Role of Microglia in Sculpting Multisensory Midbrain Circuits

小胶质细胞是一种多功能的吞噬细胞，在建立成熟的神经网络中发挥着不可或缺的作用。这个 小胶质细胞对其微环境中的信号作出反应以主动吞噬的机制 外来突触对地形图的形成、兴奋性-抑制性平衡和突触至关重要 改建。在早期关键时期的MGC扰动会产生不精确的回路，包括行为和社交 某些神经发育障碍的损害，包括自闭症。在众多激活中 神经表达的Fractalkine(CX3CL1)和补体(C1q，C3)蛋白是MGC的关键蛋白 向未充分利用的突触募集和主动吞噬。这些和/或他们的淘汰赛 相应的小胶质细胞受体(CX3CR1；CR3)抑制MGC介导的串扰 突触消除。这种相互作用在形成视觉、躯体感觉和 海马区连接，但类似的机制是否也引导听觉和 多感官回路仍然存在疑问。中脑下丘(IC)是一个有趣的模型结构 因为它的外侧皮质(LCIC)被组织成接收特定通道输入的离散区域。它的模块化-外模块化框架和接口投影模式同时发展，出生后不久就出现了 并通过听证开始变得清晰。最初的扩散和重叠，躯体感觉和听觉 随着LCIC的成熟，输入分离，目标是互补模块(GAD积极)和外部模块 (Calretinin阳性)结构域。本研究的目的是：1)确定时空分布 MGCS和Fractalkine/补体表达相对于新出现的LC IC间隔的模式，2)到 评估Fractalkine/补体参与塑造不同的多感官中脑回路，以及3)测试 如果在投影整形的早期关键期期间MGC功能受损导致非典型响应 行为。第一个目标是利用免疫细胞化学方法在对照和转基因小鼠(GAD67-GFP，CX3CR1-GFP)中显示mGCS和Fractalkine/补体的表达。 LCIC微体系结构，以及测试信令是否受损(CX3CR1GFP/GFP、C1qKO、C3KO、CR3KO) 改变了模块化--模块化外开发。建议的顺行活体切片听觉标记实验 而体感传入直接测试小胶质细胞的修剪/降解的额上LCIC突触。 最后，在听觉和/或体感预脉冲提示(即预脉冲)之后的声学惊吓反应 抑制)将识别不同品系之间的任何多模式心理物理差异。项目成果将 加深对小胶质细胞-神经元信号在多模式中脑建立中的理解 舱室，它们的投影图，以及它们的行为意义。进一步定义MGC的影响 在电路组装的关键时期，将告知他们的功能障碍如何与受损 多感官处理，沟通困难，和其他神经发育障碍的病因。

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.