Acute vagus nerve stimulation enhances reversal learning in rats
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.
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