Role of neuroimmune interactions in shaping spontaneous activity and cortical circuit development.

神经免疫相互作用在塑造自发活动和皮质回路发育中的作用。

• 批准号: 10219271
• 负责人: Ali Saddam Hamodi Alshuwaykh
• 金额: $ 10.15万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219271
• 关键词: Adolescent; Affect; Amblyopia; Architecture; Astrocytes; Autoimmune Diseases; Axon; Brain; CRISPR/Cas technology; Calcium; Cell Proliferation; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Computing Methodologies; Coupling; Data Analyses; Development; Double-Stranded RNA; Environmental Risk Factor; Epilepsy; Equilibrium; Event; Exhibits; Eye; Functional disorder; Genes; Goals; Growth; IFNAR1 gene; Image; Immune response; Immune system; Impaired cognition; Impairment; Infection; Inflammation; Injections; Interferon Type I; Interleukin-17; Interleukin-4; Interleukin-6; Interneurons; Investigation; Knowledge; Link; Lipopolysaccharides; Maintenance; Maps; Measurement; Measures; Mediating; Mentors; Microglia; Monitor; Morphology; Neonatal; Nervous System Physiology; Neuraxis; Neurodevelopmental Disorder; Neuroglia; Neuroimmune; Neurons; Parvalbumins; Pathologic; Pathway interactions; Patients; Pattern; Phase; Play; Poly I-C; Population; Positioning Attribute; Pregnant Women; Property; Regulation; Reporting; Research Personnel; Resolution; Retina; Risk Factors; Role; Sensory; Shapes; Signal Transduction; Sinus; Somatostatin; Sorting - Cell Movement; Source; Structural defect; Structure; Study models; Synapses; TNF gene; Techniques; Therapeutic Intervention; Training; Viral; Virus Diseases; Vision; Visual; Visual Cortex; Visual Perception; Visual system structure; autism spectrum disorder; cell type; cytokine; data visualization; excitatory neuron; fetal; genome editing; immune activation; in utero; in vivo; inhibitory neuron; insight; interferon alpha receptor; migration; mouse model; neocortical; neural circuit; neural patterning; neurodevelopment; neurogenesis; neuronal circuitry; neuronal survival; neurotransmission; novel; offspring; orientation selectivity; postnatal; precursor cell; pregnant; receptive field; receptor; recruit; retinotopic; sensory cortex; sensory input; spatiotemporal; synaptic pruning; synaptogenesis; two-photon; vision development; visual processing

PROJECT SUMMARY The developing cortex exhibits complex patterns of spontaneous activity (SA) that is essential for proper development of neural circuits. Before the onset of vision, the majority of SA in the visual system is generated in the retina and propagates up the neuraxis to the cortex. These waves of SA drive glia-mediated synaptic pruning to promote circuit refinement. However, little is known at cellular resolution about the contribution of different cell classes (i.e. excitatory vs. inhibitory neurons (IN)) to the dynamics of wave propagation in visual cortex (VC), or the role of specific cell types in the emergence of central features of visual processing that are already established by eye-opening (EO), such as retinotopy, orientation-selectivity (OS) and direction- selectivity (DS). Furthermore, it is unknown how SA propagation is affected by environmental factors such as maternal immune activation (MIA). MIA is a major risk factor for cognitive impairment in offspring and causes a range of deficits in neurological function such as dysfunction of cortical INs. INs are particularly vulnerable to MIA since they do not finish migrating and sorting into their specific cortical layers until P7, yet little is known about how they become functionally integrated into circuits in the developing cortex. Balanced integration of excitatory and INs during cortical development is essential for proper flow of visual signals and modulating neuronal circuit function, with disruptions in E/I balance associated with many neurodevelopmental disorders such as autism, epilepsy, and amblyopia. The primary goal of my proposal is to establish the properties and role of different cell classes, including glia and subtypes of INs, in the development of SA in VC, and determine the role and mechanism of different types of MIA on SA before EO and emergence of cortical neuron receptive field properties after EO. These investigations will significantly enhance our understanding of neuroimmune interactions and expand my training in experimental and analytical techniques as I prepare for an independent investigator position. My proposal consists of three specific aims: 1) Determine the cortical cell types involved in retinal wave-driven activity and their role in emergence of OS and DS at EO, 2) Determine the role of MIA in shaping SA in the developing cortex, 3) Determine the role and mechanism of glial signaling, IL-17, IL-6, TNF, and IL-4 in development of structural and functional cortical architecture under MIA and normal conditions. During the K99 phase, under the guidance of Dr. Michael Crair and the support of my co-mentor Dr. Carla Rothlin, I will become proficient in several techniques, including in vivo 2- photon and widefield calcium imaging, computational methods for data analysis and visualization, and immune system regulation. During the R00 phase and beyond, my goal is to combine an array of techniques (such as specific immune system manipulations in utero, genome editing using CRISPR/Cas9, large-scale monitoring of SA before EO) to study interactions between various forms of MIA and early development of the visual system, and how these interactions underlie visual perception in both normal and pathological states.

项目总结 发育中的皮质表现出复杂的自发活动(SA)模式，这是正常发育所必需的 神经回路的发展。在视觉开始之前，视觉系统中的大部分SA都是产生的 在视网膜中，并沿着神经轴向上传播到皮质。这些SA波驱动神经胶质细胞介导的突触 修剪以促进电路精细化。然而，在细胞分辨率方面，人们对此知之甚少。 不同细胞类别(即兴奋性神经元和抑制性神经元(IN))对视觉电波传播动力学的影响 皮层(VC)，或特定细胞类型在视觉处理的中心特征出现中的作用，这些中心特征是 已经建立了由睁眼(EO)，如视网膜复制，定向选择性(OS)和方向- 选择性(DS)。此外，SA传播如何受到环境因素的影响尚不清楚，例如 母体免疫激活(MIA)。MIA是子代认知障碍的主要危险因素及其原因 一系列神经功能缺陷，如皮质胰岛素障碍。移民局特别脆弱 到MIA，因为它们直到P7才完成迁移和分选到它们特定的皮质层，但几乎没有 已知它们如何在功能上整合到发育中的皮质中的回路中。平衡式 皮层发育过程中兴奋性和INS的整合对于视觉信号的正常流动和 调节神经元回路功能，E/I平衡紊乱与许多 神经发育障碍，如自闭症、癫痫和弱视。我的建议的主要目标是 确定不同细胞类别的属性和作用，包括胶质细胞和INS亚型在发育中的作用 并确定不同类型的MIA在EO发生前和出现前对SA的作用和机制 电针后皮质神经元感受场特性的变化。这些调查将大大加强我们的 了解神经免疫相互作用，扩大我在实验和分析技术方面的培训 因为我正在准备一个独立调查员的职位。我的建议包括三个具体目标：1)确定 参与视网膜波驱动活动的皮质细胞类型及其在EO时OS和DS出现中的作用， 2)确定MIA在发育皮层中形成SA中的作用；3)确定MIA在发育中皮质中的作用和机制 神经胶质信号、IL-17、IL-6、肿瘤坏死因子和IL-4在结构和功能皮质结构发育中的作用 在MIA和正常情况下。在K99阶段，在Michael Crair博士和 在我的合作导师Carla Rothlin博士的支持下，我将精通几种技术，包括在体内2- 光子和广域钙成像，数据分析和可视化的计算方法，以及 免疫系统调节。在R00阶段及以后，我的目标是组合一系列技术 (例如子宫内的特定免疫系统操作、使用CRISPR/Cas9的基因组编辑、大规模 在EO前监测SA)，以研究各种形式的MIA与早期发展的相互作用 视觉系统，以及这些相互作用如何在正常和病理状态下形成视觉感知。