GABAergic circuit interactions within the behaving mouse dLGN

行为小鼠 dLGN 内 GABA 能电路的相互作用

• 批准号: 9449526
• 负责人: MARTHA E BICKFORD
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9449526
• 关键词: Action Potentials; Acute; Address; Affect; Anatomy; Animals; Area; Attention; Behavior; Behavioral; Brain; Butyric Acids; Caliber; Cannulas; Cell Nucleus; Cells; Disease; Disinhibition; Dorsal; Drug Delivery Systems; Electrodes; Elements; Epilepsy; Eye Movements; Fiber Optics; Frequencies; Goals; Head; In Vitro; Individual; Injury; Interneurons; Intervention; Knowledge; Lateral Geniculate Body; Light; Link; Mediating; Membrane Potentials; Methodology; Methods; Modeling; Movement; Mus; Neurons; Neurotransmitters; Output; Pattern; Physiology; Pupil; Reporting; Retina; Running; Schizophrenia; Shapes; Signal Transduction; Sleep; Slice; Source; Speed; Synapses; Techniques; Testing; Thalamic structure; Tungsten; Vision; Visual; Whole-Cell Recordings; active vision; awake; base; behavior measurement; computer generated; experimental study; extracellular; in vivo; insight; nervous system disorder; neural circuit; optogenetics; response; retinogeniculate; technique development; tool; transmission process; visual information

Abstract The flow of visual information from the retina, through the dorsal lateral geniculate nucleus (dLGN) to the cortex, is regulated by behavior. However, the dynamic circuit interactions that occur in the dLGN of awake animals, and their modulation by behavior, have yet to be revealed. The purpose of this proposal is to develop tools to determine how inhibitory circuits of the dLGN (which utilize the neurotransmitter gamma amino butyric acid, GABA) interact in vivo, and how they collectively shape vision in the context of behavior. The premise of this study is based on two key pieces of information: 1) Our previous ultrastructural analyses and in vitro optogenetic experiments suggest that two extrinsic GABAergic inputs to the dLGN, originating from the thalamic reticular nucleus (TRN) and pretectum (PT), serve to suppress or enhance retinogeniculate transmission respectively. 2) Previous studies suggest that the TRN and PT are active during different behavioral states. Thus, we hypothesize that these two sources of inhibition serve to suppress or enhance visual signals in the dLGN during different behavioral states. We propose to test this hypothesis by recording dLGN visual responses in behaving mice while selectively and independently manipulating TRN and/or PT terminals within the dLGN. In head-fixed alert mice, we will record the visual responses of dLGN neurons to computer-generated visual displays while simultaneously recording running speed, eye movements, and pupil diameter. The Aim 1 experiments will test the hypothesis that the PT functions to enhance retinogeniculate transmission immediately following eye movements, to boost cortical activation following visual target acquisition. For this aim, geniculate responses will be recorded during optogenetic silencing or activation of PT terminals, chemogenetic silencing of TRN terminals, or the combined optogenetic/chemogenetic manipulation of PT and TRN terminals. The Aim 2 experiments will test the hypothesis that the TRN dampens retinogeniculate transmission during quiescent states. For this aim, geniculate responses will be recorded during optogenetic silencing or activation of TRN terminals, chemogenetic silencing of PT terminals, or the combined optogenetic/chemogenetic manipulation of TRN and PT terminals. The development of techniques to manipulate circuits in vivo, in addition to our existing anatomical and in vitro experiment strategies, will provide a powerful multipronged approach to deciphering how the individual components of brain circuits are integrated. Once these in vivo methods are perfected, our methodologically-integrated approach can be used to answer a wide variety of outstanding questions regarding thalamic function.

摘要 视觉信息从视网膜流经外侧膝状体背侧核 (DLGN)到大脑皮层，受行为调节。然而，动态电路相互作用发生在 清醒动物的dlgn及其行为的调节尚未被揭示。目的 这一建议的目的是开发工具来确定dLGN的抑制电路(利用 神经递质伽马氨基丁酸(GABA)在体内相互作用，以及它们共同形成的方式 行为语境中的视觉。这项研究的前提是基于两条关键信息： 1)我们先前的超微结构分析和体外光遗传实验表明，有两个 外源性GABA能传入dLGN，来源于丘脑网状核(TRN)和 孕期前(PT)，分别用于抑制或增强视黄醇原基传递。2)上一次 研究表明，在不同的行为状态下，TRN和PT是活跃的。因此，我们 假设这两种抑制源起到抑制或增强视觉信号的作用 不同行为状态下的DLGN。我们建议通过记录dLGN视觉来检验这一假设 选择性和独立操作TRN和/或PT时小鼠的行为反应 DLGN内的端子。在头部固定的警觉小鼠中，我们将记录dLGN的视觉反应 神经元到计算机生成的视觉显示，同时记录运行速度，眼睛 运动和瞳孔直径。目标1的实验将检验PT功能的假设 在眼球运动后立即增强视黄素生成的传递，以促进皮质 视觉目标获取后的激活。为此，将记录膝状反应 在光发生沉默或PT末端激活期间，TRN末端的化学发生沉默， 或PT和TRN末端的光发生/化学发生联合操作。《目标2》 实验将验证这样的假设，即TRN抑制视黄素原基传递 静止状态。为此，将在光遗传沉默期间记录膝状反应或 TRN末端的激活、PT末端的化学沉默或其组合 TRN和PT终末的光发生/化学发生操作。技术的发展，以 除了我们现有的解剖学和体外实验策略外，还可以在体内操纵电路， 将提供一种强大的多管齐下的方法来破译大脑的各个组成部分 电路是集成的。一旦这些活体方法完善，我们的方法学整合 方法可以用来回答关于丘脑功能的各种悬而未决的问题。