Contribution of Innate Immune Receptors to Neurological Dysfunction After Traumatic Brain Injury: Mechanisms and Therapeutic Implications

先天免疫受体对脑外伤后神经功能障碍的贡献：机制和治疗意义

• 批准号: 10608933
• 负责人: Vijayalakshmi Santhakumar
• 金额: $ 45.23万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608933
• 关键词: Acceleration; Address; Adult; Affect; American; Animals; Award; Behavioral Assay; Biochemical; Biological Assay; Birth; Brain Injuries; Cell Culture Techniques; Cells; Communication; Control Animal; Coupling; Data; Development; Early Intervention; Economic Burden; Electroencephalography; Endopeptidases; Epilepsy; Epileptogenesis; Equilibrium; Event; Feedback; Frequencies; Functional disorder; Gelatinase B; Genetic; Healthcare; Hippocampus; Histologic; Histology; Immunologic Receptors; In Situ; Injury; Link; Mediating; Memory; Memory Loss; Memory impairment; Mission; Modeling; Molecular; Mus; National Institute of Neurological Disorders and Stroke; Neocortex; Neurologic Dysfunctions; Neuronal Plasticity; Neurons; Parahippocampal Gyrus; Pathologic; Pathway interactions; Patients; Pharmacology; Physiological; Physiology; Pilot Projects; Predisposition; Prevention strategy; Publishing; Quality of life; Regulation; Reporter; Role; Seizures; Signal Transduction; Source; Stroke; Structure; Synapses; Synaptic plasticity; TLR4 gene; Techniques; Testing; Therapeutic; Transgenic Mice; Trauma; Traumatic Brain Injury; adult neurogenesis; adverse outcome; antagonist; brain dysfunction; care burden; cell motility; cognitive disability; dentate gyrus; disability; disability burden; entorhinal cortex; experimental study; fluid percussion injury; genetic approach; granule cell; immune function; improved; in vivo; memory consolidation; memory process; migration; neocortical; nervous system disorder; neurochemistry; neurogenesis; neuropathology; neurophysiology; novel; physically handicapped; post stroke; prevent; timeline

Project Summary: Neurological disorders such as epilepsy and memory loss develop several years after traumatic brain injury (TBI) and are a major source of physical disability and economic burden. The delay between the initial trauma and eventual disability results from progressive neuropathology that could be limited by early interventions. However, mechanisms by which TBI impacts memory and seizure susceptibility are not fully understood. The hippocampal dentate gyrus, a circuit critical for memory processing, a key regulator of information transfer from entorhinal cortex to hippocampus, and a niche region for adult neurogenesis, is a focus of neuronal damage and increased excitability after TBI. Although adult born granule cells (abGCs) are implicated in memory processing, the contribution of abGCs to dentate spikes which represent entorhinal cortex to dentate information flow and support memory consolidation is not known and how injury-induced changes in neurogenesis affect memory processing is not fully understood. Unexpectedly, we find that suppressing injury-induced increase in neurogenesis reduces dentate excitability one week after TBI, during the same period when posttraumatic increase the innate immune receptor, toll-like receptor 4 (TLR4) augments dentate excitability. TLR4 is known to suppress neurogenesis in naïve animals and paradoxically increase neurogenesis in stroke. While the molecular mechanisms by which TLR4 regulates excitability and neurogenesis are unknown, recent findings that TLR4 enhances the endopeptidase, matrix metalloproteinase- 9 (MMP-9), a critical player in synaptic plasticity and neurogenesis provides a promising molecular link between trauma, TLR4 and aberrant network plasticity. In an integrative approach spanning molecular to cellular to network function, we propose that early increase in neurogenesis and excitability after TBI disrupt dentate regulation of cortico-hippocampal throughput and contribute deficits in memory processing by TLR4- dependent persistent elevation of MMP-9 activity. Using the fluid percussion injury model in mice and current in vivo and ex vivo electro- and optophysiological techniques, Aim 1 will determine the role of TLR4 signaling in altered development, maturation and circuit integration of abGCs born after injury. Aim 2 will test if altered DG excitability and neurogenesis after TBI compromise oscillatory coupling between dentate and hippocampus which can be prevented by blocking TLR4 early after injury. Finally, Aim 3 will use a combination of histological, biochemical, physiological, and behavioral assays to test if aberrant TLR4 signaling after TBI results in persistent increase in MMP-9 which can be targeted to limit aberrant neurogenesis, deficits in oscillatory coupling and memory deficits after TBI. Such preventive strategies will greatly improve the quality of life of patients after TBI and address the NINDS mission of decreasing the long-term health care burden posed by post-traumatic neurological diseases.

项目摘要：几年后的神经系统疾病，例如癫痫和记忆力丧失 创伤性脑损伤（TBI），是身体残疾和经济负担的主要来源。延迟 在最初的创伤和最终的残疾之间，可能受到限制的渐进神经病理学产生 通过早期干预。但是，TBI会影响记忆和癫痫发作易感性的机制不是 完全理解。海马齿状回，这是一种记忆加工至关重要的电路， 信息从内嗅皮层转移到海马，以及用于成人神经发生的细分区域是一个 TBI后神经元损伤的重点和增加的兴奋性。尽管成人出生的颗粒细胞（ABGC）是 在内存处理中实现，ABGC对代表内hin的齿状尖峰的贡献 齿状信息流和支持记忆巩固的皮层尚不清楚以及如何受伤诱导 神经发生的变化影响记忆处理尚不完全了解。出乎意料的是，我们发现 抑制损伤引起的神经发生的增加可在TBI后一周降低齿状兴奋性 创伤后增加先天免疫受体的同一时期，Toll样受体4（TLR4） 增强齿状令人兴奋。众所周知，TLR4会抑制幼稚动物的神经发生和矛盾的是 增加中风中的神经发生。而TLR4调节令人兴奋和的分子机制 神经发生是未知的，最近的发现TLR4增强了内肽酶基质金属蛋白酶 - 9（MMP-9），突触可塑性和神经发生的关键参与者提供了有希望的分子链接 在创伤，TLR4和异常网络可塑性之间。在跨越分子的集成方法中 细胞到网络功能，我们提出TBI破坏后神经发生和兴奋性的早期增加 皮质 - 海马吞吐量的齿状调节，并促成TLR4-的记忆处理 MMP-9活性的依赖持续升高。在小鼠中使用流体打击乐损伤模型，并在 Vivo和Ex ex Vivo电和光生理技术，AIM 1将确定TLR4信号在 受伤后出生的ABGC的发育，成熟和电路整合改变了。 AIM 2将测试是否更改DG TBI折衷振荡和海马之间的兴奋性和神经发生 受伤后可以提早阻止TLR4来预防。最后，AIM 3将使用 组织学，生化，物理和行为测定，以测试TBI后异常TLR4信号是否异常 结果导致MMP-9的持续增加，可以针对限制异常神经发生的目标 振荡耦合和内存定义在TBI之后。这种预防策略将大大提高 TBI后患者的生活，并解决了减少长期医疗保健伯恩的NINDS任务 通过创伤后神经系统疾病。