Mechanisms that regulate microglial dynamics in the context of plasticity (Supplement)

可塑性背景下调节小胶质细胞动力学的机制（补充）

• 批准号: 10286201
• 负责人: Anna K Majewska
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286201
• 关键词: Accounting; Adrenergic Agents; Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Anesthesia procedures; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Applications Grants; Arousal; Behavior; Brain; Complex; Cues; Data; Dementia; Deposition; Disease; Disease Progression; Environment; Exhibits; Fiber; Future; Goals; Grant; Image; Immune; Impaired cognition; Impairment; Inflammation; Inflammatory; Inflammatory Response; Knock-out; Knockout Mice; Label; Lead; Maintenance; Microglia; Morphology; Mus; Nerve Degeneration; Neuraxis; Neuroglia; Neuromodulator; Neurons; Norepinephrine; Paint; Parents; Pathologic; Pathology; Pathway interactions; Pattern; Periodicity; Pharmacology; Physiological; Play; Quality of life; Reporting; Role; Senile Plaques; Shapes; Signal Transduction; Sleep disturbances; Somatosensory Cortex; Stimulus; Synapses; Testing; Time; United States; Wakefulness; Work; age related; awake; base; beta-2 Adrenergic Receptors; brain cell; cell type; density; experience; experimental study; genetic approach; locus ceruleus structure; mouse model; neural network; neuroinflammation; noradrenergic; response

Project Summary Alzheimer's disease (AD) is the most common age-related dementia, accounting for the progressive cognitive impairment and compromised life quality of approximately 5.8 million people in the United States. AD is characterized by neuroinflammation and microglia have a complex role in both the early and late stages of the disease. AD is also characterized by dysregulation of norepinephrine (NE) signaling, degeneration of noradrenergic neurons in the locus coeruleus (LC) and sleep disturbances that further alter normal patterns of NE release. Signaling through β2 adrenergic receptors (β2 ARs) has been shown to be anti-inflammatory and to alter microglial behavior in the context of AD, although its effects on AD pathology have been controversial and the details of NE signaling to microglia have not been defined. In this supplement proposal, we will build on the aims of the parent RO1 in which we have discovered that endogenous NE signaling to microglia through microglial β2 ARs reduces the size of the microglial arbor and inhibits microglial surveillance of the brain, limiting microglial interactions with neurons and impairing experience-dependent plasticity. Based on this work, we believe that the normal patterns of NE release that fluctuate as a function of arousal state allow microglia to cycle through “active” and “passive” states. When NE release is blunted due to LC neuron degeneration or sleep disruption in AD, microglia no longer cycle through these different states. This alters their behavior and impacts their ability to interact with amyloid deposits, protect synapses from elimination, and respond appropriately to cues in their environment. The work presented in this supplement will generate preliminary data to show how β2 AR signals are altered in microglia over time in a mouse model of AD, and how this correlates with AD pathology. We will also determine how long-term periodic pharmacological stimulation of β2 AR signaling alters microglial dynamics and AD pathology to set the stage for future experiments where we use microglial specific knock out of β2 ARs to test the contribution of microglia in this context. Lastly, we will use these microglial specific β2 AR KO mice, in the absence of AD pathology, to determine whether long-term loss of β2 AR signaling in microglia alters inflammatory responses. These aims are highly synergistic with those of the parent R01 and have clear relevance to AD. Together they will generate supporting data for a future grant application built on our broad hypothesis that cyclical stimulation of microglial β2 ARs is critical for the maintenance of microglial responses that are beneficial in the context of AD pathology.

项目摘要 阿尔茨海默氏病（AD）是最常见的与年龄相关的痴呆症 美国约有580万人的损害和损害生活质量。广告是 神经炎症和小胶质细胞的特征在 疾病。 AD还具有去甲肾上腺素（NE）信号传导的失调，变性 基因座（LC）中的去甲肾上腺素能神经元和睡眠障碍，以进一步改变正常模式 NE释放。通过β2肾上腺素受体（β2AR）的信号已显示为抗炎和TO 在AD背景下改变小胶质行为，尽管其对AD病理的影响一直存在争议，并且 NE信号对小胶质细胞的细节尚未定义。在这项补充建议中，我们将建立在 母体RO1的目的，我们发现内源性NE信号传导通过 小胶质细胞β2ARS降低小胶质植物的大小，并抑制大脑的小胶质细胞监视，限制 与神经元的小胶质相互作用和损害经验依赖性可塑性。基于这项工作，我们 认为随着唤醒状态的函数波动的NE释放的正常模式使小胶质细胞循环 通过“主动”和“被动”状态。当NE释放由于LC神经元变性或睡眠而钝化时 AD的破坏，小胶质细胞不再循环通过这些不同的状态。这改变了他们的行为并影响 他们与淀粉样蛋白沉积物相互作用，保护突触免受进化的能力，并适当回应 在他们的环境中提示。该补充剂中介绍的工作将产生初步数据，以显示β2如何 在AD的小鼠模型中，小胶质细胞的AR信号会改变，以及与AD病理的相关性。 我们还将确定β2AR信号的长期周期性药物刺激如何改变小胶质细胞 动力学和AD病理学为将来的实验奠定了基础 在这种情况下测试小胶质细胞的贡献的β2AR。最后，我们将使用这些小胶质特异性β2AR 在没有AD病理学的情况下，KO小鼠确定小胶质细胞中的β2AR信号的长期损失是否 改变炎症反应。这些目标与父母R01的目标高度协同作用，并且很清楚 与AD相关。他们将共同为未来的赠款应用程序生成支持数据 假设小胶质细胞β2ARS的周期性模拟对于维持小胶质细胞至关重要 在AD病理的背景下有益的反应。