Project Summary Modulating the activity of peripheral nerves innervating specific organs and defined cell types within these organs will help us understand the relationship between neural signals and organ function. We propose to develop and validate the use of non-invasive neural modulation in the peripheral nervous system in vivo. Many tools can be used for temporal regulation of neural activity in the CNS, from light activated channels to designer receptors but these are not universally applicable, particularly in the periphery. Optical methods require permanent implants which may be difficult to fix or even cause damage in peripheral tissues. In addition, these tools only activate local neural populations in a small portion of an organ. In contrast, designer receptors and their ligands can target neurons across a larger area but have a relatively slow time course. Neural modulation with radiowaves or magnetic fields allows remote, rapid activation or inhibition of neural activity across an entire organ. We have recently shown that a distinctive combination of non-invasive radiowave and magnetic field signals, biological ferritin nanoparticles and bioengineered ion channels can be used to remotely activate and inhibit CNS neural activity in freely moving animals. Targeted neurons express genetically encoded nanoparticles tethered to a modified ion channel, transient receptor potential vanilloid 1, TRPV1. Radiowaves or magnetic fields freely penetrate tissue to heat and/or move the nanoparticle and activate TRPV1. Modifications of TRPV1 allow either neural activation or silencing. We will now develop and validate tools for non-invasive activation and silencing of peripheral nerves using viral vectors applicable to several species and we will demonstrate their utility by modulating innervation of the endocrine pancreas. Specifically, we will develop, validate and characterize 1) tools for remote activation and inhibition of neurons innervating the pancreas using viruses with retrograde spread and neuron-specific expression of activating or inhibitory constructs and 2) tools for remote activation and inhibition of specific neural pathways (parasympathetic, sympathetic and sensory) innervating the pancreas. We will develop a range of tools for remote modulation of parasympathetic, sympathetic and sensory peripheral nerves innervating an organ. These tools will be broadly applicable and extend the methods available to investigate the physiological roles of peripheral nerves in regulating organ function.

Project Narrative This proposal aims to validate and characterize novel tools for non-invasive, rapid, targeted modulation of peripheral nerves in vivo. We will use electromagnetic fields (radiowaves and magnetic fields) and biological nanoparticles to activate ion channels that switch on and switch off defined peripheral nerves (parasympathetic, sympathetic or sensory) innervating a specific organ, the pancreas. The studies proposed in this application will provide a new set of tools that are broadly applicable to modulating peripheral nerves innervating many organs and with the potential for translation to clinical applications.