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: 9568835
• 负责人: MARTHA E BICKFORD
• 金额: $ 19.25万
• 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 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9568835
• 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.

抽象的 视网膜通过背侧侧向核的视觉信息流动 （DLGN）到皮质，受到行为的调节。但是，发生的动态电路相互作用发生在 清醒动物的DLGN及其按行为调节尚待揭示。目的 该建议的是开发工具来确定如何使用DLGN的抑制作用（该电路 神经递质伽马氨基丁酸，gaba）在体内相互作用，以及它们如何集体塑造 在行为背景下的视觉。这项研究的前提是基于两个关键信息： 1）我们以前的超微结构分析和体外光遗传学实验表明两个 DLGN的外部GABA能输入，源自丘脑网状核（TRN）和 假定（PT）分别抑制或增强视网膜生成的传播。 2）以前 研究表明，在不同的行为状态下，TRN和PT具有活性。因此，我们 假设这两种抑制源可以抑制或增强视觉信号 在不同行为状态下的DLGN。我们建议通过记录DLGN Visual来检验这一假设 在有选择性和独立操纵TRN和/或PT的同时，行为小鼠的反应 DLGN内的终端。在头部固定警报小鼠中，我们将记录DLGN的视觉响应 神经元到计算机生成的视觉显示，同时记录跑步速度，眼睛 运动和瞳孔直径。 AIM 1实验将测试PT功能的假设 在眼睛运动后立即增强视网膜生成的传播，以增强皮质 视觉目标获取后激活。为此，将记录基因响应 在PT末端的光遗传沉默或激活期间，TRN末端的化学遗传沉默， 或PT和TRN末端的光遗传学/化学遗传操作。目标2 实验将检验以下假设，即TRN会在 静止状态。为此，将在光学遗传沉默期间记录遗传反应或 TRN末端的激活，PT末端的化学遗传沉默或组合 TRN和PT末端的光遗传学/化学作用操纵。技术的发展 除了我们现有的解剖学和体外实验策略外，在体内操纵电路 将提供一种强大的多收益方法来解密大脑的单个组成部分 电路已集成。一旦完善了这些体内方法，我们的方法论综合 方法可用于回答有关丘脑功能的各种杰出问题。