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: 10527380
• 负责人: Jeanne T Paz
• 金额: $ 41.24万
• 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/10527380
• 关键词: 3-Dimensional; Acute; Affect; American; Area; Astrocytes; Brain; Brain Injuries; Bypass; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic; Clinic; Cognition; Convulsants; Cytoprotection; Data; Development; Electrocorticogram; Electroencephalography; Electrophysiology (science); Epilepsy; Epileptogenesis; Equilibrium; Euthanasia; Excitatory Synapse; Flow Cytometry; Functional disorder; Funding; Health; Human; Immune; Immune system; Immunocompetent; Immunohistochemistry; Immunology; Immunotherapy; Impaired cognition; Infiltration; Inflammation; Inhibitory Synapse; Injury; Innate Immune Response; Ipsilateral; Lymphocyte; Macrophage; Maintenance; Mediating; Microglia; Modeling; Mus; Myelogenous; Nerve Degeneration; Neurologic Deficit; Neuronal Plasticity; Neurons; 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; TBI Patients; Testing; Thalamic structure; Therapeutic; Therapeutic Intervention; Three-Dimensional Imaging; Time; Tissue imaging; Traumatic Brain Injury; blood-brain barrier penetration; brain tissue; controlled cortical impact; design; disability; effective therapy; genetic manipulation; glial activation; immune imaging; in vivo; monocyte; mortality; mouse model; network dysfunction; neural; neural circuit; neuroinflammation; neuron loss; optogenetics; prevent; protective effect; recruit; sleep epilepsy; sleep spindle; synergism; 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.

摘要 创伤性脑损伤(TBI)每年影响数百万美国人，并可能导致认知功能障碍， 感觉处理困难，睡眠中断，以及癫痫的发展。一种常见的神经 脑损伤的结局是电生理异常的发展，可能导致创伤后癫痫 (PTE)或睡眠结构中断。然而，这些神经缺陷产生的机制 作为TBI的结果，人们对此仍然知之甚少。 初步证据表明，炎症导致了电生理异常， 中度脑外伤小鼠模型的PTE和睡眠障碍。事实上，TBI的特点是既有 星形胶质细胞和小胶质细胞等胶质细胞的激活以及周围免疫细胞的渗透 单核细胞来源的巨噬细胞和T细胞。而神经炎症会立即发生在皮质区域 在急性损伤时，继发性神经炎在同侧丘脑发展缓慢，推测为 大脑皮质和丘脑之间失去亲密的相互联系的结果。因为皮质-丘脑-- 皮层(CTC)回路在认知、睡眠和癫痫发作中起着关键作用，这些都受到脑损伤的影响， 延迟性神经可塑性在这个回路是梳理免疫之间相互作用的一个很好的模型。 颅脑损伤后的细胞和神经回路。 在脑损伤的背景下，外周免疫细胞的作用尤其未被研究。 电生理缺陷，如PTE和睡眠障碍。我们建议使用受控皮质撞击 中度创伤性脑损伤小鼠模型判断迟发性单核细胞来源的作用 巨噬细胞和CD4+T细胞在继发性神经元丢失(AIM 1)中的兴奋/抑制失衡 皮层-丘脑环路(目标2)和睡眠中断等脑电异常的发展 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、流式细胞术、免疫-神经相互作用的3D成像、突触生理学 脑片和慢性无线脑电记录。 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 颅脑损伤后可引起神经功能障碍的发展。鉴于已经有一些治疗方法可用于 临床阻断CD4+T细胞和巨噬细胞，这项研究有可能迅速影响脑外伤的治疗 在人类病人身上。