GABAergic circuit interactions within the behaving mouse dLGN

行为小鼠 dLGN 内 GABA 能电路的相互作用

基本信息

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
项目类别：
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

项目摘要

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.

抽象的来自视网膜的视觉信息流通过背外侧膝状核 (dLGN) 到皮质，受行为调节。然而，动态电路相互作用发生在清醒动物的 dLGN 及其行为调节尚未被揭示。目的该提案的目的是开发工具来确定 dLGN 的抑制电路（利用神经递质 γ 氨基丁酸 (GABA) 在体内相互作用，以及它们如何共同形成行为背景下的愿景。这项研究的前提基于两个关键信息： 1）我们之前的超微结构分析和体外光遗传学实验表明，两个 dLGN 的外在 GABA 能输入，源自丘脑网状核 (TRN) 和 pretectum (PT)，分别用于抑制或增强视网膜原代传输。 2) 上一页研究表明 TRN 和 PT 在不同的行为状态下是活跃的。因此，我们假设这两种抑制源可以抑制或增强视觉信号不同行为状态下的 dLGN。我们建议通过记录 dLGN 视觉来检验这一假设选择性且独立地操纵 TRN 和/或 PT 时行为小鼠的反应 dLGN 内的终端。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，同时记录跑步速度、眼睛运动和瞳孔直径。目标 1 实验将检验 PT 功能的假设增强眼球运动后立即的视网膜传输，促进皮质视觉目标获取后激活。为此，将记录膝状反应在 PT 末端的光遗传学沉默或激活、TRN 末端的化学遗传学沉默期间，或 PT 和 TRN 末端的组合光遗传学/化学遗传学操作。目标2 实验将检验 TRN 抑制视网膜原化传输的假设静止状态。为此，将在光遗传学沉默或 TRN 末端的激活、PT 末端的化学遗传学沉默或组合 TRN 和 PT 末端的光遗传学/化学遗传学操作。技术的发展除了我们现有的解剖和体外实验策略之外，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如何电路是集成的。一旦这些体内方法得到完善，我们的方法论整合该方法可用于回答有关丘脑功能的各种悬而未决的问题。