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

合作研究：NCS-FR：通过先进纳米材料和成像了解脑回路的神经肽调节

• 批准号: 2123830
• 负责人: Paul Slesinger
• 金额: $ 99.99万
• 依托单位: Icahn School of Medicine at Mount Sinai
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2123830&HistoricalAwards=false
• 关键词: Collaborative; Research; NCS; FR; Understanding

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.

人脑活动被称为神经调节剂的一组分子修饰。但是，由于工具不足，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新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跟踪神经调节剂在大脑中的运动，确定其对脑电路的作用，并揭示其如何改变行为。跨学科团队采取了广泛的方法来结合生物工程，细胞生理学，全脑成像和行为，以开发和优化这些工具。该项目的完成将产生一些广泛的影响。从科学上讲，研究人员将可以使用一套新的工具，用于使用光线在清醒的动物中打开或关闭神经调节剂向大脑的特定区域传递。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的大脑活动的理解。该协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培训。该项目将在实验室和社区外展计划中为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群体提供指导和研究机会。神经肽是大脑中重要的神经调节剂，但对于她们的时空传播，对神经回路的作用以及对行为的影响，他们的时空传播传播知之甚少。该提案着重于开发新的神经技术来研究时空控制释放（线1），它们对脑电路和行为的作用（线程2）以及脑部范围和电路特异性激活模式（线程3），研究神经肽扩散（线程1）。具体而言，这项工作将开发和理解一类新的可通过照片开关纳米嵌段，可以通过广泛可用的二极管激光器和发光二极管激活。我们将将其与神经肽传感器（即基于细胞的神经递质荧光工程受体（CNIFER））整合在一起，以研究在皮质中的神经肽（SomaToStatin，oxytocin）在光耐酶时的神经肽（Somatostatin，oxytocin）扩散。然后，我们将研究光释放的催产素对自由移动动物的脑回路和社会行为的影响。这些努力与新的荧光共振能量转移（FRET）的Miniscope的发展紧密整合在一起，以检测行为释放的神经递质。通过多模式的功能磁共振成像平台，这项研究将确定光性催产素的大脑和电路特异性激活模式，因此首次使确定局部神经肽信号传导与脑范围效应的整合。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，并更广泛地促进新的神经药理学研究，目前尚不可用，该研究目前尚不可用。该奖项反映了NSF的法定任务，并通过使用该基金会的知识优点和广泛的影响来评估NSF的法定任务。