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

项目摘要：数年后出现癫痫和记忆丧失等神经系统疾病 创伤性脑损伤（TBI）是造成身体残疾和经济负担的主要原因。延迟 最初的创伤和最终的残疾是由进行性神经病理学导致的，可能是有限的 通过早期干预。然而，TBI 影响记忆和癫痫易感性的机制尚不明确。 完全明白了。海马齿状回是记忆处理的关键电路，也是记忆的关键调节器 从内嗅皮层到海马体的信息传递，以及成人神经发生的利基区域，是一个 TBI 后神经元损伤的焦点和兴奋性增加。尽管成体出生的颗粒细胞 (abGC) 与记忆处理有关，abGC 对代表内嗅的齿状尖峰的贡献 皮层对齿状信息流和支持记忆巩固的作用尚不清楚，以及如何诱发损伤 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 抑制损伤引起的神经发生的增加会降低 TBI 后一周的齿状体兴奋性，在 创伤后的同一时期先天免疫受体Toll样受体4（TLR4）增加 增强齿状突的兴奋性。已知 TLR4 会抑制幼稚动物的神经发生，但矛盾的是 增加中风的神经发生。而 TLR4 调节兴奋性和 神经发生尚不清楚，最近发现 TLR4 增强内肽酶、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前途的分子联系 创伤、TLR4 和异常网络可塑性之间的关系。采用跨越分子到 细胞到网络功能，我们认为 TBI 破坏后神经发生和兴奋性的早期增加 TLR4-皮质海马吞吐量的齿状调节和记忆处理缺陷 MMP-9 活性的依赖性持续升高。在小鼠中使用流体冲击损伤模型和当前的 体内和离体电生理学和光生理学技术，目标 1 将确定 TLR4 信号传导在 损伤后产生的 abGC 的发育、成熟和电路整合发生改变。目标 2 将测试 DG 是否已更改 TBI 后的兴奋性和神经发生损害齿状和海马之间的振荡耦合 这可以通过损伤后早期阻断 TLR4 来预防。最后，Aim 3 将结合使用 通过组织学、生化、生理学和行为分析来测试 TBI 后 TLR4 信号传导是否异常 导致 MMP-9 持续增加，可用于限制异常神经发生、神经元缺陷 TBI 后的振荡耦合和记忆缺陷。这种预防策略将大大提高 TBI 后患者的生活，并履行 NINDS 减轻长期医疗保健负担的使命 由创伤后神经系统疾病引起。

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.