Selective and Semi-invasive Neuromodulation by Upconversion Nanoparticles

The main objective of this proposal is to develop a minimally invasive method to stimulate selective neuropathways located within the motor cortices. We intend to use a non electrical, non electromagnetic, and non electrode-based implantation approach to depolarize targeted neurons in the motor cortices. We have three objectives. First, we intend to replace a conventional approach to emit visible light by stimulating dye- sensitized upconversion nanoparticles (UCNPs) using our Near Infrared - Light Emitting Diodes (NIR-LED) illumination system with a broadband excitation wavelength range (800 nm). We will optimize the visible light emission of newly engineered upconversion nanoparticles in order to activate light sensitive ion channels, Channelrhodopsin-2 (ChR2), in transfected neuropathways. In addition, UCNPs will be modified and will be up taken by ChR2 expressing neurons through endocytosis. The endocytosed nanoparticles will be in much closer proximity to the membrane bound ChR2s, which enhances energy transfer efficiency between the UCNPs and ChR2s. Hence, less NIR irradiation power is sufficient to drive the neural activities. Second, we will investigate the biocompatibility of transplanted UCNPs and NIR-LED illumination system. Third, the feasibility and efficacy of UCNPs - NIR-LED system to activate specific ChR2-transfected cortical motor-neurons will be investigated in an in vivo rodent model. To this end, a miniaturized NIR-LED irradiation system will be implanted on the skull of rats for activation of UCNPs-ChR2. We hypothesize that a minimally invasive NIR-LED illumination approach can be used to depolarize selective cortical motor-neurons with spatiotemporal precision, using our innovative UCNPs adjacent to ChR2s. This will also provide us with a powerful tool to target deeper neural pathways in the brain selectively. The novelty of our proposal lies in the construct of an advanced generation of UCNPs. The significance of this project lies in our ability to selectively and semi-invasively depolarize and induce action potential in neurons located in motor cortices. This presents a powerful tool for functional recovery and it could be exploited for rehabilitation and improvement of motor behavior. This technology also has the potential for further development and future applications, for example, in the deeper structure of central, peripheral and visceral nervous systems for neuromodulation. The application of UCNPs – NIR-LED will enable safer access to regions beyond conventional intervention such as invasive electrode implantation and electrical or electromagnetic based stimulation. Success in this proposal will pave the way for scientists and physicians in diverse fields of Neuroscience and Neuromodulation.