand how VNS can lead to specific circuit modulation, we leveraged genetic tools including optogenetics and in vivo calcium imaging in mice learning a skilled reach task. We find that VNS enhances skilled motor learning in healthy animals via a cholinergic reinforcement mechanism, producing a rapid consolidation of an expert reach trajectory. In primary motor cortex (M1), VNS drives precise temporal modulation of neurons that respond to behavioral outcome. This suggests that VNS may accelerate motor refinement in M1 via cholinergic signaling, opening new avenues for optimizing VNS to target specific disease-relevant circuitry. [Display omitted] •VNS paired with success enhances skilled motor learning in healthy animals•Enhanced motor performance is due to accelerated consolidation of an expert motor plan•Enhanced motor learning depends on cholinergic neural activity in the basal forebrain•In primary motor cortex, VNS specifically modulates outcome-activated neurons Stimulation of the vagus nerve paired with behavior has been shown to enhance rehabilitation following neurologic injury, but the mechanism remains unknown. Bowles, Hickman, Peng et al. demonstrate that VNS applied after a successful reach improves skilled motor learning via a cholinergic reinforcement mechanism, resulting in selective modulation of M1 neurons.