Optical control of synaptic transmission for in vivo analysis of brain circuits and behavior

突触传递的光学控制用于脑回路和行为的体内分析

• 批准号: 8934227
• 负责人: Ehud Isacoff
• 金额: $ 77.07万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8934227
• 关键词: Action Potentials; Behavior; Brain; Brain region; Cells; Disease; Engineering; Excitatory Synapse; G-Protein-Coupled Receptors; GABA Receptor; Gated Ion Channel; Genetic Engineering; Glutamate Receptor; Glutamates; Goals; Health; Individual; Inhibitory Synapse; Ion Pumps; Life; Ligands; Light; Mediating; Methods; Mus; Neurons; Neurosciences; Neurotransmitter Receptor; Neurotransmitters; Opsin; Optics; Pharmacology; Photophobia; Point Mutation; Property; Receptor Cell; Retina; Role; Series; Specificity; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; Visual Cortex; Zebrafish; cell type; genetic manipulation; in vivo; light gated; microbial; neural circuit; new technology; novel strategies; optogenetics; postsynaptic; presynaptic; prevent; receptor; relating to nervous system; tool; transmission process

 DESCRIPTION (provided by applicant): Optogenetics has revolutionized neuroscience by making it possible to use heterologously expressed light-gated ion channels and pumps to stimulate or inhibit action potential firing of genetically selected neurons in order to define ther roles in brain circuits and behavior. Since the flow of information through neural circuits depends on synaptic transmission between cells, an important next technological step is to bring optogenetic control to the neurotransmitter receptors of the synapse. The Optogenetic Pharmacology that we propose makes this possible. In this approach genetically-engineered neurotransmitter receptor channels and G protein coupled receptors (GCPRs) from synapse are derivatized with synthetic Photoswitched Tethered Ligands (PTLs) and thereby made controllable by light. Our goal is to develop this new technology to gain optical control over synaptic transmission and plasticity in the living brain for studies of neural circuits and behavio. We focus on the two fundamental synapses of the brain: the excitatory glutamatergic synapse and inhibitory GABAergic synapse. An initial series of light-regulated glutamate and GABA receptors has already been made. This series will be optimized for in vivo use and expanded to obtain comprehensive control of these synapses. The receptors are minimally-modified, with a single point mutation enabling PTL attachment. Thus they retain their normal ability to respond to neurotransmitters. However, they can be blocked to prevent normal synaptic transmission or the induction of certain forms of plasticity, or they can be activated to mimic transmission or trigger plasticity changes, with cell and subtype specificity as well as high spatial and temporal precision. The receptors integrate into synapses, and control can be exerted across broad spatial scales, from individual pre- or postsynaptic terminals, to one or more dendritic branches, to individual or groups of cells, to entire brain regions. New methods for genetic manipulation allow the modified receptors to be genomically substituted for their wild-type counterparts, exactly replicating the number and distribution of endogenous receptors in the brain. Optogenetic Pharmacology provides a powerful approach for understanding brain circuits and behavior in health and disease.

 描述（由申请人提供）：光遗传学彻底改变了神经科学，使得使用异源表达的光门控离子通道和泵来刺激或抑制基因选择的神经元的动作电位放电，以定义它们在大脑回路和行为中的作用成为可能。信息通过神经回路的流动取决于 关于细胞间的突触传递，下一步重要的技术步骤是对突触的神经递质受体进行光遗传学控制，我们提出的光遗传学药理学使这成为可能。 ) ) 从突触中衍生出合成的光开关系留配体 (PTL)，从而使其可由光控制。我们的目标是开发这项新技术。为了获得对活体大脑中突触传递和可塑性的光学控制，以研究神经回路和行为，我们重点关注大脑的两个基本突触：兴奋性谷氨酸突触和抑制性 GABA 突触。 GABA 受体已被制成，将针对体内使用进行优化，并进行扩展以获得对这些突触的全面控制。使 PTL 附着的单点突变因此它们保留了对神经递质做出反应的正常能力，但是，它们可以被阻止以阻止正常的突触传递或诱导某些形式的可塑性，或者它们可以被激活以模仿传递或触发可塑性。受体整合到突触中，具有细胞和亚型特异性以及高空间和时间精度，并且可以在广泛的空间尺度上进行控制，从单个突触前或突触后末端到一个或多个树突。基因操作的新方法允许修饰的受体在基因组上取代其野生型囊肿，从而精确复制大脑中内源性受体的数量和分布。一种了解健康和疾病中的大脑回路和行为的强大方法。