Anxiety disorders are the most common mental illness in the United States. Current treatments include medications that alleviate the symptoms of the disorders but do not target the underlying cause. Attempts to treat the variety of symptoms that can arise in complex anxiety disorders with polypharmacy increase the potential for dangerous interactions. A promising alternative to medication in the treatment of anxiety disorders is Cognitive Behavioral Therapy (CBT).
The aim of CBT is to rehabilitate, rather than to treat symptoms. CBT depends on the principle of fear extinction, which involves exposure to fear-associated cues until new associations are learned. Recent developments indicate that rehabilitation can be improved with adjunct therapies. Our research indicates that the vagus nerve plays a role in the consolidation of emotionally arousing memories. The vagus nerve serves as a bridge between the peripheral and central nervous systems, responding to increases in circulating stress hormones by increasing plasticity in the brain to enable rapid storage of memories of threatening or emotionally exciting events. The vagus nerve reciprocates sympathetic activation with parasympathetic effects on the heart and other organs. For this reason it is called the """"""""vagal brake"""""""" on the sympathetic response to stress. Anxiety disorders are characterized by altered vagal responses to stress and impaired ability to extinguish conditioned fear. We recently discovered that stimulation of the vagus nerve during extinction training enhanced extinction of two forms of conditioned fear in rats. Vagus nerve stimulation (VNS) is approved by the Federal Food and Drug Administration for treatment of epileptic seizures and depression, but it is not currently administered as adjunct therapy. Instead, VNS is administered as a pacemaker to maintain a certain brain state. The proposed research is based on the concept that extinction failure leads to anxiety disorders and stimulation of the vagus nerve can enhance extinction. If VNS holds promise as a novel approach to the treatment of anxiety disorders, the mechanism/s of action should be better understood. The projection from the infralimbic cortex to the amygdala is implicated in extinction.
Aim 1 will test the hypothesis that VNS modulates experience-dependent plasticity and the individual contributions of extinction training, VNS, and VNS paired with extinction on plasticity in an extinction-related neural pathway will be investigated.
Aims 2 and 3 will examine whether VNS affects the same modulatory and synaptic systems that are involved in natural extinction. The proposed research will bring notoriety to a burgeoning center for neuroscience. NIH support will bring stability to student-led neuroscience research at a time when the university is rapidly growing by trial and error. Four exceptional undergraduate students, all neuroscience majors aspiring to careers in research and medicine and with GPAs over 3.7, will join two graduate students and two mentors to ask the basic question of how a potential therapy works.

Public Health Relevance

Anxiety disorders affect up to 18% of the US population. Studies of extinction of conditioned fear in rats have been translated to therapies used to treat human anxiety disorders. The proposed studies aim to understand the mechanisms by which vagus nerve stimulation, a potential novel therapy, enhances extinction of conditioned fear in rats.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Academic Research Enhancement Awards (AREA) (R15)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-A (96))
Program Officer
Vicentic, Aleksandra
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas-Dallas
Other Domestic Higher Education
United States
Zip Code
LaLumiere, Ryan T; McGaugh, James L; McIntyre, Christa K (2017) Emotional Modulation of Learning and Memory: Pharmacological Implications. Pharmacol Rev 69:236-255
Alvarez-Dieppa, Amanda C; Griffin, Kimberly; Cavalier, Sheridan et al. (2016) Vagus Nerve Stimulation Enhances Extinction of Conditioned Fear in Rats and Modulates Arc Protein, CaMKII, and GluN2B-Containing NMDA Receptors in the Basolateral Amygdala. Neural Plast 2016:4273280
Childs, Jessica E; Alvarez-Dieppa, Amanda C; McIntyre, Christa K et al. (2015) Vagus Nerve Stimulation as a Tool to Induce Plasticity in Pathways Relevant for Extinction Learning. J Vis Exp :e53032
Ploski, Jonathan E; McIntyre, Christa K (2015) Emotional modulation of synapses, circuits and memory. Front Behav Neurosci 9:35
Powers, Mark B; Medina, Johnna L; Burns, Stephanie et al. (2015) Exercise Augmentation of Exposure Therapy for PTSD: Rationale and Pilot Efficacy Data. Cogn Behav Ther 44:314-27
Peña, David Frausto; Childs, Jessica E; Willett, Shawn et al. (2014) Vagus nerve stimulation enhances extinction of conditioned fear and modulates plasticity in the pathway from the ventromedial prefrontal cortex to the amygdala. Front Behav Neurosci 8:327
McReynolds, Jayme R; Holloway-Erickson, Crystal M; Parmar, Tulja U et al. (2014) Corticosterone-induced enhancement of memory and synaptic Arc protein in the medial prefrontal cortex. Neurobiol Learn Mem 112:148-57
McReynolds, Jayme R; Anderson, Kelly M; Donowho, Kyle M et al. (2014) Noradrenergic actions in the basolateral complex of the amygdala modulate Arc expression in hippocampal synapses and consolidation of aversive and non-aversive memory. Neurobiol Learn Mem 115:49-57