Acute vagus nerve stimulation enhances reversal learning in rats

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.

Keywords: Cognitive flexibility; Reversal learning; Vagus nerve stimulation.

Fig. 1.

Visual discrimination reversal learning task performed in touchscreen operant chambers. The task consisted of an initial Acquisition phase and a Reversal phase. Rats initially learned to discriminate between two distinct pairs of visual stimuli (Pair 1: A+, B−, and Pair 2: C+, D−). On each trial, touching the correct stimulus (+) in each pair yielded a food reward, whereas touching the incorrect stimulus (−) resulted in a 5 s “time out”. After learning each discrimination to criterion, the reward contingencies of one stimulus pair were reversed (Reversed problem: A−, B+), whereas the contingencies on the other stimulus pair remained unchanged (Constant problem: C+, D−). Each experiment involved two rounds of acquisition and reversal: one in which rats received VNS or drug (panel A), and one in which rats were tethered but no VNS was delivered, or vehicle was administered (panel B). Novel, counter-balanced stimuli were used for each experiment.

Fig. 2.

Vagus nerve implant and experimental setup used during behavioral testing. A) Image of vagus nerve stimulating electrode that was implanted around the left vagus nerve. B) Illustration showing experimental setup for in vivo stimulation of the vagus nerve performed in touchscreen operant chambers.

Fig. 3.

Effects of systemic baclofen on reversal learning. A) Baclofen enhanced accuracy of reversal learning compared to the vehicle control condition. A1) Baclofen produced a significant reduction in the number of trials required for rats to reach criterion performance on the reversed problem set. B) Baclofen did not affect performance accuracy on the constant problem set. In all graphs, error bars represent standard error of the mean (SEM).

Fig. 4.

Effects on reversal learning of 30 Hz VNS delivered during presentation of the reversed problem set. A) VNS (30 Hz) significantly enhanced reversal learning accuracy compared to no stimulation control (CON) conditions on the reversed problem set. A1) Under these conditions, VNS produced a significant reduction in the number of trials required to reach criterion performance. B) There was no effect of VNS on accuracy of the constant problem set. In all graphs, error bars represent standard error of the mean (SEM).

Fig. 5.

Effects on reversal learning of 30 Hz VNS delivered during presentation of the constant problem set. A) VNS (30 Hz) administered concurrently with the constant problem set did not affect reversal learning accuracy compared to no stimulation control (CON) conditions. A1) Under these conditions, VNS had no effect on the number of trials to reach criterion performance. B) There was no effect of VNS on accuracy of the constant problem set. In all graphs, error bars represent standard error of the mean (SEM).

Fig. 6.

Effects on reversal learning of 10 and 50 Hz VNS delivered during presentation of the reversed problem set. There were no effects of VNS compared to control (CON) conditions on the measures of reversal learning when delivered at either 10 Hz (A, A1) or 50 Hz(C, C1). There were similarly no effects of VNS on performance of the constant problem set when delivered at either 10 Hz (B) or 50 Hz (D). In all graphs, error bars represent standard error of the mean (SEM).

Fig. 7.

Effects of 30 Hz VNS on off-target measures. Compared to no-VNS control (CON) conditions, delivery of 30 Hz VNS for 8 consecutive days (1 h/day) had no effect on body weight (A), food intake (B), or locomotor activity (C). In all graphs, circles represent values for individual rats and bars represent group means.

Fig. 8.

Effects of systemic atomoxetine on reversal learning. A) Atomoxetine enhanced accuracy of reversal learning compared to the vehicle control condition. A1) Atomoxetine had no significant effect on the number of trials required to reach criterion performance. B) Atomoxetine did not affect performance accuracy on the constant problem set. In all graphs, error bars represent standard error of the mean (SEM).