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.

抽象的光遗传学是神经科学领域的一项革命性技术，它将光敏蛋白与颅内蛋白质相结合。光传递，光遗传学提供了前所未有的、细胞类型特异性的神经活动控制。已成为研究小鼠和苍蝇等小动物模型神经回路的主要方法。不幸的是，光遗传学迄今为止未能对使用更大动物的研究产生重大影响与人类相似，例如猕猴，破坏了其对人类患者的转化潜力。开展了一项世界范围的开放科学计划，以确定灵长类动物尚待解决的挑战光遗传学（Tremblay et al. Neuron，2020）我们确定了猕猴大脑的巨大尺寸，这比小鼠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我们的多学科研究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）使用大规模、安全的超敏感视蛋白递送基因治疗技术；2) 可长期植入、超薄、灵活、生物相容性的LED 阵列；植入式电池供电 LED 驱动器，用于在不受约束的自然行为期间进行无线控制。该方法将允许以细胞类型特异性和毫秒精确控制灵长类动物的大量大脑在不受身体约束的猴子中解决问题，从而允许对介导的神经回路进行因果解剖该技术平台可以与理解和治疗人类大脑疾病相关的自然行为。可直接应用于患有神经系统疾病的人类的细胞类型特异性光遗传学疗法影响特定神经群体，例如局灶性癫痫。