Vagus Nerve Stimulation Enhances Extinction of Conditioned Fear in Rats and Modulates Arc Protein, CaMKII, and GluN2B-Containing NMDA Receptors in the Basolateral Amygdala.

Amanda C Alvarez-Dieppa,Christa K Mcintyre,Kimberly Griffin,Sheridan Cavalier

doi:10.1155/2016/4273280

Amanda C Alvarez-Dieppa, Christa K Mcintyre + Show 2 more

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https://doi.org/10.1155/2016/4273280

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Journal: Neural plasticity	Publication Date: Jan 1, 2016
Citations: 49	License type: CC BY 4.0

Affiliation: The University of Texas at Dallas

Abstract

Vagus nerve stimulation (VNS) enhances the consolidation of extinction of conditioned fear. High frequency stimulation of the infralimbic cortex (IL) produces long-term potentiation in the basolateral amygdala (BLA) in rats given VNS-paired extinction training, whereas the same stimulation produces long-term depression in sham-treated rats. The present study investigated the state of synaptic plasticity-associated proteins in the BLA that could be responsible for this shift. Male Sprague-Dawley rats were separated into 4 groups: auditory fear conditioning only (fear-conditioned); fear conditioning + 20 extinction trials (extended-extinction); fear conditioning + 4 extinction trials paired with sham stimulation (sham-extinction); fear conditioning + 4 extinction trials paired with VNS (VNS-extinction). Freezing was significantly reduced in extended-extinction and VNS-extinction rats. Western blots were used to quantify expression and phosphorylation state of synaptic plasticity-associated proteins such as Arc, CaMKII, ERK, PKA, and AMPA and NMDA receptors. Results show significant increases in GluN2B expression and phosphorylated CaMKII in BLA samples from VNS- and extended-extinction rats. Arc expression was significantly reduced in VNS-extinction rats compared to all groups. Administration of the GluN2B antagonist ifenprodil immediately after fear extinction training blocked consolidation of extinction learning. Results indicate a role for BLA CaMKII-induced GluN2B expression and reduced Arc protein in VNS-enhanced extinction.

Highlights

Extinction of conditioned fear is the process by which repeated exposure to a cue in the absence of the reenforcer leads to reduced expression of the conditioned fear response
Rats were subjected to auditory fear conditioning followed by extinction training paired with either Vagus nerve stimulation (VNS) (VNS-extinction rats) or sham stimulation, and tissue was collected from the basolateral complex of the amygdala (BLA) 45 min later (Figure 1(a))
Rats given VNS during extinction training showed a significant increase in phosphorylation of CaMKII at Thr286 compared to shamextinction rats (Figure 1(b); t(13) = 2.305, p = 0.038); no difference was seen in total levels of CaMKIIα (Figure 1(c); t(6) = 0.231, p = 0.825) or CaMKIIβ (Figure 1(d); t(6) = 0.947, p = 0.380)

Summary

Introduction

Extinction of conditioned fear is the process by which repeated exposure to a cue in the absence of the reenforcer leads to reduced expression of the conditioned fear response. This process requires the formation of a new memory that competes with the fear memory, thereby diminishing the fear response [1]. Administration of VNS to rats during trials of fear extinction reduces expression of conditioned fear faster than extinction training alone [7], suggesting that VNS could be an effective adjunct to exposure therapies used to treat trauma-related and anxiety disorders.

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