External control over rapid and precise release of chemicals in the brain potentially provides a powerful interface with neural activity. Optical manipulation techniques such as optogenetics and caged compounds enable remote control of neural activity and behavior with fine spatiotemporal resolution. However, these methods are limited to chemicals that are naturally present in the brain or chemically suitable for caging. Here, we demonstrate the ability to interface with neural functioning via a wide range of neurochemicals released by stimulating loaded liposomal nanostructures with femtosecond lasers. Using a commercial 2-photon microscope, we released inhibitory or excitatory neurochemicals to evoke sub and supra-threshold changes in membrane potential in a live mouse brain slice. The responses were repeatable and could be controlled by adjusting laser stimulation characteristics. We also demonstrate release of a wider range of chemicals – which previously were impossible to release by optogenetics or uncaging – including synthetic analogs of naturally occurring neurochemicals. In particular, we demonstrate release of a synthetic receptor-specific agonist that exerts physiological effects on long-term synaptic plasticity. Further, we show that the loaded liposomal nanostructures remain functional for weeks in a live mouse. In conclusion, we demonstrate new techniques capable of interfacing with live neurons, and extendable to in vivo applications.
Significance Statement: We describe a novel neural manipulation method using laser and liposomal nanostructures. The method enables us to release various types of neurochemicals and drugs in mouse brain, beyond the range used by existing optical manipulation methods such as optogenetics and caged compounds. We also demonstrate repeated and stable neural manipulation modulated by laser intensity. Given the established biocompatibility and stability of liposomes in the body, these findings suggest that the liposomal neural manipulation methods would be a useful tool for neuroscience research and further treatment of neurological disorders.
Conflict of Interest: Authors report no conflict of interest
Funding source: Okinawa Institute of Science and Technology