Microglial remodeling of the extracellular matrix in memory circuits

记忆电路中细胞外基质的小胶质细胞重塑

• 批准号: 10317061
• 负责人: Anna V Molofsky
• 金额: $ 52.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-10 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10317061
• 关键词: Address; Adult; Alzheimer' s Disease; Animals; Astrocytes; Brain; Brain region; Calcium; Cells; Chondroitin Sulfate Proteoglycan; Cognition Disorders; Communication; Data; Dendritic Spines; Dependence; Development; Discrimination; Disease; Extracellular Matrix; Extracellular Matrix Proteins; Family; Filopodia; Fright; Goals; Head; Hippocampus (Brain); Homeostasis; Image; Immune; Immune System Diseases; Immune signaling; Immune system; Impaired cognition; Impairment; Interleukin-1; Interleukins; Interneurons; Learning; Link; Matrix Metalloproteinases; Mediating; Memory; Microglia; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome; Parvalbumins; Pathway interactions; Pattern; Peptide Hydrolases; Phagocytes; Population; Process; Publishing; Regulation; Role; Schizophrenia; Shapes; Signal Pathway; Signal Transduction; Stress; Structure; Synapses; Synaptic plasticity; Testing; Time; Tissues; Training; Traumatic Brain Injury; Vertebral column; Work; aggrecan; base; brain cell; brain parenchyma; brain remodeling; brevican; conditioned fear; cytokine; excitatory neuron; experience; fear memory; frontal lobe; gain of function; inhibitory neuron; interest; long term memory; macrophage; memory consolidation; memory encoding; memory recall; memory retrieval; neurogenesis; neuronal patterning; novel; optogenetics; receptor; recruit; response; synaptogenesis; transcriptome sequencing

PROJECT SUMMARY Structural remodeling of synapses and circuits is essential to experience-dependent plasticity, as occurs during the consolidation of learned experiences into long-term memory. Immune dysfunction has been implicated in numerous cognitive disorders, including schizophrenia and neurodegenerative diseases, leading to increasing interest in the function of brain-resident macrophages known as microglia, which are the dominant immune cell in the brain parenchyma. We previously published that the IL-1 family cytokine Interleukin-33, which is made by astrocytes during development, signals to its obligate receptor IL1RL1 expressed on microglia to promote microglial activation and phagocytic function. In preliminary data that forms the basis for this proposal, we identify a novel population of IL-33 expressing neurons in two adult brain regions: hippocampus and frontal cortex. In detailed structural analyses in the hippocampus, we find that neuron-specific deletion of IL-33 or microglial- specific deletion of IL-33 R leads to fewer dendritic spines, diminished markers of spine plasticity known as spine head filopodia, and impaired neurogenesis. Furthermore, loss of this signaling pathway leads to deficits in contextual fear conditioning: mice are able to normally learn to recognize a fear context but have a progressive decrease in their ability to discriminate the fear context from a neutral context emerging at 15-30 days post training. Mechanistically, we find that extracellular matrix proteins (the chondroitin sulfate proteoglycans brevican and aggrecan) accumulate in the hippocampus of IL-33 deficient animals. We find that microglia engulf aggrecan, and that loss of IL-33 signaling diminishes this engulfment. We also developed a neuronal gain of function construct that constitutively secretes IL-33. We find this is sufficient to increase hippocampal spine numbers, microglial ECM engulfment, and to clear ECM around dendritic spines. Based on these preliminary data, this proposal will test the central hypothesis that neuron-derived IL-33 drives microglial remodeling of ECM to promote circuit plasticity in support of memory consolidation. Aim One will explore the molecular regulation of IL-33 release from neurons and its activity dependence, and test two candidate proteases mediating microglial remodeling in response to IL-33. Aim Two will test the impact of this neuron-microglia signaling on the ECM composition of the frontal cortex with a focus on perineuronal nets and determine its impact on connectivity of the cortical microcircuit. Aim 3 will use calcium imaging in a contextual fear conditioning task to test how neuronal activity patterns shift during the transition from recent to remote memories, addressing key questions regarding the structural changes that underlie memory consolidation. Together, these studies will systematically dissect the role of a novel cellular circuit regulating plasticity in the healthy brain. The outcome of this work has implications for understanding cognitive dysfunction in numerous diseases linked to microglia and the immune system , including schizophrenia and neurodegenerative conditions such as Alzheimer's Disease.

项目摘要 突触和电路的结构重塑对于经验依赖性可塑性至关重要，如在 将学习经验的整合到长期记忆中。免疫功能障碍已与 许多认知障碍，包括精神分裂症和神经退行性疾病，导致增加 对被称为小胶质细胞的脑居民巨噬细胞功能的兴趣，这是主要的免疫细胞 在大脑实质中。我们先前发表了IL-1家族细胞因子白介素-33，这是由 在开发过程中，星形胶质细胞在小胶质细胞上表达的强制受体IL1RL1信号以促进 小胶质激活和吞噬功能。在构成该建议基础的初步数据中，我们确定 IL-33在两个成年大脑区域中表达神经元的新型人群：海马和额叶皮层。在 海马中的详细结构分析，我们发现IL-33或小胶质细胞的神经元特异性缺失 IL-33 r的特定缺失导致树突状棘更少，脊柱可塑性的标记降低 头丝霉菌和神经发生受损。此外，此信号通路的丢失会导致缺陷 上下文恐惧条件：小鼠通常能够学会识别恐惧背景，但具有进步性 减少他们在15-30天后出现的中立环境区分恐惧环境的能力 训练。从机械上讲，我们发现细胞外基质蛋白（硫酸软骨蛋白蛋白聚糖蛋白酶brevican 和Aggrecan）积聚在IL-33不足动物的海马中。我们发现小胶质细胞engulf aggrecan， IL-33信号传导的损失减少了这种吞噬。我们还发展了功能的神经元增益 构建组成性分泌IL-33。我们发现这足以增加海马脊柱数量， 小胶质ECM吞噬，并清除树突状刺周的ECM。基于这些初步数据，这 提案将检验以神经元衍生的IL-33驱动ECM的小胶质重塑为中心假设 促进电路塑性以支持内存巩固。 AIM ONE将探讨 IL-33从神经元释放及其活性依赖性，并测试介导小胶质细胞的两个候选蛋白酶 响应IL-33的重塑。 AIM两个将测试该神经元 - 神经元信号对ECM的影响 额叶皮层的组成，重点是周神经元网，并确定其对连通性的影响 皮质微电路。 AIM 3将在上下文恐惧调节任务中使用钙成像来测试神经元如何 活动模式从最近的回忆转变为远程记忆，解决了有关的关键问题 记忆合并基础的结构变化。这些研究将共同​​剖析 新型细胞回路调节可塑性在健康大脑中的作用。这项工作的结果有 了解与小胶质细胞和免疫相关的许多疾病的认知功能障碍的影响 系统，包括精神分裂症和神经退行性疾病，例如阿尔茨海默氏病。