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

项目概述：癫痫和记忆力丧失等神经疾病在几年后发展为 创伤性脑损伤(TBI)是身体残疾和经济负担的主要来源。延误 最初的创伤和最终的残疾之间的关系是由进行性神经病理造成的，这可能是有限的 通过早期干预。然而，脑损伤影响记忆和癫痫敏感性的机制并不是 完全理解。海马齿状回是记忆处理的关键电路，也是 从内嗅觉皮质到海马体的信息传递，是成人神经发生的一个生态位区域。 脑外伤后神经元损伤灶和兴奋性增加。尽管成体出生颗粒细胞(AbGC)是 与记忆处理有关，abGC对代表内嗅觉的齿状棘波的贡献 大脑皮质对齿状回信息流和支持记忆巩固的支持作用尚不清楚，以及损伤是如何诱导的 神经发生的变化对记忆处理的影响尚不完全清楚。没想到，我们发现 抑制损伤诱导的神经发生增加降低脑损伤后一周的齿状突起兴奋性 与创伤后增加先天免疫受体Toll样受体4(TLR4)的时期相同 增强齿状突起的兴奋性。已知TLR4抑制幼稚动物的神经发生，而且矛盾的是 增加中风患者的神经再生。而TLR4调节兴奋性和 神经发生机制尚不清楚，最近的研究发现TLR4增强了内肽酶、基质金属蛋白酶- 9(基质金属蛋白酶-9)，突触可塑性和神经发生的关键参与者提供了一个有希望的分子联系 创伤、TLR4与异常网络可塑性之间的关系。在一种跨越分子到 细胞到网络的功能，我们认为脑外伤后早期神经发生和兴奋性的增加 TLR4对大脑皮质-海马区吞吐量的齿状回调节作用及其在记忆加工中的作用 依赖持续升高的基质金属蛋白酶-9活性。小鼠液压冲击伤模型的建立及应用 体内和体外电和光生理学技术，Aim 1将确定TLR4信号在 损伤后出生的abGC的发育、成熟和回路整合的改变。目标2将测试是否改变了DG 颅脑损伤后海马齿状回振荡偶联受抑后的兴奋性和神经发生 这可以通过在损伤后早期阻断TLR4来预防。最后，《目标3》将结合使用 组织学、生化、生理学和行为学检测脑损伤后TLR4信号是否异常 导致基质金属蛋白酶-9持续增加，这可以作为限制异常神经发生的靶点，在 颅脑损伤后的振荡耦合和记忆障碍。这种预防战略将极大地提高教育质量。 脑外伤后患者的生活并解决NINDS减轻长期医疗负担的使命 由创伤后神经系统疾病所致。

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.