Role of Noradrenergic Signaling in the Medial Prefrontal Cortex in Extinction Enhancement Produced by Vagus Nerve Stimulation

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.