Extinction Learning Paired with Vagus Nerve Stimulation Enhances Behavioral Outcomes and Drives Plasticity in Extinction Networks

Extinction learning is integral to the treatment of substance use disorder (SUD), and anxiety and trauma related disorders such as phobia, generalized anxiety, and post-traumatic stress disorder (PTSD). These disorders feature maladaptive responses to conditioned stimuli. In SUD, patients exposed to drug-associated cues or environments experience anxiety, craving, and renewal of drug-seeking behavior. In phobia and PTSD, patients develop fearful responses to otherwise harmless stimuli, and when exposed to these conditioned stimuli experience disruptive levels of fear, avoidance, and anxiety. Unfortunately, extinction learning is frequently impaired in these patient populations, making extinction-based cognitive behavioral exposure therapy difficult. Several interventions have been applied to increase the efficacy of exposure therapy including the use of drugs such as antidepressants, anxiolytics, or nootropics; other types of cognitive behavioral therapy such as mindfulness or coping strategies; and deep brain stimulation among others, each with varying degrees of success. Vagus nerve stimulation (VNS) is FDA-approved for the treatment of epilepsy and treatmentresistant depression, and has been found to enhance memory consolidation in rats and in humans and to drive other types of neuroplasticity. The work of this dissertation investigates the use of VNS to enhance extinction learning in a model of conditioned fear and in a model of drugtaking. In Chapter 2 I describe experiments that examined the effects of VNS on the extinction of an auditory fear memory. In these experiments we found lower rates of conditioned fear in animals that were given VNS during extinction. When we investigated connectivity between the infralimbic prefrontal cortex (IL) and the basolateral amygdala (BLA), a pathway involved in extinction learning, we found that the conditions for the induction of plasticity were changed in VNS animals compared to sham-stimulated animals. In Chapters 3 and 4 I describe experiments in which we applied VNS during extinction from drug-seeking, and found reduced renewal of drug-seeking during cued- and contextual renewal. As in our model of fear conditioning, VNS animals extinguished from drug-seeking also had altered IL-BLA connectivity. These results provide preclinical evidence for VNS as an effective adjunct to extinction training. Because of the advantages treatment with electrical stimulation offers over other methods, VNS paired with extinction should be further investigated for use in the clinical setting