Project Summary/Abstract 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 are believed to be central 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. While these neural pathways hold promising therapeutic potential, current devices have significant limitations. Electrode- based devices used in existing VNS therapies apply current broadly to the nerve. The non-specific nature of this electrical stimulation activates off-target pathways causing adverse effects to the patient, and furthermore, does not provide an adequate tool to study and understand therapeutically relevant nerve pathways. The proposed research will develop a new device for optogenetic 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. The current study will develop and validate a 3D printed vagus nerve cuff system for optogenetic studies. Novel micro- resolution stereolithographical 3D-printing capabilities will be leveraged to produce a biocompatible, single-component, optical stimulation nerve implant (Aim 1). This approach will enable an easy-to-fabricate and easy-to-implant device that can be applied to study and identify neural circuits across many disease states. The device will be validated in a transgenic animal model (Aim2) in which cholinergic pathways will be optogenetically stimulated in mouse models of acute and chronic systemic inflammation. Modulation of pro-inflammatory mediators will be measured in vivo over a period of two months along with the cholinergic-vagal heart rate response to test efficacy of the system. It is hypothesized that this device will enable a simply-employed system for chronic optogenetic vagus nerve stimulation that will reduce systemic inflammatory mediators in an animal model.

R21NS124313

2021-08-01

2023-01-31