Role of Myeloid And CD4+ T Immune Cells in Post-Traumatic Plasticity

骨髓和 CD4 T 免疫细胞在创伤后可塑性中的作用

• 批准号: 10367851
• 负责人: Jeanne T Paz
• 金额: $ 43.47万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367851
• 关键词: 3-Dimensional; Acute; Affect; American; Area; Astrocytes; Blood - brain barrier anatomy; Brain; Brain Injuries; Bypass; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic; Clinic; Cognition; Data; Development; Electrocorticogram; Electroencephalography; Electrophysiology (science); Epilepsy; Epileptogenesis; Equilibrium; Euthanasia; Excitatory Synapse; Flow Cytometry; Functional disorder; Funding; Health; Human; Imaging Device; Immune; Immune system; Immunocompetent; Immunohistochemistry; Immunology; Immunotherapy; Impaired cognition; Infiltration; Inflammation; Inhibitory Synapse; Injury; Innate Immune Response; Ipsilateral; Lead; Lymphocyte; Maintenance; Mediating; Microglia; Modeling; Mus; Myelogenous; Nerve Degeneration; Neurologic Deficit; Neuronal Plasticity; Neurosciences; Outcome; Patients; Peripheral; Persons; Pharmaceutical Preparations; Phase; Physiology; Play; Population; Post-Traumatic Epilepsy; Rodent Model; Role; Secondary to; Seizures; Sensory; Severities; Sleep; Sleep Architecture; Sleep Deprivation; Sleep Stages; Sleep disturbances; Slice; Symptoms; Synapses; T-Lymphocyte; Testing; Thalamic structure; Therapeutic; Therapeutic Intervention; Three-Dimensional Imaging; Time; Traumatic Brain Injury; brain tissue; controlled cortical impact; design; disability; effective therapy; genetic manipulation; glial activation; immune imaging; in vivo; macrophage; monocyte; mortality; mouse model; network dysfunction; neural circuit; neuroinflammation; neuron loss; optogenetics; prevent; protective effect; recruit; relating to nervous system; sleep epilepsy; sleep spindle; therapeutic target; tool; wireless

ABSTRACT Traumatic brain injury (TBI) impacts millions of Americans each year and can lead to cognitive dysfunction, difficulty with sensory processing, sleep disruption, and the development of epilepsy. One common neural outcome of TBI is the development of electrophysiological abnormalities that can lead to post-traumatic epilepsy (PTE) or disruptions in sleep architecture. However, the mechanisms by which these neurological deficits arise as a consequence of TBI remain poorly understood. Preliminary evidence indicates that inflammation contributes to the electrophysiological abnormalities that underlie PTE and sleep disruption in a mouse model of moderate TBI. Indeed, TBI is characterized by both the activation of glial cells like astrocytes and microglia and by the infiltration of peripheral immune cells like monocyte-derived macrophages and T-cells. While neuroinflammation occurs immediately in the cortical region of acute injury, secondary neuroinflammation develops slowly in the ipsilateral thalamus, presumably as a result of loss of intimate reciprocal connections between cortex and thalamus. Because the cortico-thalamo- cortical (CTC) circuit plays a key role in cognition, sleep, and seizures, which are all impacted by TBI, the delayed neural plasticity in this circuit is a good model for teasing apart the interaction between the immune cells and neural circuits after TBI. The role of peripheral immune cells is particularly understudied in the context of TBI-derived electrophysiological deficits like PTE and sleep disruption. We propose to use a controlled-cortical impact mouse model of moderate TBI to determine the role of delayed infiltration of monocyte-derived macrophages and CD4+ T cells in secondary neuronal loss (Aim 1), excitation/inhibition imbalance in the cortico-thalamic circuit (Aim 2), and the development of electrographic abnormalities such as sleep disruption and PTE (Aim 3). To do so, we will combine cutting-edge tools from both neuroscience and immunology, including genetic manipulations, flow cytometry, 3D imaging of immune-neural interactions, synaptic physiology in brain slices, and chronic wireless EEG recordings. Funding of this study will enable us to better understand how the immune system interacts with neural circuits after TBI to cause the development of neurological deficits. Given that there are treatments already available in clinic to block CD4+ T cells and macrophages, this study has the potential to rapidly impact how TBI is treated in human patients.

抽象的 每年创伤性脑损伤（TBI）会影响数百万的美国人，并可能导致认知功能障碍， 感觉处理，睡眠中断和癫痫发育的困难。一种常见的神经 TBI的结果是电生理异常的发展，可能导致创伤后癫痫 （PTE）或睡眠体系结构中断。但是，这些神经系统缺陷的机制是 由于TBI的理解仍然很少。 初步证据表明，炎症有助于电生理异常，即 在中等TBI的小鼠模型中，PTE和睡眠破坏是基础。确实，TBI的特征是 通过胶质细胞和小胶质细胞等神经胶质细胞的激活，以及通过外周免疫细胞浸润 单核细胞衍生的巨噬细胞和T细胞。神经炎症立即发生在皮质区域 急性损伤，次生神经炎症在同侧丘脑中缓慢发展，大概是 皮质和丘脑之间亲密互相连接的丧失结果。因为皮质 - thalamo- 皮质（CTC）电路在认知，睡眠和癫痫发作中起关键作用，这些作用都受TBI的影响， 该电路中的延迟神经可塑性是嘲笑免疫之间相互作用的好模型 TBI之后的细胞和神经回路。 在TBI衍生的背景下，周围免疫细胞的作用特别研究 PTE和睡眠中断等电生理缺陷。我们建议使用受控的皮质影响 中等TBI的小鼠模型，以确定单核细胞衍生的延迟浸润的作用 二次神经元丧失的巨噬细胞和CD4+ T细胞（AIM 1），激发/抑制失衡 皮质 - 丘脑电路（AIM 2），以及电图异常的发展，例如睡眠中断 和PTE（目标3）。为此，我们将结合神经科学和免疫学的尖端工具， 包括遗传操作，流式细胞仪，免疫神经相互作用的3D成像，突触生理学 在大脑切片和慢性无线脑电图记录中。 这项研究的资金将使我们能够更好地了解免疫系统如何与神经回路相互作用 TBI导致神经系统缺陷的发展。鉴于已经有治疗 诊所以阻止CD4+ T细胞和巨噬细胞，这项研究有可能快速影响TBI的处理方式 在人类患者中。