Projection Specific Modulation of Neural Activity with A Non-genetic Method

用非遗传方法投射特异性神经活动调节

• 批准号: 10296391
• 负责人: Huiliang Wang
• 金额: $ 6.89万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-14 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10296391
• 关键词: Address; Advisory Committees; Affect; Animal Behavior; Animals; Anxiety; Axon; Axonal Transport; Bathing; Behavior; Behavioral; Brain; Brain region; Calcium; Cells; Chemicals; Clinical; Complement; Development; Disease; Effectiveness; Electron Microscopy; Electrophysiology (science); Engineering; Equilibrium; Fiber; Fluorescence Microscopy; Foundations; Future; Gene-Modified; Generations; Genetic; Gold; Image; In Vitro; Injections; Ion Channel; Ions; Light; Location; Mammals; Mental Depression; Mental disorders; Methods; Modeling; Modification; Molecular; Mus; Nature; Neurology; Neurons; Neurosciences; Opsin; Outcome; Penetration; Photometry; Presynaptic Terminals; Process; Psychiatry; Rewards; Rodent; Safety; Slice; Speed; Techniques; Technology; Therapeutic; Time; Tissues; Toxic effect; Transfection; Translations; Viral; Viral Genes; Virus; Visible Radiation; Work; Yang; absorption; autism spectrum disorder; base; biomaterial compatibility; brain tissue; channel blockers; clinical application; clinical translation; experimental study; gene therapy; in vitro activity; in vivo; member; microbial; nanomaterials; nanoparticle; nanorod; nervous system disorder; neural circuit; neuronal cell body; neurophysiology; non-genetic; optogenetics; patch clamp; relating to nervous system; retrograde transport; tool; uptake

Project Summary In psychiatry and neurology, there are many debilitating disorders based on aberrant circuits for which we do not have adequate treatment methods. Recent developments in optogenetics and viral technology have demonstrated that modulating the neural activity of specific projections in the brain is capable of rescuing behavioral deficits, including those relevant to depression, autism and anxiety. However, this approach requires genetic modification of neurons via viral transduction, which introduces a significant barrier for clinical applications due to safety concerns. Also, the current projection-targeted neural modulation methods all use visible light, limiting both the light penetration depth and the number of independent channels neuroscientists can use for recording and modulating neural activity. Here, I would like to propose a non-genetic method for projection-specific modulation of neural activity in freely behaving mammals. This approach will use gold nanorods, a near-infrared (NIR) absorber and heat generation for neural modulations. Our preliminary results have demonstrated that gold nanorods are internalized by neuron soma or axon terminals, are transported retrograde/anterograde through neural axons and are sufficient to modulate neural activity under NIR light after axon transport in vitro. The aim of this work is to continue the development of this approach from in vitro to in vivo, which will be crucial for its future clinical translation. In Aim 1, I will determine the internalization and axon transport of gold nanorods in vivo by characterizing brain slices with fluorescence microscopy and electron microscopy. CLARITY will be used to visualize the nanoparticles in the whole projection. The in vivo toxicity of gold nanorods will also be studied. In Aim 2, I will determine the mechanism of photothermal modulation of neural activity by patching clamp, particularly the types of ions and ion channels involved during the modulation process. I will also verify the conductions for in vivo modulation of neural activity using fiber photometry. In Aim 3, I will examine the effectiveness of projection-specific modulation of rodent behaviors with our developed gold nanorod methods in model circuits related to reward and anxiety. The completion of the aims will result in the first non-genetic method for projection-targeted modulation of neural activity. This method will complement optogenetic neural modulation and calcium imaging with an orthogonal NIR channel and will present a better opportunity for clinical therapeutic applications due to its non- genetic and non-viral nature. The work will be accomplished under a team of advisory members consisting of a good balance of neuroscientists and nanomaterial experts: Dr. Karl Deisseroth, Dr. Sam Gambhir, Dr. Hongjie Dai, Dr. Fan Yang and Dr. Talia Lerner. After the completion of the project, I will become proficient in various in vivo techniques, such as optogenetics, fiber photometry, CLARITY and rodent behavior experiments.

项目摘要 在精神病学和神经病学中，有许多基于异常回路的衰弱性疾病，我们确实 没有足够的治疗方法。光遗传学和病毒技术的最新发展 研究表明，调节大脑中特定投射的神经活动能够挽救 行为缺陷，包括与抑郁症、自闭症和焦虑有关的行为缺陷。但是这种方法 需要通过病毒转导对神经元进行遗传修饰，这为临床应用引入了重大障碍。 出于安全考虑。此外，目前的投射靶向神经调制方法都使用 可见光，限制了光的穿透深度和独立通道的数量 可用于记录和调节神经活动。在这里，我想提出一个非遗传的方法 用于自由行为的哺乳动物的神经活动的投射特异性调制。这种方法将使用 金纳米棒、近红外（NIR）吸收剂和用于神经调节的热生成。我们的初步 结果表明，金纳米棒被神经元索马或轴突末梢内化， 通过神经轴突逆行/顺行运输，并足以在 体外轴突运输后的NIR光。这项工作的目的是继续发展这种方法， 从体外到体内，这对它未来的临床转化至关重要。在目标1中，我将确定 金纳米棒在体内内化和轴突转运的荧光脑切片表征 显微镜和电子显微镜。将使用EQUILITY来可视化整体中的纳米颗粒 投影还将研究金纳米棒的体内毒性。在目标2中，我将确定 通过膜片钳的神经活动的光热调制，特别是离子和离子通道的类型 在调制过程中。我还将验证在体内调节神经细胞的传导， 使用纤维光度法测定活性。在目标3中，我将检查特定于投影的调制的有效性， 啮齿动物的行为与我们开发的金纳米棒方法在模型电路有关的奖励和焦虑。 目标的完成将导致第一个非遗传方法的投影靶向调制的 神经活动这种方法将补充光遗传神经调节和钙成像， 正交近红外通道，并将提供更好的机会，临床治疗应用，由于其非- 遗传和非病毒性质。这项工作将在一个咨询成员小组的领导下完成， 神经科学家和纳米材料专家的良好平衡：Karl Deisseroth博士，Sam Gambhir博士，Hongjie博士 Dai，Dr. Fan Yang and Dr. Talia Lerner.项目完成后，我将精通各种 活体技术，如光遗传学、纤维光度学、免疫学和啮齿动物行为实验。