Investigation of an Optogenetic Vagus Nerve Stimulation Device in an Animal Model of Post-traumatic Stress Disorder

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The proposed research will develop a novel system for optogenetic vagus nerve stimulation and investigate the impact of vagal stimulation in a rodent model of post-traumatic stress disorder (PTSD). Therapeutic interventions using peripheral nerves of the autonomic nervous system are increasingly being considered and applied to modulate organ function for disease treatments. Vagus nerve stimulation (VNS) has been clinically approved for over two decades for its treatment of epileptic seizures and depression. It has also demonstrated positive clinical outcomes in the treatment of inflammatory disorders such as rheumatoid arthritis and Crohn’s disease, while clinical and pre-clinical data suggest therapeutic benefit in heart disease and diabetes. Cholinergic (parasympathetic) pathways of the vagus nerve are an important factor in the therapeutic effects that are observed. The ‘cholinergic anti-inflammatory pathway’ is an established signaling mechanism by which the expression and release of pro-inflammatory cytokines are reduced in the spleen and in other visceral tissues. Because inflammation is a driver of numerous diseases, the ability to regulate inflammatory mediators is of major interest. In state-of-the-art electrical vagus nerve stimulation (VNS), however, current is applied broadly to the nerve and the non-specific nature of this stimulation activates off- target pathways causing adverse effects to the patient, and furthermore, does not provide adequate precision to study and understand therapeutically relevant nerve pathways. The proposed research will develop and apply an optogenetic system for vagus nerve stimulation that can eliminate these off-target complications. With optogenetic tools, light-sensitive actuators can be targeted to cell-types of interest via genetic targeting and tissue-specific viral delivery, thus enabling highly specific activation and investigation of neural circuits. This neuromodulation methodology will be applied to PTSD, a highly prevalent burden among the U.S. Veteran population. PTSD is highly correlated with elevated inflammation and often co-morbid with many of the diseases mentioned above. In addition to the anti-inflammatory pathways of the vagus nerve, beneficial impacts observed in psychiatric and inflammatory disorders suggest that vagal stimulation may be effective in treating PTSD, and indeed, VNS in rodent models enhances fear extinction and reduces anxiety. The current study will develop a 3D-printed vagus nerve cuff system for optogenetic studies (Aim 1). This biocompatible, single-component, optical stimulation nerve implant will enable an easy-to-fabricate and easy-to-implant device for chronic stimulation. The effectiveness and longevity of the system will be validated by assessing cardiac responsivity longitudinally in surgically implanted mice (Aim 2), before testing the system in a PTSD mouse model (Aim 3). A previously described single electric footshock protocol will be used to condition associative fear to a conditioned stimulus – the shock chamber. Vagal stimulation of optogenetically targeted efferent (cholinergic) and/or afferent (glutamatergic) fiber subtypes will be applied concurrently with exposure to the conditioned stimulus over a period of 5 days. Extinction of fear, and anxiety level measured with the ‘elevated plus maze’ test will be assessed in stimulated and non-stimulated control animals.