Magnetic Modulation on Targeted Neural Circuits in Autism

对自闭症目标神经回路的磁调制

• 批准号: 10385860
• 负责人: Siyuan Rao
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385860
• 关键词: Advisory Committees; Affect; Award; Behavior assessment; Behavioral; Behavioral Assay; Biological Assay; Brain; Callithrix; Chemicals; Chemistry; Child; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Committee Members; Communities; Diagnosis; Electronics; Engineering; Ensure; Equilibrium; Etiology; Functional disorder; Future; Genes; Glutamate Metabolism Pathway; Glutamates; Goals; Human; Infrastructure; Institutes; Interdisciplinary Study; Intervention; Investigation; Knowledge; Laboratory Research; Lead; Ligands; Light; Link; Magnetic nanoparticles; Magnetism; Mentors; Mission; Modeling; Molecular; Mus; Mutation; Nanotechnology; Neuromodulator; Neurons; Neurosciences; Nucleic Acids; Outcome; Pathology; Pathway interactions; Penetration; Pharmacology; Phase; Phase Transition; Phenotype; Population; Prevalence; Property; Protocols documentation; Research; Resources; Risk; Rodent; Science; Shapes; Site; Social Behavior; Social Interaction; Source; Specificity; Structure; Supervision; Surface; Synapses; System; Techniques; Technology; Testing; Therapeutic; Training; Transgenic Mice; Viral; Wild Type Mouse; Work; autism spectrum disorder; awake; behavior observation; behavior test; behavioral outcome; behavioral phenotyping; behavioral study; brain research; career; cell type; chemical synthesis; design; effective therapy; empowered; experience; flexibility; gene therapy; genetic manipulation; implantation; improved; liposome vector; magnetic field; minimally invasive; mouse model; nanocarrier; nervous system disorder; neural circuit; neurobehavioral; neurobehavioral test; neuromechanism; neurophysiology; neuroregulation; non-viral gene delivery; nonhuman primate; optogenetics; post-doctoral training; professor; programs; receptor; relating to nervous system; remote control; scientific atmosphere; side effect; skills; social; social deficits; theranostics; tool; translation to humans; wireless

Project Summary and Abstract My overall career goal is to establish an independent research program focused on leveraging cutting-edge technologies of materials engineering, genetic manipulation and neurobehavioral science to study neural circuits underlying autism spectrum disorders (ASDs). I hypothesize that a remotely controlled magnetic neuromodulation tool will link precise circuit-level neural modulation to behavioral outcomes, and thus empower neural circuitry interrogation with systems neuroscience. To realize this goal, I have received training in extensive research fields including materials engineering, nanotechnology, cellular neurophysiology, and neuroscience. With this award, in my future career I will open up a new interdisciplinary research pathway of developing remotely controlled magnetic tools that enable pharmacological and gene-editing intervention on specific neural circuits along with the behavioral assessment on freely moving mice and awake, untethered non-human primates (NHPs). In the mentored phase, I will work under the supervision of Professor Polina Anikeeva - an expert in optoelectronic and magnetic neural interfaces, with the guidance of my advisory committee consisting of Professors Guoping Feng, Feng Zhang, Mriganka Sur, and Zhigang He. With their strong supports, I will receive additional training in gene editing, social behavioral test design and experimental experience with autism models of mice and marmosets, which will equip me with the knowledge and skills necessary to further the study of neural underpinnings of ASDs and launch my independent career. The work in mentored phase will be done at the Research Laboratory of Electronics and the McGovern Institute for Brain Research at MIT, which offer an active multidisciplinary research atmosphere, expansive infrastructural resources and a valuable intellectual community necessary for the implementation of the proposed project. During my Simons postdoctoral training at MIT, I established a chemomagnetic technique to pharmacologically modulate identifiable neural populations with behavioral assessment in freely moving mice. Hence, my immediate goal is to advance this technique into a multiplexed toolkit that enables multiple-site bidirectional control of circuit-level neural modulation. In Aim 1, I will improve the chemical synthesis of magnetic nanoparticles (MNPs) and liposomal nanocarriers to enable multiplexing control with paired ligand-receptors under disparate magnetic field conditions and implement the multiple-site neural modulation of brain structures that coordinate social behaviors. Next (Aim 2), I will advance this magnetic technique with gene editing approaches to enable non-viral gene delivery to cell-type specific neural circuits relevant to social processing. In the independent phase (Aim 3), I will validate the magnetic modulation on the targeted neural circuits to ameliorate social behavior deficits in transgenic mice, e.g. Shank3- /-. With the advanced magnetic electronics apparatuses, I will further adapt this technique to social interaction assessment in marmosets and introduce a potential magnetic field-assisted theranostic platform for ASDs.

项目概要和摘要 我的总体职业目标是建立一个独立的研究项目，专注于利用尖端技术 利用材料工程、基因操作和神经行为科学技术来研究神经回路 潜在的自闭症谱系障碍（ASD）。我假设一个远程控制的磁力 神经调节工具将精确的电路级神经调节与行为结果联系起来，从而增强 系统神经科学的神经回路询问。为了实现这个目标，我接受了广泛的培训 研究领域包括材料工程、纳米技术、细胞神经生理学和神经科学。 凭借这个奖项，我将在未来的职业生涯中开辟一条新的跨学科研究路径 远程控制的磁性工具，可以对特定神经进行药理学和基因编辑干预 电路以及对自由移动的小鼠和清醒、不受束缚的非人类灵长类动物的行为评估 （NHP）。在指导阶段，我将在 Polina Anikeeva 教授的监督下工作——Polina Anikeeva 教授是该领域的专家。 光电和磁神经接口，在我的顾问委员会的指导下 冯国平、张峰、Mriganka Sur 和何志刚教授。在他们的大力支持下，我将获得 基因编辑、社会行为测试设计和自闭症模型实验经验的额外培训 小鼠和狨猴的研究，这将使我具备进一步研究所需的知识和技能 自闭症谱系障碍的神经基础并开始我的独立职业生涯。指导阶段的工作将在 麻省理工学院的电子研究实验室和麦戈文脑研究所，提供了 活跃的多学科研究氛围、广泛的基础设施资源和宝贵的知识分子 实施拟议项目所需的社区。在我的西蒙斯博士后培训期间 麻省理工学院，我建立了一种化学磁技术来药理学调节可识别的神经群体 对自由活动的小鼠进行行为评估。因此，我的近期目标是将这项技术推进到 一个多路复用工具包，可实现电路级神经调制的多站点双向控制。在目标 1 中，我 将改进磁性纳米颗粒（MNP）和脂质体纳米载体的化学合成，以实现 在不同磁场条件下用配对配体受体进行多重控制并实现 协调社会行为的大脑结构的多位点神经调节。接下来（目标2），我会前进 这种磁性技术与基因编辑方法能够将非病毒基因传递到特定的细胞类型 与社会处理相关的神经回路。在独立阶段（目标 3），我将验证磁性 调节目标神经回路以改善转基因小鼠的社会行为缺陷，例如刀柄3- /-.借助先进的磁电子设备，我将进一步将这项技术应用于社交互动 对狨猴进行评估，并为 ASD 引入潜在的磁场辅助治疗平台。