Collaborative Research: NCS-FR: Understanding the neuropeptide modulation of brain circuits by advanced nanomaterials and imaging

人类的大脑活动是由一组被称为神经调节剂的分子调节的。然而，由于工具不足，人们对这些分子如何工作和影响大脑活动知之甚少。该项目旨在开发一个最先进的工具箱来研究这些重要的分子。这些新工具将使科学家能够追踪大脑中神经调节剂的运动，确定它们在大脑回路中的作用，并揭示它们是如何改变行为的。跨学科团队采用生物工程，细胞生理学，全脑成像和行为相结合的广泛方法来开发和优化这些工具。这个项目的完成将产生几个广泛的影响。在科学上，研究人员将获得一套新的工具，可以利用光打开或关闭神经调节剂向清醒动物大脑特定区域的传递。该结果将促进我们对神经调节剂如何影响局部大脑区域和整个大脑活动的理解。合作团队将在纳米技术、工程、化学和神经科学领域为研究生和博士后研究人员提供跨学科的培训。该项目将通过实验室和社区外展项目为K-12学生提供STEM教育。最后，该项目还将为妇女和代表性不足的少数民族提供指导和研究机会。神经肽是大脑中重要的神经调节剂，但人们对其时空分布、对神经回路的作用以及对行为的影响知之甚少。本研究的重点是开发新的神经技术来研究神经肽在时空控制释放（线程1）下的扩散，它们对大脑回路和行为的作用（线程2），以及全脑和特定回路的激活模式（线程3）。具体来说，这项工作将开发和理解一类新的光开关纳米囊泡，它们可以被广泛使用的二极管激光器和发光二极管激活。我们将结合神经肽传感器，即基于细胞的神经递质荧光工程受体（CNiFER），研究神经肽（生长抑素，催产素）在光释放时在皮层和纹状体中的扩散。然后，我们将研究光释放催产素对自由活动动物脑回路和社会行为的影响。这些努力与一种新的荧光共振能量转移（FRET）为基础的微型显微镜的发展紧密结合，以检测行为释放的神经递质。通过多模态功能磁共振成像平台，本研究将确定光释放催产素的全脑和电路特异性激活模式，从而首次将确定局部神经肽信号与全脑效应相结合。这些新开发的技术将促进我们对神经调节剂在大脑中的作用的理解，并在更广泛的范围内促进新的神经药理学研究，目前还无法获得靶向递送和局部释放化合物。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Human brain activity is modified by a group of molecules called neuromodulators. However, little is known about how these molecules work and affect brain activity, due to inadequate tools. This project seeks to develop a state-of-the-art toolbox to study these important molecules. These new tools will enable scientists to track the movement of neuromodulators in the brain, determine their action on brain circuits, and reveal how they alter behavior. The interdisciplinary team takes a broad approach of combining bioengineering, cellular physiology, whole-brain imaging and behavior to develop and optimize these tools. Completion of this project will have several broad impacts. Scientifically, researchers will have access to a new set of tools for turning on or off the delivery of neuromodulators to specific regions of the brain in awake animals using light. The results will advance our understanding of how neuromodulators impact brain activity in localized brain regions and across the brain. The collaborative team will provide interdisciplinary training for graduate students and postdoctoral researchers with cutting-edge technologies in the fields of nanotechnology, engineering, chemistry, and neuroscience. This project will provide STEM education to K-12 students both in the lab and through community outreach programs. Finally, this project will also offer mentoring and research opportunities for women and underrepresented minorities.Neuropeptides are important neuromodulators in the brain and yet remarkably little is known about their spatiotemporal spread, action on neural circuits, and effect on behavior. This proposal focuses on developing new neurotechnologies to study neuropeptide diffusion upon spatiotemporally controlled release (thread 1), their actions on brain circuits and behavior (thread 2), and brain-wide and circuit-specific activation patterns (thread 3). Specifically, this work will develop and understand a new class of photoswitchable nanovesicles that can be activated with widely available diode lasers and light emitting diodes. We will integrate this with a neuropeptide sensor, namely the cell-based neurotransmitter fluorescent-engineered receptor (CNiFER), to study neuropeptide (somatostatin, oxytocin) diffusion in the cortex and striatum upon photorelease. We will then investigate the impact of photoreleased oxytocin on brain circuits and social behavior in freely-moving animals. These efforts are closely integrated with the development of a new fluorescence resonance energy transfer (FRET)-based miniscope to detect behaviorally released neurotransmitters. Through a multi-modal functional magnetic resonance imaging platform, this research will determine the brain-wide and circuit- specific activation patterns of photoreleased oxytocin, thus enabling for the first time the integration of determining local neuropeptide signaling with brain-wide effects. These newly developed techniques will advance our understanding of the role of neuromodulators in the brain and more broadly, promote new neuropharmacology research where targeted delivery and localized release of a compound are currently unavailable.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.