Vagus nerve stimulation enhances extinction of conditioned fear and modulates plasticity in the pathway from the ventromedial prefrontal cortex to the amygdala.

David Frausto Peã±A,Shawn Willett,Sven Kroener,Christa K Mcintyre,Jessica E Childs,Analicia Vital

doi:10.3389/fnbeh.2014.00327

David Frausto Peã±A, Shawn Willett + Show 4 more

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https://doi.org/10.3389/fnbeh.2014.00327

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Abstract

Fearful experiences can produce long-lasting and debilitating memories. Extinction of the fear response requires consolidation of new memories that compete with fearful associations. Subjects with posttraumatic stress disorder (PTSD) show impaired extinction of conditioned fear, which is associated with decreased ventromedial prefrontal cortex (vmPFC) control over amygdala activity. Vagus nerve stimulation (VNS) enhances memory consolidation in both rats and humans, and pairing VNS with exposure to conditioned cues enhances the consolidation of extinction learning in rats. Here we investigated whether pairing VNS with extinction learning facilitates plasticity between the infralimbic (IL) medial prefrontal cortex and the basolateral complex of the amygdala (BLA). Rats were trained on an auditory fear conditioning task, which was followed by a retention test and 1 day of extinction training. Vagus nerve stimulation or sham-stimulation was administered concurrently with exposure to the fear-conditioned stimulus and retention of fear conditioning was tested again 24 h later. Vagus nerve stimulation-treated rats demonstrated a significant reduction in freezing after a single extinction training session similar to animals that received 5× the number of extinction pairings. To study plasticity in the IL-BLA pathway, we recorded evoked field potentials (EFPs) in the BLA in anesthetized animals 24 h after retention testing. Brief burst stimulation in the IL produced LTD in the BLA field response in fear-conditioned and sham-treated animals. In contrast, the same stimulation resulted in potentiation of the IL-BLA pathway in the VNS-treated group. The present findings suggest that VNS promotes plasticity in the IL-BLA pathway to facilitate extinction of conditioned fear responses (CFRs).

Highlights

Extinction of conditioned fear is the process of attenuating fearful behavioral responses to neutral stimuli when they no longer predict aversive outcomes
These findings indicate that Vagus nerve stimulation (VNS) facilitated extinction of conditioned fear, bringing it to the level achieved by extended extinction (EE) training, consistent with our previous results (Peña et al, 2013), and in addition, VNS facilitated extinction to the context as evidenced by reduced freezing behavior during the inter-tone intervals
Neural activity in the ventromedial prefrontal cortex (vmPFC) is increased during recall of extinction memory (Milad and Quirk, 2002), and high-frequency stimulation (HFS) of the IL following retrieval of a conditioned fear memory enhances subsequent fear extinction learning (Maroun et al, 2012)

Summary

Introduction

Extinction of conditioned fear is the process of attenuating fearful behavioral responses to neutral stimuli when they no longer predict aversive outcomes. Extinction requires new learning about the conditioned stimuli (CS). Experiments in rat models of fear learning suggest that the vmPFC is required for the modulation and expression of extinction memory (SierraMercado et al, 2011) and that plasticity in the vmPFC-amygdala pathway underlies the suppression of fear via attenuation of central amygdala activity (Marek et al, 2013). The encoding of fear memory and extinction results in functional changes in neurons in the BLA (Amano et al, 2011). The encoding of learned events results in synaptic changes that modulate subsequent induction of plasticity, or Frontiers in Behavioral Neuroscience www.frontiersin.org

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