(650e) Projection-Specific Modulation of Neural Activity with a Non-Genetic Method

Recent developments in optogenetics and viral technology have demonstrated that modulating the neural activity of specific projections in the brain is capable of rescuing behavioral deficits, including those relevant to depression, autism and anxiety. However, this approach requires genetic modification of neurons via viral transduction, which introduces a significant barrier for clinical applications due to safety concerns. Also, the current projection-targeted neural modulation methods all use visible light, limiting both the light penetration depth and the number of independent channels neuroscientists can use for recording and modulating neural activity. Here, we are developing a non-genetic, nanoparticle-based approach to achieve projection-specific modulation of neural activity in freely behaving mice. First, we observed that gold nanorods were rapidly endocytosed into cultured neurons after just a few minutes of incubation. Transmission electron microscopy images illustrate that gold nanorods are located both inside and outside the endosome. Second, we showed that the endocytosed gold nanorods were transported retrogradely/anterogradely along neuron axons, with a room temperature average speed of 0.2 μm/s (1.7 cm/day). Third, we demonstrated the effectiveness of photothermal inhibition of neural activity with axon-transported gold nanorods, illustrating the concept of projection-specific modulation of neural activity in vitro. The mechanism of photothermal neural modulation is likely due to the thermal response of potassium channels, as shown from our in vitro electrophysiology studies. In addition, we demonstrated the excellent biocompatibility of gold nanorods with neurons after at least one-week incubation and photothermal neural modulation. Finally, we observed the neural uptake and axonal transport of gold nanorods in vivo, as well as neural modulation in mice with this technology. Overall, our nanoparticle-based methodology demonstrates a promising approach towards non-genetic, projection-specific modulation of neural activity.