Sonogenetic control of neurons in a large volume of the rodent brain

啮齿动物大脑大体积神经元的声遗传学控制

• 批准号: 9925113
• 负责人: Sreekanth H. Chalasani
• 金额: $ 264.34万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925113
• 关键词: Action Potentials; Affect; Animals; Area; BRAIN initiative; Behavior; Behavioral; Benchmarking; Biological Assay; Biomedical Engineering; Brain; Caenorhabditis elegans; Cell Culture Techniques; Cells; Chimera organism; Code; Codon Nucleotides; Data; Defect; Development; Devices; Diffuse; Disease; Electromagnetics; Electromyography; Electrophysiology (science); Epilepsy; Exhibits; Female; Frequencies; Generations; Genetic; Grant; Heart; Homologous Gene; Human; Hypothalamic structure; Image; In Vitro; Interneurons; Invertebrates; Kinetics; Length; Light; Mammalian Cell; Mammals; Marine Invertebrates; Mechanics; Methods; Motor Neurons; Mus; Neuroglia; Neurons; Neurosciences; Operative Surgical Procedures; Peptides; Pharmacology; Physiologic pulse; Polyps; Population; Property; Proteins; Rodent; Skin; Slice; Source; Stimulus; Structural Models; Syndrome; System; Technology; Testing; Therapeutic; Thinness; Transducers; Translating; Ultrasonic Transducer; Ultrasonic wave; Ultrasonography; Variant; adeno-associated viral vector; agouti protein; base; behavior test; bone; brain volume; cell type; design; effectiveness testing; efficacy testing; experimental study; feeding; genetic analysis; genetic approach; in vitro Assay; in vivo; innovation; lithium niobate; mechanotransduction; method development; millisecond; models and simulation; mouse model; novel; novel therapeutics; optogenetics; response; small molecule; spatiotemporal; structural biology; tool; transcriptome

Abstract A key challenge in neuroscience is the development of methods to non-invasively manipulate specific neuronal cell types in vivo. While recent opto-, chemo- and magneto-genetic approaches have revolutionized our ability to control both neuronal and non-neuronal cell types, they each suffer from critical drawbacks, including the inability to deliver light to targets deep within the brain or to large volumes of the brain (opto-), and the lack of precise temporal control for both chemo- and magneto-genetic approaches. The Chalasani lab has recently demonstrated a noninvasive method for controlling the activity of neurons using ultrasound, a system they call sonogenetics. They have demonstrated that mechanosensitive TRP-N channel homologs from C. elegans, Hydractinia, and Hydra magnipapillata can be used to non-invasively activate mammalian cells both in vitro and in vivo. They hypothesize that target cells expressing these TRP-N channels are rendered sensitive to mechanical deformations generated by non-invasive ultrasound waves. This proposal aims to extend the sonogenetic approach to control specific neuronal populations throughout large volumes of the mouse brain, a system that would be useful for reversing electrophysiological and behavioral deficits seen in epilepsy, for example. They will identify channels with non-overlapping ultrasound stimulus ranges by testing variants and chimeras of the Hydra TRP-N channels in high-throughput imaging and slice culture electrophysiology assays in vitro, as well as in feeding and electromyography assays in vivo (Aim 1). They also plan to develop a new lithium niobate-based transducer that will deliver ultrasound throughout the mouse brain. Specifically, they will use Schroeder’s optimal diffuser design in a device that will generate spatiotemporally incoherent ultrasound that upon reflection, avoids interference and localized spikes in ultrasound (Aim 2). Finally, they plan to activate GABAergic inhibitory interneurons broadly throughout the brain to alleviate behavioral and electrophysiological deficits in mouse models of epilepsy and Rhett’s syndrome. Optogenetic, chemogenetic, and pharmacological methods have been previously used to control these cell populations, providing benchmarks for comparison. These studies will develop a noninvasive method for manipulating the activity of specific cells within large volumes of the rodent brain or body. Further, these methods can be translated into the human system to target specific cell populations for therapeutic purposes.

抽象的 神经科学中的关键挑战是开发非侵入性操纵特定神经元的方法 细胞类型，近期光学 为了控制神经元和非神经元细胞类型，它们每个都有关键缺点，包括 无法为大脑内部或大脑大脑深处的目标传递光（光（Opto-）），并且缺乏 Chalasani实验室的化学和磁化方法的精确时间控制。 展示了一种使用超声来控制神经元活动的无创方法，他们称之为系统 他们已经证明了秀丽隐杆线虫的机械敏感性TRP-N通道同源物 氢化菌和hydra magpapillata可用于在体外和 在体内。 非侵入性超声波产生的机械变形旨在扩展 在大量小鼠大脑中控制特定神经元流行的超音速方法 系统可用于逆转癫痫中的电溶性和行为缺陷 例如，他们将识别具有非重叠超声刺激范围的通道 在高槽成像和切片培养电子生理学测定中，Hydra TRP-N通道的嵌合体 在体内的体外以及进食和肌电图测定法（AIM 1）。 基于硝酸锂的传感器将传递小鼠大脑的超声波。 在将产生时空不一致的超声的设备中，使用Schroed的最佳扩散器扩散器设计 反思后，避免了超声波（AIM 2）的干扰和局部峰值。 GABA能抑制性中间神经元在整个大脑中脑部脑部和电生理学 癫痫和瑞特的小鼠模型的缺陷。 先前已使用方法来控制这些细胞群体，提供基准进行比较。 这些研究将开发一种无创方法来操纵大型细胞的活性 啮齿动物大脑或身体的体积。 用于治疗目的的特定细胞普及。