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

项目概述：癫痫和记忆丧失等神经系统疾病在几年后发展 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， 早期干预。然而，TBI影响记忆和癫痫易感性的机制并不清楚。 完全理解海马齿状回是记忆处理的关键回路，也是大脑皮层的关键调节器。 从内嗅皮层到海马的信息传递，以及成年神经发生的生态位区域，是一个重要的神经元发生机制。 TBI后神经元损伤和兴奋性增加的焦点。虽然成人出生的颗粒细胞（abGC）是 与记忆处理有关，abGCs对代表内嗅的齿状棘波的贡献 皮层齿状信息流和支持记忆巩固是未知的，以及如何损伤诱导 神经发生的变化影响记忆处理还不完全清楚。出乎意料的是，我们发现， 抑制损伤诱导的神经发生的增加降低了TBI后一周的齿状兴奋性， 创伤后同一时期先天性免疫受体Toll样受体4（TLR 4）增加 增强齿状兴奋性。已知TLR 4抑制幼稚动物的神经发生， 增加中风中神经发生。虽然TLR 4调节兴奋性和 神经发生是未知的，最近的研究发现，TLR 4增强内肽酶，基质金属蛋白酶- MMP-9是突触可塑性和神经发生中的一个重要参与者，它提供了一个有希望的分子联系 创伤、TLR 4和异常网络可塑性之间的联系。在一个整合的方法，跨越分子， 细胞到网络的功能，我们认为，早期增加神经发生和兴奋性后，创伤性脑损伤破坏 齿状调节皮质-海马吞吐量，并通过TLR 4- MMP-9活性依赖性持续升高。采用小鼠液压冲击伤模型， 体内和离体电和光生理学技术，目的1将确定TLR 4信号传导在 损伤后出生的abGCs的发育、成熟和电路整合的改变。目标2将测试是否更改DG 脑外伤后齿状回和海马振荡耦合的兴奋性和神经发生 这可以通过在损伤后早期阻断TLR 4来预防。最后，目标3将使用以下组合： 组织学、生物化学、生理学和行为学分析，以测试TBI后是否存在异常TLR 4信号传导 导致MMP-9的持续增加，MMP-9可以限制异常神经发生， 振荡耦合和记忆缺陷。这种预防性战略将大大提高 TBI后患者的生活，并解决NINDS的使命，减少长期的医疗保健负担， 创伤后神经系统疾病

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.