A fundamental goal of neuroscience is to understand the function(s) of defined neural populations in a complex organism. We propose to develop and validate a technology for non- invasive modulation of neural activity in vivo. There has been huge progress in developing tools for temporal regulation of neural activity. These techniques, from light activated channels to designer receptors, enable modulation of defined neural populations in vivo to examine their roles in many physiological functions. But current technologies have their limitations. Optical methods require permanent implants and activate only local neural populations while designer receptors and their specific ligands have a significantly slower time course. Ideally, tools would be capable of remote modulation of neural activity in local or dispersed neural populations at multiple stages of development with rapid temporal resolution. We address this challenge by using a distinctive combination of non-invasive radiowave and magnetic field signals, biological ferritin nanoparticles and bioengineered ion channels for non- invasive modulation of neural activity in freely moving animals. Radiofrequency or magnetic fields remotely modulate neurons that express nanoparticles formed in a modified ferritin shell. These are tethered to a modified ion channel, transient receptor potential vanilloid 1, TRPV1. Radiowaves or magnetic fields penetrate tissue to heat or move the nanoparticle respectively and activate TRPV1. Modifications of TRPV1 allow either neural activation or silencing. We will develop and validate tools for non-invasive activation and silencing of neural populations using viral vectors applicable to several species and demonstrate their utility in regulating complex behaviors. Specifically, we will 1) characterize the electrophysiological responses to RF and magnetic manipulation of neural populations in vitro, 2) examine the responses to RF or magnetic field modulation of hypothalamic neurons in vivo and compare them to optogenetic modulation and 3) determine the effects of modulating a neural population that is dispersed through a cortical lamina, the cerebellar Purkinje cells, in vivo in comparison to designer receptors exclusively activated by designer drugs (DREADD) modulation. Using bioengineered nanoparticles to transduce electromagnetic signals, we will develop a unique technology for targeted, non-invasive manipulation of neural activity that is applicable to local or dispersed cells through development. Our technology will be a valuable addition to the available tools to investigate the physiological roles of neural populations.
This application aims to validate and characterize a novel technology, radiogenetics, for external, non-invasive activation of defined cell populations in living animals. We will use radiowaves or magnetic fields and biological nanoparticles to activate ion channels to switch on and switch off neural activity. We will develop viruses for remote modulation of local and dispersed neural populations in vivo and validate their efficacy. The studies proposed in this application will provide a new technology that is broadly applicable to neuroscience with the potential for translation to clinical applications.
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