Role of Microglia in Sculpting Multisensory Midbrain Circuits

小胶质细胞在塑造多感觉中脑回路中的作用

• 批准号: 10041307
• 负责人: Mark Lawrence Gabriele
• 金额: $ 42.37万
• 依托单位: JAMES MADISON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10041307
• 关键词: Acoustics; Address; Affect; Auditory; Behavioral; Birth; Brain; Brain region; CX3CL1 gene; Cell Count; Cell physiology; Cellular Morphology; Characteristics; Clinical; Communication; Communication impairment; Complement; Complex; Cues; Development; Diffuse; Eating; Equilibrium; Etiology; Female; Fractalkine; Functional disorder; Genotype; Goals; Hearing; Hippocampus (Brain); Homeostasis; Immune; Impairment; Inferior Colliculus; Instruction; Knock-out; Label; Lateral; Link; Location; Macrophage-1 Antigen; Maps; Measures; Mediating; Memory; Microglia; Midbrain structure; Modality; Mus; Neuraxis; Neurodevelopmental Disorder; Neurons; Outcome; Pattern; Phagocytes; Physiologic pulse; Play; Preparation; Process; Psychophysics; Reflex action; Registries; Reporting; Research; Risk; Role; Schizophrenia; Sensory; Series; Severities; Shapes; Signal Transduction; Slice; Source; Startle Reaction; Stream; Structural Models; Symptoms; Synapses; System; Testing; Touch sensation; Transgenic Mice; Vision; Visual; autism spectrum disorder; autistic; behavioral response; calretinin; clinically relevant; critical period; experimental study; insight; macrophage; male; motor learning; multimodality; multisensory; mutant; neural network; neurotransmission; novel; prepulse inhibition; preservation; receptor; recruit; relating to nervous system; segregation; social; somatosensory; spatiotemporal; synaptic pruning; undergraduate student

Microglia are versatile phagocytic cells that play an integral role in establishing mature neural networks. The mechanisms whereby microglial cells (MGCs) respond to signals in their microenvironment to actively engulf extraneous synapses are crucial for topographic map formation, excitatory-inhibitory balance, and synaptic remodeling. MGC perturbation during early critical periods yields unrefined circuits with behavioral and social impairments indicative of certain neurodevelopmental disorders, including autism. Among many activation cues, neuronally-expressed fractalkine (CX3CL1) and complement (C1q, C3) proteins are key players for MGC recruitment to, and active engulfment of underutilized synapses. Knockouts for these and/or their corresponding microglial receptors (CX3CR1; CR3) compromise crosstalk necessary for MGC-mediated synapse elimination. Such interactions have been implicated in shaping visual, somatosensory, and hippocampal connections, but whether similar mechanisms also guide the maturation of auditory and multisensory circuits remains in question. The midbrain inferior colliculus (IC) is an intriguing model structure as its lateral cortex (LCIC) is organized into discrete zones that receive modality-specific inputs. Its modular-extramodular framework and interfacing projection patterns develop concurrently, emerging shortly after birth and becoming well-defined by hearing onset. Initially diffuse and overlapping, somatosensory and auditory inputs segregate as the LCIC matures, targeting complementary modular (GAD-positive) and extramodular (calretinin-positive) domains, respectively. The present study aims: 1) to determine the spatiotemporal patterning of MGCs and fractalkine/complement expression relative to emerging LCIC compartments, 2) to assess fractalkine/complement involvement in sculpting distinct multisensory midbrain circuits, and 3) to test if compromised MGC function during an early critical period of projection shaping results in atypical response behaviors. The first objective utilizes immunocytochemical approaches in control and transgenic mice (GAD67-GFP, CX3CR1-GFP) to visualize MGCs and fractalkine/complement expression with respect to the emerging LCIC microarchitecture, as well as testing if compromised signaling (CX3CR1GFP/GFP, C1qKO, C3KO, CR3KO) alters modular-extramodular development. Proposed anterograde living slice experiments labeling auditory and somatosensory afferents directly test microglial pruning/degradation of supranumerary LCIC synapses. Finally, acoustic startle responses following auditory and/or somatosensory pre-pulse cues (i.e. pre-pulse inhibition) will identify any multimodal psychophysical differences across strains. Project outcomes will advance our understanding of microglial-neuronal signaling in the establishment of multimodal midbrain compartments, their projection maps, and their behavioral significance. Further defining MGC influences during critical periods of circuit assembly will inform how their dysfunction correlates with impaired multisensory processing, communication difficulties, and other neurodevelopmental disorder etiologies.

小胶质细胞是多功能的吞噬细胞，在建立成熟的神经网络中起着不可或缺的作用。这 小胶质细胞（MGC）在其微环境中响应信号以积极吞噬的机制 外部突触对于地形图的形成，兴奋性抑制平衡和突触至关重要 重塑。 MGC在关键时期早期的扰动会产生带有行为和社会的未精制电路 障碍指示某些神经发育障碍，包括自闭症。在许多激活中 提示，神经表达的分裂（CX3CL1）和补体（C1Q，C3）蛋白是MGC的关键参与者 招募并积极吞噬未充分利用的突触。这些和/或他们的淘汰赛 相应的小胶质细胞受体（CX3CR1; CR3）折衷于MGC介导的串扰 消除突触。这种相互作用与塑造视觉，体感和 海马连接，但是类似机制是否也指导听觉的成熟和 多感官电路仍然有问题。中脑下丘（IC）是一种有趣的模型结构 由于其侧向皮质（LCIC）被组织到接收特定于模态输入的离散区域。它的模块化解码框架和连接投影模式同时发展，出生后不久出现 并通过听力发作明确定义。最初是分散和重叠，体感和听觉的 输入分离为LCIC成熟，靶向互补模块化（GAD阳性）和录音 （钙网蛋白阳性）域分别。本研究的目的：1）确定时空 相对于新兴LCIC室的MGC和分面/补体表达的图案，2） 评估分子/补体参与雕刻不同的多感觉中脑电路，3）测试 如果在投影塑造的关键早期造成的MGC功能受到损害会导致非典型响应 行为。第一个目标是利用对照小鼠（GAD67-GFP，CX3CR1-GFP）中的免疫细胞化学方法来可视化MGC和Fractalkine/firactalkine/补体表达 LCIC微体系结构，以及测试是否损害信号（CX3CR1GFP/GFP，C1QKO，C3KO，CR3KO） 改变模块化型的发展。提议的地下活动切片实验标记了听觉 以及体感传入直接测试额外LCIC突触的小胶质细胞修剪/降解。 最后，听觉和/或体感之前的声音反应在脉冲前提示（即脉冲前脉 抑制作用）将确定各种菌株之间的任何多模式心理物理差异。项目成果将 在建立多模式中脑中，我们了解了我们对小胶质细胞神经元信号的理解 车厢，投影图及其行为意义。进一步定义MGC影响 在关键时期，电路组装将告知其功能障碍与受损 多感官处理，沟通困难和其他神经发育障碍的病因。