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

Abstract EN

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.