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: 10657645
• 负责人: Mrinalini Hoon
• 金额: $ 37.54万
• 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/10657645
• 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; Light; Maintenance; Mediating; Mus; Nervous System; 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; Stereotyping; Stimulus; Synapses; Testing; Transgenic Organisms; Visual; Visual Pathways; cell type; dark rearing; developmental plasticity; experience; gamma-Aminobutyric Acid; glutamatergic signaling; in vivo; light microscopy; neurotransmission; patch clamp; photoreceptor degeneration; presynaptic; protein expression; receptor; recruit; repair strategy; response; retinal rods; retinogenesis; sensory feedback; synaptic function; synaptic inhibition; synaptogenesis; tool; visual information

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.

定位于感觉神经元轴突终末的突触前抑制性突触对 信息流经感官回路，允许有机体与其外部环境进行有意义的互动 环境。虽然对突触前抑制性突触的功能作用已知很多，但 感觉回路；对调节发育、成熟和发育的机制知之甚少 维持这些抑制性突触。使用特性良好的暗光(杆)视觉电路 哺乳动物视网膜我们发现了在GABA能突触前抑制物组装过程中的突触重组 调节弱光视网膜输出的突触。目前的提案旨在确定细胞-自治和 在抑制物组装过程中调节这种发育可塑性的非细胞自主机制 调节感觉(视网膜)信号传输增益的反馈电路。我们的研究将得出基本的结论 关于以下方面的信息：(一)视网膜回路组件(二)感觉回路的组织和调节机制 感觉反馈，以及(Iii)在建立抑制回路过程中调节受体可塑性的原则 横跨中南欧。我们将结合小鼠转基因方法和高分辨率光学显微镜，3D 电子显微镜和电生理学解决以下三个目标。在目标1中，我们将确定发育中的视网膜杆双极神经元中氯转运蛋白表达的细胞自主性变化是否驱动 并调控发育中GABAA受体重组的时机和/或发生。目标2将 兴奋性和抑制性神经传递对大鼠视网膜视杆双极神经元的贡献(S) 调节发育中的GABAA受体可塑性。目标3将决定早期视觉体验的作用 在调节弱光反馈抑制突触的GABAA受体重组和组装中的作用 视网膜回路。我们的研究将揭示细胞自主机制、突触输入、 反馈抑制回路建立和成熟过程中的网络活动和环境线索 调节感官输出。我们的研究还将揭示可以被招募来改善的电路可塑性模体 视网膜疾病期间的功能障碍。此外，我们的发现将决定人类的发育顺序 体内突触前抑制回路组装过程中的成熟与体外视网膜组装的比较 就像多能干细胞用于视网膜再生一样。