Developing a noninvasive method to manipulate specific cell types within the mammalian brain

开发一种非侵入性方法来操纵哺乳动物大脑内的特定细胞类型

• 批准号: 9355229
• 负责人: Sreekanth H. Chalasani
• 金额: $ 92.99万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9355229
• 关键词: Affect; Alpha Cell; Amphibia; Animal Behavior; Animals; Ankyrin Repeat; Area; Basal Ganglia; Behavioral; Benchmarking; Bioinformatics; Biomedical Engineering; Brain; Brain region; Caenorhabditis elegans; Calcium; Cell Culture Techniques; Cells; Codon Nucleotides; Corpus striatum structure; Custom; Development; Devices; Disease; Dopamine D2 Receptor; Dose; Drosophila genus; Effectiveness; Electrodes; Electrophysiology (science); Family; Fiber Optics; Fishes; Focused Ultrasound; Frequencies; Genetic; Glues; Head; High Resolution Computed Tomography; Human; Image; In Vitro; Interneurons; Invertebrates; Kinetics; Light; MRI Scans; Mechanics; Methods; Microfabrication; Mus; Neuroglia; Neurons; Neurosciences; Operative Surgical Procedures; Parvalbumins; Physiologic pulse; Population; Printing; Property; Public Health; Research; Rodent; Skin; Stimulus; Surface; System; Technology; Testing; Therapeutic; Thinness; Translating; Ultrasonic Transducer; Ultrasonic wave; Ultrasonography; Variant; Vertebrates; Viral Vector; Work; X-Ray Computed Tomography; base; bone; cell type; design; efficacy testing; experimental study; high throughput screening; imaging modality; improved; in vivo; innovation; light weight; mechanotransduction; member; new technology; optogenetics; receptor; relating to nervous system; response; tool

Summary A central challenge in neuroscience is to develop methods to manipulate specific cell types within the mammalian brain. Recent developments in optogenetics have revolutionized our ability to control the activity of both neurons and non-neuronal cells. However, this approach suffers from one drawback, the difficulty in delivery light stimulus to target cells that are located deep within the brain or the body. The Chalasani lab has recently demonstrated a noninvasive method to control the activity of neurons. They have identified a pore- forming subunit of a mechanosensitive channel (TRP-4) that responds to low-intensity ultrasound. Further, they showed that expressing this channel is specific cells renders those target cells sensitive to mechanical deformations generated by noninvasive ultrasound waves. This proposal aims to develop this approach (they have termed “sonogenetics”) to control specific cells within the mouse brain. Further, they find that this approach can be used to control the activity of mammalian neurons in vitro. They plan on using a high- throughput assay system to test whether other members of the TRP-N family are sensitive to ultrasound pulses. Additionally, they will also analyze whether altering the number of ankyrin repeats affects the ultrasound responsiveness of these channels (consistent with a recent study showing similar results in the Drosophila TRP-N channel) (Aim 1). They also plan on developing a new head device with a slot for a tiny, lightweight ultrasound transducer to deliver ultrasound stimulus to the mouse brain (Aim 2). Finally, they will test the efficacy of the sonogenetic approach in vivo using electrophysiological and behavioral analysis. They will express TRP-4 or other mechanosensitive channels in cortical PV interneurons, striatal D1 or D2 medium spiny projection neurons and control their activity in vivo. Optogenetic methods have been previously used to control these cell populations providing benchmarks for comparison. These studies will develop a noninvasive method to manipulate the activity of specific cells within the rodent brain or its body. Further, these methods can be translated into the human to target specific cell populations for therapeutic purposes.

概括 神经科学的一个核心挑战是开发操纵特定细胞类型的方法 哺乳动物的大脑。光遗传学的最新发展彻底改变了我们控制细胞活性的能力 神经元细胞和非神经元细胞。然而，这种方法有一个缺点，即难以 将光刺激传递到位于大脑或身体深处的目标细胞。查拉萨尼实验室有 最近展示了一种控制神经元活动的非侵入性方法。他们发现了一个孔隙—— 形成响应低强度超声波的机械敏感通道 (TRP-4) 亚基。此外，他们 表明表达该通道的是特定细胞，使得这些靶细胞对机械敏感 非侵入性超声波产生的变形。该提案旨在发展这种方法（他们 被称为“声遗传学”）来控制小鼠大脑内的特定细胞。此外，他们发现这 该方法可用于在体外控制哺乳动物神经元的活动。他们计划使用高 用于测试 TRP-N 家族其他成员是否对超声波敏感的通量测定系统 脉冲。此外，他们还将分析改变锚蛋白重复次数是否会影响 这些通道的超声反应性（与最近的一项研究一致，显示了类似的结果） 果蝇 TRP-N 通道）（目标 1）。他们还计划开发一种新的头部设备，带有一个用于微型、 轻型超声换能器向小鼠大脑传递超声刺激（目标 2）。最后，他们将 使用电生理学和行为分析测试体内声遗传学方法的功效。他们 将在皮质 PV 中间神经元、纹状体 D1 或 D2 介质中表达 TRP-4 或其他机械敏感通道 多刺投射神经元并控制它们在体内的活动。光遗传学方法以前曾被用来 控制这些细胞群，提供比较基准。这些研究将开发一种非侵入性 操纵啮齿动物大脑或其体内特定细胞活动的方法。此外，这些方法 可以转化为人类以靶向特定细胞群以达到治疗目的。