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Optimizing Optogenetics for Cell-type-specific Control in Freely-moving Primates

优化光遗传学以实现自由移动灵长类动物的细胞类型特异性控制

基本信息

批准号：
10621931
负责人：
MICHAEL L PLATT
金额：
$ 64.7万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621931
关键词：
Address Affect Animal Model Animals Antigen-Antibody Complex Behavior Behavioral Biological Assay Brain Brain Diseases Cardiac pacemaker Chronic Clinical Collaborations Contrast Media Convection Devices Diffusion Dissection Dura Mater Encephalitis Epilepsy FDA approved Gene Delivery Gene Expression General Population Generations Genes Genetic Goals Histology Human Immune response Immune system Implant Individual Injections Lasers Light Lighting Macaca Magnetic Resonance Imaging Mediating Medical Mental disorders Monkeys Movement Mus Neuroanatomy Neurologic Neurons Neurosciences Operative Surgical Procedures Opsin Paresis Partial Epilepsies Patients Pattern Persons Physical Restraint Pilot Projects Polymers Population Primates Proteins Research Research Personnel Resolution Rodent Safety Scotoma Serotyping Shapes Source Specificity Surface Techniques Technology Testing Therapeutic Thick Time Tissues Viral biomaterial compatibility brain volume cell type cisterna magna clinically significant commercialization delivery vehicle design energy efficiency experience experimental study flexibility fly gene therapy immunoreaction in vivo individuals with autism spectrum disorder industry partner light weight loss of function microsystems millisecond mind control multidisciplinary nervous system disorder neural neural circuit neural implant neurophysiology neuroregulation neurotechnology new technology nonhuman primate open data optogenetics programs promoter restraint targeted treatment technology platform tool translational potential translational therapeutics virology wearable device wireless wireless electronic

项目摘要

ABSTRACT Optogenetics is a revolutionary technique in neuroscience. By combining light-sensitive proteins with intracranial light delivery, optogenetics offers unprecedented, cell-type specific control over neuronal activity. The technique has become the dominant approach for studying neural circuits in small animal models such as mice and flies. Unfortunately, optogenetics has so far failed to have a major impact on research using larger animals more similar to humans, such as macaque monkeys, undermining its translational potential for human patients. We conducted a world-wide Open Science initiative to identify the challenges remaining to be solved in primate optogenetics (Tremblay et al. Neuron, 2020). We identified the sheer size of the macaque monkey brain, which is 200 times bigger than the mouse brain, as well as its immune system, as the main challenges for both gene expression and light delivery. Our multidisciplinary team of investigators will overcome these obstacles by developing and optimizing three new technologies: 1) large-scale, safe delivery of ultra-sensitive opsins using gene therapy techniques; 2) chronically-implantable, ultra-thin, flexible, biocompatible LED arrays; and 3) implantable, battery-powered LED drivers for wireless control during unrestrained, naturalistic behavior. This approach will allow precise control of large volumes of the primate brain with cell-type specificity and millisecond resolution in monkeys free of physical restraint, thus permitting causal dissection of the neural circuits mediating natural behavior relevant for understanding and treating human brain disorders. This technology platform could be directly applied as a cell-type-specific optogenetic therapy for humans suffering from neurological disorders that affect specific neural populations, such as focal epilepsy.

摘要光遗传学是神经科学中的一项革命性技术。通过将光敏蛋白与颅内结合在光传递方面，光遗传学对神经元活动提供了前所未有的、细胞类型的特定控制。这项技术已经成为研究小动物模型(如老鼠和苍蝇)神经回路的主要方法。不幸的是，光遗传学到目前为止还没有对更多使用更大动物的研究产生重大影响。类似于人类，如猕猴，破坏了其对人类患者的翻译潜力。我们开展了一项世界范围的开放科学倡议，以确定灵长类中有待解决的挑战光遗传学(Tremblay等人)神经元，2020)。我们确定了猕猴大脑的绝对大小，这是比小鼠的大脑及其免疫系统大200倍，这是这两个基因面临的主要挑战表情和轻盈的传递。我们的多学科调查团队将通过以下方式克服这些障碍开发和优化三项新技术：1)大规模、安全地输送超灵敏光学元件基因治疗技术；2)长期植入、超薄、灵活、生物兼容的发光二极管阵列；以及3) 可植入电池供电的LED驱动器，可在自由、自然的行为中进行无线控制。这这种方法将允许精确控制大量灵长类动物的大脑，具有细胞类型特异性和毫秒级在猴子中不受身体约束的分解，从而允许对调节的神经回路进行因果解剖与理解和治疗人类大脑疾病相关的自然行为。这一技术平台可以作为一种针对细胞类型的光遗传疗法，直接应用于患有神经疾病的人类影响特定神经群体的疾病，例如局灶性癫痫。