Short-term Effects of Vagus Nerve Stimulation on Learning and Evoked Activity in Auditory Cortex

Abstract

2Chronic vagus nerve stimulation (VNS) can facilitate learning of sensory and motor behaviors. 3 VNS is believed to trigger release of neuromodulators, including norepinephrine and acetylcholine, 4 which can mediate cortical plasticity associated with learning. Most previous work has studied 5 effects of VNS over many days, and less is known about how acute VNS influences neural coding 6 and behavior over the shorter term. To explore this question, we measured effects of VNS on 7 learning of an auditory discrimination over 1-2 days. Ferrets implanted with cuff electrodes on 8 the vagus nerve were trained by classical conditioning on a tone frequency-reward association. 9 One tone was associated with reward while another tone, was not. The frequencies and reward 10 associations of the tones were changed every two days, requiring learning of a new relationship. 11 When the tones (both rewarded and non-rewarded) were paired with VNS, rates of learning 12 increased on the first day following a change in reward association. To examine VNS effects 13 on auditory coding, we recorded single-and multi-unit neural activity in primary auditory cortex 14 (A1) of passively listening animals following brief periods of VNS (20 trials/session) paired with 15 tones. Because afferent VNS induces changes in pupil size associated with fluctuations in 16 neuromodulation, we also measured pupil during recordings. After pairing VNS with a neuron's 17 1 Jesyin Lai Short-term VNSbest-frequency (BF) tone, responses in a subpopulation of neurons were reduced. Pairing with 18 an off-BF tone or performing VNS during the inter-trial interval had no effect on responses. 19 We separated the change in A1 activity into two components, one that could be predicted by 20 fluctuations in pupil and one that persisted after VNS and was not accounted for by pupil. The 21 BF-specific reduction in neural responses remained, even after regressing out changes that 22 could be explained by pupil. In addition, the size of VNS-mediated changes in pupil predicted the 23 magnitude of persistent changes in the neural response. This interaction suggests that changes 24 in neuromodulation associated with arousal gate the long-term effects of VNS on neural activity. 25 Taken together, these results support a role for VNS in auditory learning and help establish VNS 26 as a tool to facilitate neural plasticity. 27 28

Graded recruitment of pupil-linked neuromodulation by parametric stimulation of the vagus nerve

“…Pupil dilation also tracks neuromodulatory brain state in humans and non-human primates [30,31]. Here, we test the hypothesis that pupil dilation can serve as a biosensor of VNS-evoked titratable effects on neuromodulatory brain state, as suggested by recent studies [32,33]. Indeed, we find that VNS results in pupil dilation with a magnitude that tracks the stimulation parameters.…”

Vagus nerve stimulation accelerates motor learning through cholinergic modulation

“…This makes it difficult to disentangle direct VNS effects from changes in arousal. In contrast, another recent work demonstrated a VNS-driven suppression of neural response to an auditory tone that persisted even after arousal state was regressed from the neural response 88 . Our trial design controls for movement state, as the comparison between the VNS trial and no-stimulation trial occurs at the exact same reach position, and VNS did not produce any noticeable acute motor response.…”

Graded recruitment of pupil-linked neuromodulation by parametric stimulation of the vagus nerve

“…Pupil dilation also tracks the neuromodulatory brain state in humans and nonhuman primates 30,31 . Here, we test the hypothesis that pupil dilation can serve as a biosensor of VNS-evoked titratable effects on neuromodulatory brain state, as suggested by recent studies 32,33 . Indeed, we find that VNS results in pupil dilation with a magnitude that tracks the stimulation parameters.…”