Optogenetic Inhibition of the Locus Coeruleus Blocks Vagus Nerve Stimulation-induced Enhancement of Extinction of Conditioned Fear in Rats

Overview

Journal Learn Mem

Specialty Neurology

Date 2024 Dec 16

PMID 39681462

Authors

Debora R Calderon-Williams

Rimenez Rodrigues de Souza

Ching T Tseng

Herve Abdi

Alfredo Sandoval-Flores

Jonathan E Ploski

Catherine A Thorn

Christa K McIntyre

Affiliations

Soon will be listed here.

Abstract

Vagus nerve stimulation (VNS) is a therapeutic intervention previously shown to enhance fear extinction in rats. VNS is approved for use in humans for the treatment of epilepsy, depression, and stroke, and it is currently under investigation as an adjuvant to exposure therapy in the treatment of PTSD. However, the mechanisms by which VNS enhances extinction of conditioned fear remain unresolved. VNS increases norepinephrine levels in extinction-related pathways, but recent studies indicate that norepinephrine release from the locus coeruleus interferes with extinction learning. The purpose of this study is to elucidate the role of the locus coeruleus (LC) in VNS-enhanced fear extinction. Adult male and female tyrosine hydroxylase (Th)-Cre rats were implanted with a stimulating cuff electrode around the left cervical vagus nerve, and a Cre-dependent viral vector expressing the inhibitory opsin ArchT3.0 was infused bilaterally into the LC. Rats then underwent auditory fear conditioning followed by extinction training. During extinction training, rats were divided into four treatment groups: Sham stimulation, Sham with LC inhibition, VNS, and VNS with LC inhibition. Consistent with previous findings, VNS treatment during extinction training significantly reduced freezing 24 h and 2 weeks later. This effect was blocked by optogenetic LC inhibition, suggesting that VNS enhances extinction by engaging the LC.

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