NCS-FO: Sub-millisecond Optically-triggered Compound Release to Study Real-time Brain Activity and Behavior

了解大脑是如何控制行为的，需要先进的工具来操纵大脑的活动。受光遗传学(即通过基因改造和光刺激控制选定类型的脑细胞的技术)最新进展的启发，该项目寻求开发一套新的工具，允许对大脑活动进行局部和超快的控制，以影响自由活动的动物的行为。这将通过使用光刺激来快速释放包裹在微小纳米颗粒中的化合物来实现。这种新型复合技术的超快特性非常适合于操纵大脑活动，这种活动通常发生在毫秒级。重要的是，这项新技术适合于包装和释放各种化学和生物化合物，以及这些化合物的组合。该项目的成功将产生一些更广泛的影响。从科学上讲，这个项目将产生一项新技术，以更好地了解大脑是如何工作的，从而获得关于大脑和行为的新知识。超快化合物释放方法有可能发展成为其他研究领域的平台技术，包括大脑外的神经系统。该项目的协作环境将为两名拥有工程和神经科学领域尖端技术的研究生提供跨学科培训机会。最后，该项目将在实验室和社区外展计划中促进STEM教育。神经科学研究方法和工具的进步往往导致对中枢和外周神经系统功能的基本洞察。目前使用相对较大的金属插管进行药物输注的方法对于自由行为动物的研究并不理想，因为药物输送缓慢，而且插管经常破坏研究中的大脑区域和/或覆盖的大脑区域。需要新的方法在自由活动的动物中以最小侵入性的方式进行药物输注或局部释放。受光遗传学最新发展的启发，PI将开发一种多功能的光触发系统，用于亚毫秒级的化合物爆发释放，用于实时研究大脑活动和行为。血浆脂质体，即包裹着金壳层的脂质体，可以包裹广泛的分子化合物，并局部沉积在大脑中。由于脑内细胞外间隙的宽度较小，清除能力较差，血浆脂质体可以设计为在注射区域停留较长时间。然后，被包裹的化合物可以通过植入的光纤由近红外脉冲激光快速突发释放。被包裹的化合物可以被设计成通过重复触发释放，从而允许在行为研究的较长时间内发生多次按需药物释放事件。在这个项目中，将开发一种集成的方法来传递和释放包裹的化合物，并利用巴甫洛夫恐惧条件反射实时研究由此产生的大脑活动和行为变化。这种亚毫秒级光触发突发释放技术的成功开发将代表着一项重大的技术进步，它解决了目前行为研究技术的局限性。具体地说，通过一次性纳米颗粒输注和按需光触发药物释放，有望改善生物兼容性和降低侵袭性。这项新技术的快速释放功能将为在神经科学研究中研究神经元通信提供足够的速度。此外，这项技术将在神经药理学研究中得到广泛应用，目前还不能提供靶向递送和局部快速释放。

1631910Qin, ZhenpengUnderstanding 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.