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.

项目概要 突触和电路的结构重塑对于经验依赖性可塑性至关重要，正如在 将学到的经验巩固到长期记忆中。免疫功能失调与 许多认知障碍，包括精神分裂症和神经退行性疾病，导致越来越多的人 对大脑驻留巨噬细胞（称​​为小胶质细胞）的功能感兴趣，小胶质细胞是主要的免疫细胞 在脑实质中。我们之前发表了IL-1家族细胞因子Interleukin-33，它是由 星形胶质细胞在发育过程中，向小胶质细胞上表达的专性受体 IL1RL1 发出信号，以促进 小胶质细胞激活和吞噬功能。在构成该提案基础的初步数据中，我们确定 在两个成人大脑区域：海马体和额叶皮层中表达 IL-33 的新神经元群。在 通过对海马体的详细结构分析，我们发现 IL-33 或小胶质细胞的神经元特异性缺失 IL-33 R 的特异性缺失会导致树突棘减少，树突棘可塑性标记物（称为脊柱）减少 头部丝状伪足和神经发生受损。此外，该信号通路的丧失会导致 情境恐惧调节：小鼠通常能够学会识别恐惧情境，但具有渐进性 术后 15-30 天区分恐惧情境和中性情境的能力下降 训练。从机制上讲，我们发现细胞外基质蛋白（硫酸软骨素蛋白聚糖 brevican 和聚集蛋白聚糖）在 IL-33 缺陷动物的海马体中积累。我们发现小胶质细胞吞噬聚集蛋白聚糖， IL-33 信号传导的丧失会减少这种吞噬。我们还开发了神经元功能增益 组成型分泌IL-33的构建体。我们发现这足以增加海马棘的数量， 小胶质细胞 ECM 吞噬，并清除树突棘周围的 ECM。根据这些初步数据，本 该提案将检验神经元衍生的 IL-33 驱动 ECM 的小胶质细胞重塑的中心假设 促进电路可塑性以支持记忆整合。 Aim One将探索分子调控 神经元IL-33的释放及其活性依赖性，并测试介导小胶质细胞的两种候选蛋白酶 响应 IL-33 的重塑。目标二将测试这种神经元-小胶质细胞信号传导对 ECM 的影响 额叶皮层的组成，重点是神经周围网络，并确定其对神经网络连接的影响 皮质微电路。目标 3 将在情景恐惧调节任务中使用钙成像来测试神经元如何 在从最近记忆到遥远记忆的过渡过程中，活动模式发生变化，解决了以下关键问题： 记忆巩固背后的结构变化。这些研究将共同​​系统地剖析 调节健康大脑可塑性的新型细胞回路的作用。这项工作的成果有 对理解与小胶质细胞和免疫相关的多种疾病中的认知功能障碍的影响 系统，包括精神分裂症和阿尔茨海默病等神经退行性疾病。