Acute vagus nerve stimulation enhances reversal learning in rats

https://doi.org/10.1016/j.nlm.2021.107498Get rights and content

Highlights

  • A novel reversal learning task was developed in touchscreen operant chambers.

  • Vagus nerve stimulation (VNS) enhanced reversal learning.

  • Enhancing effects of VNS depended on stimulation frequency and timing of delivery.

  • Reversal learning was also enhanced by baclofen and atomoxetine.

  • Unlike the pharmacological methods, VNS-induced enhancement had no off-target effects.

Abstract

Cognitive flexibility is a prefrontal cortex-dependent neurocognitive process that enables behavioral adaptation in response to changes in environmental contingencies. Electrical vagus nerve stimulation (VNS) enhances several forms of learning and neuroplasticity, but its effects on cognitive flexibility have not been evaluated. In the current study, a within-subjects design was used to assess the effects of VNS on performance in a novel visual discrimination reversal learning task conducted in touchscreen operant chambers. The task design enabled simultaneous assessment of acute VNS both on reversal learning and on recall of a well-learned discrimination problem. Acute VNS delivered in conjunction with stimuli presentation during reversal learning reliably enhanced learning of new reward contingencies. Enhancement was not observed, however, if VNS was delivered during the session but was not coincident with presentation of to-be-learned stimuli. In addition, whereas VNS delivered at 30 HZ enhanced performance, the same enhancement was not observed using 10 or 50 Hz. Together, these data show that acute VNS facilitates reversal learning and indicate that the timing and frequency of the VNS are critical for these enhancing effects. In separate rats, administration of the norepinephrine reuptake inhibitor atomoxetine also enhanced reversal learning in the same task, consistent with a noradrenergic mechanism through which VNS enhances cognitive flexibility.

Introduction

Cognitive flexibility refers to the ability to modify behavior in response to a change in environmental contingencies. Given our rapidly changing environment, this neurocognitive process is essential for effectively navigating everyday life. Behavioral rigidity and perseveration occur in a host of neuropsychiatric conditions (including schizophrenia, obsessive compulsive disorder, attention-deficit/hyperactivity disorder, autism, and substance use disorders) as well as during the normal aging process (Beas et al., 2013, Bizon et al., 2012, Stuchlik and Sumiyoshi, 2014). As such, therapeutic strategies to enhance cognitive flexibility could have far-reaching benefits (Groman et al., 2013, Izquierdo and Jentsch, 2012).

Cognitive flexibility can be parsed into several distinct forms (e.g., set shifting and reversal learning), but all share a critical dependence on the prefrontal cortex (PFC) and can be modulated by monoaminergic and cholinergic afferents (Birrell and Brown, 2000, Bissonette et al., 2008, Borodovitsyna et al., 2017, Dias et al., 1996, Kim et al., 2011, McAlonan and Brown, 2003, Tait et al., 2014). Pharmacological manipulations targeting these neurochemical systems can enhance cognitive flexibility in both healthy and cognitively-compromised subjects (Chamberlain and Robbins, 2013, Floresco and Jentsch, 2011, Prado et al., 2017, Sadacca et al., 2017, Samanez-Larkin et al., 2013); the efficacy of these drugs is accompanied by off-target effects on behavior, however, which can counter-indicate their utility for intervention.

Electrical vagus nerve stimulation (VNS) has been approved for 30 years to treat intractable epilepsy and depression (Aaronson and Conway, 2018, Dibué-Adjei et al., 2019a, Dibué-Adjei et al., 2019b, McDonald, 2016, Reuter et al., 2019, Smucny et al., 2015, van Hoorn et al., 2019). Some individuals in these VNS treatment groups report cognitive benefits, particularly after long-term use (Aaronson and Conway, 2018, Clark et al., 1999, Clark et al., 1998, Desbeaumes Jodoin et al., 2018, Ghacibeh et al., 2006, Helmstaedter et al., 2001) (Jacobs, Riphagen, Razat, Wiese, & Sack, 2015). Moreover, a year-long trial of chronic VNS in Alzheimer’s disease patients reported improved cognitive outcomes (Merrill et al., 2006, Sjögren et al., 2002). Research in animal models further supports the efficacy of VNS for facilitating cognition. Acute VNS enhances performance in novel object recognition, water maze, and extinction learning tasks in rodents (Noble et al., 2019, Sun et al., 2017). Moreover, VNS facilitates learning to extinguish fear-related responses to a cue previously predictive of electrical shock (i.e., extinction of fear conditioning), which depends critically upon the medial PFC (Morgan and LeDoux, 1995, Morgan et al., 1993, Noble et al., 2019, Peters et al., 2009, Peña et al., 2013, Quirk et al., 2006).

Vagus nerve afferents project to the nucleus of the solitary tract (NTS) which in turn directly innervates the locus coeruleus (LC). The LC provides noradrenergic innervation to much of the brain, including the PFC (Aston-Jones and Waterhouse, 2016, Chandler and Waterhouse, 2012, Chandler et al., 2014, Chandler et al., 2013, Poe et al., 2020, Waterhouse and Navarra, 2019, Waterhouse et al., 1998, Waterhouse et al., 1983). VNS enhancement of cognitive function and neuroplasticity involves signaling through modulatory neurotransmitters, including norepinephrine. Indeed, VNS robustly drives LC neurons and stimulates norepinephrine release in forebrain, including hippocampus and neocortical regions (Hassert et al., 2004, Hulsey et al., 2017, Naritoku et al., 1995, Roosevelt et al., 2006). Moreover, intact LC neurons are critical for VNS-induced cortical plasticity (Hulsey et al., 2018, Shen et al., 2012). Noradrenergic neurons in LC innervate PFC and hippocampus, and norepineprhine signaling in these structures influences many forms of cognition, including flexibility (Arnsten, 2011, Cain et al., 2011, Cope et al., 2019, Glennon et al., 2019, Hvoslef-Eide et al., 2015, Janitzky et al., 2015, Rorabaugh et al., 2017, Sara, 2009, Seu and Jentsch, 2009, Seu et al., 2009).

In the current study, the utility of VNS for enhancing cognitive flexibility was assessed in rats using a novel visual discrimination reversal learning task conducted in touchscreen operant chambers. The task was designed to 1) evaluate the effects of VNS using a within-subjects experimental design; and 2) enable concomitant evaluation of performance on both reversal learning and recall of a well-learned discrimination problem. In Experiment 1, this new task was validated using acute administration of the GABA(B) receptor agonist baclofen, which robustly enhances cognitive flexibility (Beas, McQuail, Banuelos, Setlow, & Bizon, 2017, Beas et al., 2016). In Experiment 2, the effects of VNS paired with presentation of the reversed problem were evaluated. Additional experiments tested effects of varying VNS timing and/or stimulation parameters. Given that VNS can modulate norepinephrine release in the forebrain, Experiment 3 determined whether pharmacologically enhancing norepinephrine availability with atomoxetine mimics the effects of VNS on reversal learning.

Section snippets

Subjects

Young adult (2 months of age at the start of testing) male Brown Norway rats (N = 52) were obtained from Charles River Laboratories and housed individually in the AAALAC-accredited vivarium facility at the University of Florida McKnight Brain Institute. The vivarium was maintained at 25° C with a 12 h reversed light/dark cycle (lights on at 1900). Rats had free access to food and water at all times unless noted otherwise below. Animal procedures were approved by the University of Florida

Experiment 1: Effects of baclofen on reversal learning

Previous work showed that acute systemic administration of the GABA(B) receptor agonist baclofen enhances cognitive flexibility in a set-shifting task (Beas et al., 2016). To determine whether performance on the novel reversal learning task was similarly sensitive to baclofen, the drug was administered prior to reversal learning test sessions. Analysis of performance during the reversal learning phase of the task revealed that rats learned the reversed discrimination problem under both baclofen

Discussion

VNS has been shown previously to produce beneficial effects on neuroplasticity and cognition in a variety of contexts and species. To determine whether VNS is similarly effective for enhancing cognitive flexibility, we used a novel behavioral task design in rats to show that VNS enhances reversal learning in a manner dependent on both the timing of its delivery and the frequency of stimulation. This enhancement was evident without adverse, off-target effects, in contrast to several

CRediT authorship contribution statement

Lindsay K.-P. Altidor: Investigation, Writing – original draft. Matthew M. Bruner: Investigation, Supervision, Formal analysis. Josue F. Deslauriers: Investigation, Writing – original draft. Tyler S. Garman: Investigation, Formal analysis. Saúl Ramirez: Investigation. Elliott W. Dirr: Investigation, Methodology, Validation. Kaitlynn P. Olczak: Investigation, Methodology, Validation. Andrew P. Maurer: Conceptualization. Damon G. Lamb: Conceptualization, Writing - review & editing. Kevin J. Otto:

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

Supported by the Defense Advanced Research Projects Agency (DARPA) BTO under the auspices of Dr. Douglas Weber and Dr. Tristan McClure-Begley through the DARPA Contracts Management Office Grant No. HR0011-17-2-0019, and by the McKnight Brain Research Foundation to JLB. We thank Dr. Erica Dale for illustrations used in the manuscript, Ms. Bonnie McLaurin for conducting surgeries, and Ms. Vicky Kelley, Ms. Alyssa Finner, and Ms. Debora Calderon for assistance with behavioral testing.

References (145)

  • E.P. Buell et al.

    Cortical map plasticity as a function of vagus nerve stimulation rate

    Brain Stimulation

    (2018)
  • R.E. Cain et al.

    Atomoxetine facilitates attentional set shifting in adolescent rats

    Developmental Cognitive Neuroscience

    (2011)
  • D.J. Chandler et al.

    Identification and distribution of projections from monoaminergic and cholinergic nuclei to functionally differentiated subregions of prefrontal cortex

    Brain Research

    (2013)
  • K.B. Clark et al.

    Post-training unilateral vagal stimulation enhances retention performance in the rat

    Neurobiology of Learning and Memory

    (1995)
  • K.B. Clark et al.

    Posttraining electrical stimulation of vagal afferents with concomitant vagal efferent inactivation enhances memory storage processes in the rat

    Neurobiology of Learning and Memory

    (1998)
  • Z.A. Cope et al.

    DREADD-mediated modulation of locus coeruleus inputs to mPFC improves strategy set-shifting

    Neurobiology of Learning and Memory

    (2019)
  • M. Dibué-Adjei et al.

    Vagus nerve stimulation in refractory and super-refractory status epilepticus - A systematic review

    Brain Stimulation

    (2019)
  • M. Dibué-Adjei et al.

    30 years of vagus nerve stimulation trials in epilepsy: Do we need neuromodulation-specific trial designs?

    Epilepsy Research

    (2019)
  • K.L. Evans et al.

    Sex differences on prefrontally-dependent cognitive tasks

    Brain and Cognition

    (2015)
  • S.B. Floresco et al.

    Inactivation of the medial prefrontal cortex of the rat impairs strategy set-shifting, but not reversal learning, using a novel, automated procedure

    Behavioural Brain Research

    (2008)
  • S. Ghods-Sharifi et al.

    Differential effects of inactivation of the orbitofrontal cortex on strategy set-shifting and reversal learning

    Neurobiology of Learning and Memory

    (2008)
  • E. Glennon et al.

    Locus coeruleus activation accelerates perceptual learning

    Brain Research

    (2019)
  • P.E. Gold et al.

    Facilitation of time-dependent memory processes with posttrial epinephrine injections

    Behavioral Biology

    (1975)
  • P.E. Gold et al.

    Effects of hormones on time-dependent memory storage processes

    Progress in Brain Research

    (1975)
  • S.M. Groman et al.

    Monoamine levels within the orbitofrontal cortex and putamen interact to predict reversal learning performance

    Biological Psychiatry

    (2013)
  • G.M. Grospe et al.

    Cognitive flexibility deficits following 6-OHDA lesions of the rat dorsomedial striatum

    Neuroscience

    (2018)
  • D.A. Groves et al.

    Recordings from the rat locus coeruleus during acute vagal nerve stimulation in the anaesthetised rat

    Neuroscience Letters

    (2005)
  • C. Helmstaedter et al.

    Memory alterations during acute high-intensity vagus nerve stimulation

    Epilepsy Research

    (2001)
  • D.R. Hulsey et al.

    Reorganization of motor cortex by vagus nerve stimulation requires cholinergic innervation

    Brain Stimulation

    (2016)
  • D.R. Hulsey et al.

    Parametric characterization of neural activity in the locus coeruleus in response to vagus nerve stimulation

    Experimental Neurology

    (2017)
  • D.R. Hulsey et al.

    Norepinephrine and serotonin are required for vagus nerve stimulation directed cortical plasticity

    Experimental Neurology

    (2019)
  • I.B. Introini-Collison et al.

    Interaction of GABAergic and beta-noradrenergic drugs in the regulation of memory storage

    Behavioral and Neural Biology

    (1994)
  • H.I. Jacobs et al.

    Transcutaneous vagus nerve stimulation boosts associative memory in older individuals

    Neurobiology of Aging

    (2015)
  • J.N. Li et al.

    Sex- and afferent-specific differences in histamine receptor expression in vagal afferents of rats: A potential mechanism for sexual dimorphism in prevalence and severity of asthma

    Neuroscience

    (2015)
  • K.W. Loerwald et al.

    The interaction of pulse width and current intensity on the extent of cortical plasticity evoked by vagus nerve stimulation

    Brain Stimulation

    (2018)
  • K.W. Loerwald et al.

    Varying stimulation parameters to improve cortical plasticity generated by VNS-tone pairing

    Neuroscience

    (2018)
  • F. Luo et al.

    Inward rectifier K

    Experimental Neurology

    (2017)
  • J.M. Luque et al.

    Sexual dimorphism of the dopamine-beta-hydroxylase-immunoreactive neurons in the rat locus ceruleus

    Brain Research. Developmental Brain Research

    (1992)
  • F. Marrosu et al.

    Correlation between GABA(A) receptor density and vagus nerve stimulation in individuals with drug-resistant partial epilepsy

    Epilepsy Research

    (2003)
  • E. Mathew et al.

    Vagus nerve stimulation produces immediate dose-dependent anxiolytic effect in rats

    Journal of Affective Disorders

    (2020)
  • S.M. Matta et al.

    The influence of neuroinflammation in Autism Spectrum Disorder

    Brain, Behavior, and Immunity

    (2019)
  • K. McAlonan et al.

    Orbital prefrontal cortex mediates reversal learning and not attentional set shifting in the rat

    Behavioural Brain Research

    (2003)
  • W.M. McDonald

    Neuromodulation treatments for geriatric mood and cognitive disorders

    The American Journal of Geriatric Psychiatry

    (2016)
  • T. Miyashita et al.

    Epinephrine administration increases neural impulses propagated along the vagus nerve: Role of peripheral beta-adrenergic receptors

    Neurobiology of Learning and Memory

    (2006)
  • M.A. Morgan et al.

    Extinction of emotional learning: Contribution of medial prefrontal cortex

    Neuroscience Letters

    (1993)
  • D.K. Naritoku et al.

    Regional induction of fos immunoreactivity in the brain by anticonvulsant stimulation of the vagus nerve

    Epilepsy Research

    (1995)
  • L.J. Noble et al.

    Vagus nerve stimulation promotes generalization of conditioned fear extinction and reduces anxiety in rats

    Brain Stimulation

    (2019)
  • P.J. Nogueira et al.

    Contribution of the vagus nerve in mediating the memory-facilitating effects of substance P

    Behavioural Brain Research

    (1994)
  • J.V. Pardo et al.

    Chronic vagus nerve stimulation for treatment-resistant depression decreases resting ventromedial prefrontal glucose metabolism

    Neuroimage

    (2008)
  • D.F. Peña et al.

    Rapid remission of conditioned fear expression with extinction training paired with vagus nerve stimulation

    Biological Psychiatry

    (2013)
  • Cited by (0)

    View full text