Mechanisms regulating formation and maintenance of sensory circuits

调节感觉回路形成和维持的机制

• 批准号: 10027517
• 负责人: Mrinalini Hoon
• 金额: $ 37.43万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10027517
• 关键词: 3-Dimensional; Address; Afferent Neurons; Amacrine Cells; Automobile Driving; Axon; Bipolar Neuron; Birth; Brain; Cells; Chlorides; Cues; Data; Dendrites; Development; Electron Microscopy; Electrophysiology (science); Ensure; Environment; Equilibrium; Event; Exhibits; Eye; Feedback; Functional disorder; Gene Expression; Glutamate Receptor; Glutamates; Goals; Immunohistochemistry; Impairment; Inhibitory Synapse; Knowledge; Lead; Light; Maintenance; Mediating; Mus; Nervous system structure; Neurons; Neurotransmitters; Organism; Output; Photoreceptors; Physiology; Pluripotent Stem Cells; Positioning Attribute; Presynaptic Terminals; Research; Resolution; Retina; Retinal Degeneration; Retinal Diseases; Rod; Role; Sensory; Shapes; Signal Transduction; Synapses; Testing; Transgenic Organisms; Visual; Visual Pathways; cell type; dark rearing; developmental plasticity; experience; gamma-Aminobutyric Acid; glutamatergic signaling; light microscopy; neurotransmission; patch clamp; photoreceptor degeneration; presynaptic; protein expression; receptor; recruit; repaired; response; retinal rods; retinogenesis; sensory feedback; synaptic function; synaptogenesis; tool; visual information; visual stimulus

Presynaptic inhibitory synapses positioned across axon terminals of sensory neurons critically regulate information flow across sensory circuits, allowing meaningful interactions of an organism with its external environment. Whereas much is known about the functional role of presynaptic inhibitory synapses across sensory circuits; little is known about the mechanisms that regulate the development, maturation and maintenance of these inhibitory synapses. Using the well-characterized dim-light (rod) visual circuit of the mammalian retina we uncovered a synaptic reorganization during assembly of GABAergic presynaptic inhibitory synapses that regulate dim-light retinal output. The current proposal aims to determine the cell-autonomous and non-cell autonomous mechanisms that regulate this developmental plasticity during assembly of inhibitory feedback circuits that regulate the gain of sensory (retinal) signal transfer. Our research will yield fundamental information about: (i) retinal circuit assembly (ii) organization of sensory circuits and mechanisms that regulate sensory feedback, and (iii) principles that regulate receptor plasticity during establishment of inhibitory circuits across the CNS. We will combine murine transgenic approaches with high resolution light microscopy, 3D electron microscopy and electrophysiology to address the following three Aims. In Aim 1 we will determine if cell-autonomous alterations in chloride transporter expression across developing retinal rod bipolar neurons drive and regulate the timing and/or occurrence of the developmental GABAA receptor reorganization. Aim 2 will determine the contribution(s) of excitatory and inhibitory neurotransmission onto the retinal rod bipolar neuron in regulating the developmental GABAA receptor plasticity. Aim 3 will determine the role of early visual experience in regulating GABAA receptor reorganizations and assembly of feedback inhibitory synapses of the dim-light retinal circuit. Our research will reveal the interplay between cell-autonomous mechanisms, synaptic input, network activity and environmental cues during establishment and maturation of feedback inhibitory circuits that regulate sensory output. Our study will also reveal circuit plasticity motifs that can be recruited to ameliorate dysfunction during retinal diseases. Furthermore, our findings will determine the developmental sequence of maturation during assembly of invivo presynaptic inhibitory circuits to compare with exvivo retinal assembly such as when pluripotent stem cells are used for retinogenesis.

在感觉神经元的轴突末端定位的突触前抑制性突触严重调节 信息流跨感官电路，使生物体与其外部的有意义的相互作用 环境。尽管对跨突触前抑制突触的功能作用有很多了解 感觉电路；关于调节发展，成熟和的机制知之甚少 维护这些抑制性突触。使用良好的昏暗光（杆）视觉电路 哺乳动物视网膜我们在GABA能突触前抑制性抑制剂组装过程中发现了突触重组 调节昏暗视网膜输出的突触。当前的提案旨在确定细胞自主和 在抑制性组装过程中调节这种发展可塑性的非电池自主机制 调节感觉（视网膜）信号传递增益的反馈电路。我们的研究将产生基本 有关：（i）视网膜电路组件（ii）调节的感觉电路和机制的组织 感觉反馈和（iii）在建立抑制回路期间调节受体可塑性的原理 跨过中枢神经系统。我们将将鼠转基因方法与高分辨率光学显微镜结合在一起，3D 电子显微镜和电生理学，以解决以下三个目标。在AIM 1中，我们将确定跨发育中的视网膜双极神经元驱动氯化物转运蛋白表达的细胞自主变化 并调节发育GABAA受体重组的时间和/或发生。 AIM 2意志 确定兴奋性和抑制性神经传递对视网膜双极神经元的贡献 调节发育性GABAA受体可塑性。 AIM 3将决定早期视觉体验的作用 在调节GABAA受体的重组和昏暗的反馈抑制突触的组装方面 视网膜电路。我们的研究将揭示细胞自治机制，突触输入， 网络活动和环境线索在建立和成熟的反馈抑制电路中 调节感觉输出。我们的研究还将揭示可募集以改善的电路可塑性图案 视网膜疾病期间功能障碍。此外，我们的发现将决定 象征前抑制回路组装过程中的成熟，与Exvivo视网膜组装进行比较 就像多能干细胞用于视网膜生成时一样。