Understanding how the brain controls behavior requires advanced tools to manipulate brain activity. Inspired by recent progress in optogenetics (i.e., a technique to control selected types of brain cells with genetic modification and light stimulation), this project seeks to develop a new set of tools that will allow localized and ultrafast control of brain activity to influence behavior in freely-moving animals. This will be achieved by using light stimulation to rapidly release compounds that are encapsulated in tiny nanometer-sized particles. The ultrafast feature of this novel compound technology is ideally suited to manipulate brain activity that typically occurs on the scale of milliseconds. Importantly, this new technology is suited to packaging and releasing a wide range of chemical and biological compounds, as well as combinations of such compounds. The project's success will have a number of broader impacts. Scientifically, this project will generate a new technology to better understand how the brain works, and thus new knowledge about the brain and behavior. The ultrafast compound release method can potentially develop into a platform technology for other research areas, including the nervous system outside the brain. The collaborative environment of this project will provide interdisciplinary training opportunities for two graduate students with cutting-edge technologies in the fields of engineering and neuroscience. Finally, this project will promote STEM education both in the lab and through community outreach programs.
Advances in methodologies and tools for neuroscience research often lead to fundamental insights into the function of the central and periphery nervous system. Currently available methods for drug infusions using relatively large metal cannulas are not ideal for studies in freely behaving animals, because drug delivery is slow and the cannulas often destroy the brain area under study and/or overlying brain areas. New methods are needed to perform drug infusion or local release in a minimally invasively manner in freely moving animals. Inspired by recent developments in optogenetics, the PIs will develop a versatile optically-triggered system for sub-millisecond compound burst release for the real-time study of brain activity and behavior. Plasmonic liposomes, i.e. liposomes coated with a gold shell layer, can encapsulate a wide range of molecular compounds and be deposited locally in the brain. Due to the small width and poor clearance of the extracellular space in the brain, the plasmonic liposomes can be designed to stay in the injected area for prolonged periods of time. The encapsulated compound can then be quickly burst-released by a near-infrared pulsed laser via an implanted optical fiber. The encapsulated compounds can be designed to release by repeated triggers, allowing multiple on-demand drug release events over an extended period for behavioral studies. In this project, an integrated approach will be developed to deliver and release the encapsulated compounds, and to study the resulting brain activity and behavior change in real-time utilizing Pavlovian fear conditioning. Successful development of this sub-millisecond optically-triggered burst release technique will represent a major technological advancement that addresses the limitations of current techniques for behavioral research. Specifically, improved bio-compatibility and reduced invasiveness are anticipated by the by one-time nanoparticle infusion and on-demand light-triggered drug release. The fast release feature of the new technique will provide sufficient speed to study neuronal communication in neuroscience research. Furthermore, this technique will find wide applications in neuropharmacology research where targeted delivery and localized rapid release are currently unavailable.
