Retinal inputs signal through astrocytes to recruit interneurons into visual thalamus

视网膜通过星形胶质细胞输入信号以招募中间神经元进入视觉丘脑

• 批准号: 9806328
• 负责人: MICHAEL A FOX
• 金额: $ 24.71万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806328
• 关键词: Address; Affect; Alleles; Astrocytes; Axon; Brain; Brain Stem; Brain region; Cell Nucleus; Cells; Cues; Data; Development; Dorsal; Economic Burden; Enterobacteria phage P1 Cre recombinase; Environment; Event; Exhibits; Extracellular Matrix; Eye; Fibroblast Growth Factor; GLI gene; GLI2 gene; Genetic Transcription; Goals; Inhibitory Synapse; Instruction; Interneurons; Knowledge; Label; Lateral Geniculate Body; Light; Mediating; Molecular; Molecular Genetics; Mus; Natural regeneration; Neonatal; Nervous system structure; Neuroglia; Neurons; Patients; Persons; Phenotype; Play; Population; Receptor Signaling; Recombinant Fibroblast Growth Factor; Recombinants; Reporter; Retinal; Retinal Ganglion Cells; Role; SHH gene; Signal Pathway; Signal Transduction; Signaling Molecule; Source; Synapses; Testing; Thalamic Nuclei; Thalamic structure; Vision; Visual; Visual impairment; design; effective therapy; extracellular; genetic approach; migration; mutant; nerve supply; neural circuit; novel; recombinase; recruit; regenerative therapy; response; retinal axon; smoothened signaling pathway; social; sonic hedgehog receptor; visual information; visual processing

Currently there are no effective treatments for patients with deficits in subcortical visual circuits. In response to this unmet need, NEI has issued an Audacious Goals Initiative with the goal of gaining new knowledge that will contribute to the development of regenerative therapies aimed at restoring subcortical visual circuits. To accomplish this goal, we need a better understanding of the cell and molecular mechanisms that drive the formation of these circuits during development. Although we have made progress in our understanding of how retinal axons target and innervate subcortical brain regions (such as the dorsal and ventral lateral geniculate nuclei [dLGN and vLGN, respectively]), we lack critical knowledge about how other inputs and cells target these regions. Inputs from the cortex, thalamic nuclei, brainstem nuclei and local interneurons act as modulatory or inhibitory inputs in visual thalamus and play essential roles in the processing of visual information. These inputs far outnumber retinal inputs in visual thalamus. Interestingly, the recruitment and incorporation of these non-retinal inputs (and cells) into thalamic circuits are regulated by retinal inputs. For example, retinal inputs are necessary for the recruitment of GABAergic interneurons into visual thalamus and the incorporation of their inputs into visual circuits. This is critical since these inhibitory synapses enhance spatial and temporal selectivity of visual information as it is transmitted through the thalamus. At present we lack a clear understanding of the mechanisms through which retinal inputs influence GABAergic neuron recruitment and incorporation into visual thalamus. This proposal specifically addresses this question by testing whether a novel axo-glial-neuron signaling pathway exists in visual thalamus. Specifically, we will test whether retinal axons release SHH to induce astrocyte expression of FGF15, and whether astrocyte-derived FGF15 is necessary for interneuron recruitment into visual thalamus. Identifying the novel axon-glia-neuron signaling pathway proposed here will be a significant step forward in our understanding of the role of glia in thalamic development and in the mechanisms underlying subcortical visual circuit assembly.

目前，对于皮层下视觉回路缺陷的患者没有有效的治疗方法。响应于 为了满足这一未满足的需求，NEI发布了一项大胆的目标倡议，其目标是获得新的知识， 有助于发展旨在恢复皮层下视觉回路的再生疗法。到 为了实现这一目标，我们需要更好地了解驱动细胞和分子机制。 在发育过程中形成这些回路。尽管我们已经在理解 视网膜轴突靶向并支配皮质下脑区域（如背侧和腹侧外侧膝状体 核[dLGN和vLGN，分别]），我们缺乏关于其他输入和细胞如何靶向的关键知识 这些地区。来自皮质、丘脑核、脑干核和局部中间神经元的输入起作用， 在视丘脑的调节性或抑制性输入中起重要作用， 信息.在视丘中，这些输入的数量远远超过视网膜输入。有趣的是，招聘和 将这些非视网膜输入（和细胞）并入丘脑回路由视网膜输入调节。为 例如，视网膜输入对于将GABA能中间神经元募集到视觉丘脑中是必要的， 将他们的输入整合到视觉回路中。这是至关重要的，因为这些抑制性突触增强了 视觉信息通过丘脑传递时的空间和时间选择性。目前我们 缺乏对视网膜输入影响GABA能神经元的机制的清晰理解 募集并并入视觉丘脑。该提案通过测试来具体解决这一问题 视丘是否存在新的轴胶质神经元信号通路。具体来说，我们将测试 视网膜轴突释放SHH诱导星形胶质细胞表达FGF 15，以及星形胶质细胞衍生的FGF 15是否 这是将中间神经元募集到视丘所必需的。识别新的轴突-神经胶质-神经元信号传导 在我们理解神经胶质细胞的作用方面，这里提出的通路将是一个重要的一步。 丘脑发育和皮层下视觉电路组装的机制。