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: 10038371
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10038371
• 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.

项目摘要 发育中的皮层表现出自发活动（SA）的复杂模式，这对于适当 神经回路的发展。在视觉发作之前，会生成视觉系统中的大多数SA 在视网膜中，将神经疾病传播到皮质。这些SA驱动神经胶质介导的突触的波浪 修剪以促进电路精炼。但是，关于蜂窝分辨率知之甚少 不同的细胞类别（即兴奋性与抑制性神经元（in））与视觉传播的动力学 皮层（VC），或特定细胞类型在视觉处理中心特征的出现中的作用 已经通过大开眼症（EO）建立，例如视网膜，方向选择性（OS）和方向 选择性（DS）。此外，尚不清楚SA传播如何受环境因素的影响 母体免疫激活（MIA）。 MIA是后代认知障碍和原因的主要危险因素 神经功能功能的一系列缺陷，例如皮质INS的功能障碍。 INS特别脆弱 对MIA，因为它们没有完成迁移并分类到P7之前的特定皮质层，但是几乎没有 知道它们如何在功能上整合到发育中的皮层中的电路中。均衡 皮层发育过程中兴奋性和INS的整合对于正确流动视觉信号和 调节神经元电路函数，E/I平衡中断许多 神经发育障碍，例如自闭症，癫痫和弱视。我建议的主要目标是 在开发中建立不同细胞类别的特性和作用，包括神经胶质和INS的亚型 VC中的SA，并在EO和出现之前确定不同类型的MIA在SA上的作用和机制 EO之后的皮质神经元接受场的特性。这些调查将大大增强我们的 了解神经免疫相互作用并扩展我在实验和分析技术方面的培训 当我为独立调查员职位做准备时。我的建议包括三个特定目标：1）确定 参与视网膜波驱动活性的皮质细胞类型及其在EO中OS和DS出现中的作用， 2）确定MIA在塑造SA在发育中的皮层中的作用，3）确定的作用和机制 胶质信号传导，IL-17，IL-6，TNF和IL-4在结构和功能性皮质结构的开发中 在MIA和正常情况下。在K99阶段，在Michael Crair博士和 我的同事卡拉·罗斯林（Carla Rothlin）博士的支持，我将精通多种技术，包括体内2-- 光子和广场钙成像，用于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，我的目标是结合一系列技术 （例如子宫内特定的免疫系统操纵，使用CRISPR/CAS9的基因组编辑，大规模 在EO之前监测SA），以研究各种形式的MIA与早期发展之间的相互作用 视觉系统，以及这些相互作用如何在正常状态和病理状态下的视觉感知构成。