Role of Noradrenergic Signaling in the Medial Prefrontal Cortex in Extinction Enhancement Produced by Vagus Nerve Stimulation
Abstract
Abstract
Exposure-based therapy is the gold standard treatment for Post-Traumatic Stress Disorder (PTSD).
This therapy relies on extinguishing traumatic fears by creating new safe associations that
outcompete maladaptive conditioned fear responses. Although being an efficacious practice,
exposure-based therapy can be improved upon. Vagus nerve stimulation (VNS) shows promise as
an adjunctive strategy due to its ability to enhance fear extinction. Despite this promise, the precise
neural mechanisms by which VNS-paired extinction training enhances fear extinction remain
largely unclear. Elucidation of such mechanisms could enable opportunities to fine tune VNS
parameters and improve the efficacy of exposure-based therapy. The present study investigated
the role of noradrenergic signaling in the medial prefrontal cortex (PFC) on extinction
enhancement produced by vagus nerve stimulation. Adult male Sprague-Dawley rats underwent 2
days of auditory fear conditioning (AFC), followed by the implantation of a vagus nerve
stimulation device and the infusion of the immunotoxin saporin (SAP) in the medial prefrontal
cortex to selectively lesion incoming noradrenergic projections to that region. After recovery, rats
underwent 8 days of extinction training paired with VNS or SHAM stimulation before extinction
memory recall was tested and anxiety was examined. Extinction training results showed that SAP
lesions in the PFC led to a negation of VNS-enhanced extinction effects. Extinction recall results
showed rats that received VNS-paired extinction without SAP lesions did not exhibit an increase
in conditioned fear response when tested over 2 weeks after extinction training. No differences in
anxiety-like behaviors were observed when rats were examined in the Open field test 2 days after
extinction training. Together, the results of this study underscore the importance of noradrenergic
signaling in the medial prefrontal cortex on VNS-paired extinction training. Further research needs
to be conducted on the role noradrenergic signaling in the medial prefrontal cortex in the context
of generalized anxiolysis produced by VNS-paired extinction training.