Optogenetic Interfacing with Nerves

Bidirectional Optogenetic Peripheral Nerve Interface
Ted For Your Head_v2_Weir_Gibson (1)

Why talk to nerves using light?

To communicate with nerves, precision and non-invasiveness are key.  Light can be focused precisely to both activate and read activity within a nerve with specificity not attainable with electrode-based approaches.  These traditional electrode approaches usually deliver relatively broad and indiscriminate stimulation while also being invasive to the nerve.  By using optical nerve cuff systems, we are working  on non-tissue damaging chronic implantable devices to ‘talk’ to specific pathways within the nerve.

How can we use light to interact with nerves?

Novel Methods to ‘Talk’ to Peripheral Nerves - Our laboratory studies and develops novel techniques for interfacing with peripheral nerves, with the goal of stimulating and reading-out highly specific neural activity for rehabilitative and therapeutic purposes.  We focus on optical (optogenetic) approaches which enable axon-level control of intervention with genetic targeting and spatially selective photostimulation.  This research includes the engineering of implantable nerve devices, along with in vivo studies investigating the effect of targeted neural stimulation on organ function for disease therapies as well as prosthesis control.  We are particularly interested in the therapeutic potential of the vagus nerve, which innervates the thoracic and abdominal organs.  Photomodulation nerve cuff devices are in development to enable chronic studies in animal models for the investigation of systemic inflammation and post-traumatic stress disorder (PTSD) treatment.  Recent applications also include the optical stimulation of pathways to modulate cardiac indices and pancreas endocrine function. To facilitate the interfacing of nerves with multi-photon microscopes we utilize an optical relay lens (GRIN-lens) incorporated nerve cuff. 

3D-Printable Vagus Nerve Device for Chronic Photostimulation – This device will facilitate visible light illumination of the in vivo vagus nerve for optogenetic stimulation of select neural pathways.  Current experiments include the targeting of cholinergic and glutamatergic pathways in the nerve to study how these neural pathways may be therapeutically beneficial in reducing systemic inflammation and treating PTSD.    

Modulation of the Heart - Studies utilize transgenic rodent models as well as retrograde adeno-associated virus (AAV) delivered in the heart to specifically infect cardiac fibers of the upstream vagus nerve with light-sensitive opsin proteins.  Stimulation of these vagal pathways, using both one-photon excitation and two-photon holographic excitation enable the perturbation of heart rate, ECG parameters and cardiorespiratory reflexes [1].     

Infection of light-sensitive opsins
GRIN-Lens Nerve Cuff - A silicone pressure-molded nerve cuff was fabricated in 3D-printed maraging steel molds.  The cuff incorporated a ratcheted strap mechanism to fix the nerve within the device.  A GRIN lens provides an optical relay to interface the nerve with microscopes and other laser sources.  
Video 1: Strapping mechanism of the silicone pressure-molded vagus nerve cuff with GRIN lens.

Modulation of the Pancreas - We study whether optical activation of defined nerve pathways to the pancreas stimulates therapeutically beneficial effects on insulin and glycemic control.  Our studies have demonstrated the stimulation of insulin secretion along with reduction in blood glucose levels by targeting cholinergic pathways [2] – an effect not observed with electrical vagus nerve stimulation.  
Optogenetic photosimulation

Optical Measurement of Neural Activity In Vivo: 

In vivo GCaMP6s transients

Selective Photostimulation with Spatial Light Modulation:

Spatially selective photo-stimulation


[1]  Fontaine, A. K., Futia, G. L., Rajendran, P. S., Littich, S. F., Mizoguchi, N., Shivkumar, K., Ardell, J. L., Restrepo, D., Caldwell, J. H., Gibson, E. A. & Weir, R. F. Optical vagus nerve modulation of heart and respiration via heart ‑ injected retrograde AAV. Sci. Rep. 1–12 (2021). doi:10.1038/s41598-021-83280-3

[2]  Fontaine, A. K., Ramirez, D. G., Littich, S. F., Piscopio, R. A., Kravets, V., Schleicher, W. E., Mizoguchi, N., Caldwell, J. H., Weir, R. F. & Benninger, R. K. P. Optogenetic stimulation of cholinergic fibers for the modulation of insulin and glycemia. Sci. Rep. 1–9 (2021). doi:10.1038/s41598-021-83361-3

[3]  Futia, G. L., Fontaine, A., Littich, S., McCullough, C., Restrepo, D., Weir, R., Caldwell, J. & Gibson, E. A. In vivo holographic photo-stimulation and two photon GCaMP6 imaging of vagus nerve axons using a GRIN lens integrated nerve cuff. in Proceedings of SPIE: Optogenetics and Optical Manipulation 2019 28 (2019). doi:10.1117/12.2521830

Weir Biomechatronics Development Laboratory