Role of TLR4 in Neuronal Excitability and Memory Function

TLR4 在神经元兴奋性和记忆功能中的作用

• 批准号: 10316103
• 负责人: Susan T Nguyen
• 金额: $ 4.6万
• 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: 2021-09-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316103
• 关键词: Acute; Affect; Animals; Behavioral; Behavioral Assay; Biological Assay; Brain; Brain Concussion; Brain Injuries; Cause of Death; Cells; Centers for Disease Control and Prevention (U.S.); Cytoplasmic Granules; Data; Disease; Electrophysiology (science); Environment; Epilepsy; Epileptogenesis; Hilar; Hippocampus (Brain); Hour; Immune; Immune signaling; Immune system; Immunologic Memory; Immunologic Receptors; Impairment; In Vitro; Inflammatory Response; Injury; Interneurons; Knowledge; Ligands; Link; Memory; Memory impairment; Modeling; Morbidity - disease rate; Mus; Neuroglia; Neuronal Injury; Neurons; Opsin; Optics; Outcome; Pattern; Performance; Pharmacology; Pilot Projects; Predisposition; Process; Regulation; Research Design; Risk; Rodent; Rodent Model; Role; Seizures; Short-Term Memory; Signal Transduction; Slice; Somatostatin; Synapses; TLR4 gene; Testing; Transgenic Mice; Traumatic Brain Injury; United States; cell type; comorbidity; dentate gyrus; disability; entorhinal cortex; experimental study; fluid percussion injury; gamma-Aminobutyric Acid; granule cell; immunoregulation; improved; in vivo; injured; memory process; neuronal excitability; neuronal patterning; neurophysiology; neurotransmission; novel; optogenetics; patch clamp; public health relevance; receptor; relating to nervous system; synaptic inhibition; treatment strategy

Project Summary/Abstract Toll-Like Receptor 4 (TLR4) is an innate immune receptor that is enhanced after brain injury and is implicated in modulating excitability in the hippocampal dentate gyrus. We find that suppressing TLR4 after brain injury reduces seizure susceptibility and memory deficits however has opposite effects in controls. In pilot studies, TLR4 signaling increases synaptic inhibition to dentate granule cells in controls while reducing it after TBI, indicating that inhibition may be central to the differential TLR4 effects in control and injured brain. TLR4 is localized in dentate hilar neurons and co-localizes with somatostatin, not parvalbumin interneurons. Since TLR4 effects on inhibition correlate with dentate excitability and memory outcomes, I propose that cell type specific and injury-state dependent TLR4 modulation of GABAergic synapses regulate dentate excitability and memory processing. Using single/dual patch clamp recordings, cell-specific patterned optogenetic neuronal activation and pharmacology in a rodent model of brain injury, I will resolve TLR4 regulation of synaptic inputs from SOM+ and PV+ neurons to granule cells in control and injured animals. Mice with cell-specific deletion of TLR4 will be subject to brain injury and probed for TLR4 regulation of network function using a novel in-vitro temporal pattern separation assay and behavioral pattern separation tasks. The study will advance basic knowledge on immune regulation of excitability and memory processing and identify potential targets to limit post-traumatic changes in neuronal activity.

项目总结/摘要 Toll样受体4（TLR 4）是一种先天性免疫受体，在脑损伤后增强，并与脑损伤有关。 调节海马齿状回的兴奋性。我们发现在脑损伤后抑制TLR 4 降低癫痫发作的易感性和记忆缺陷，然而在对照组中具有相反的效果。在试点研究中， TLR 4信号传导增加对照组中对齿状颗粒细胞的突触抑制，而在TBI后减少， 这表明抑制可能是对照和损伤脑中TLR 4差异效应的核心。tlr 4是 定位于齿状门神经元，并与生长抑素，而不是小白蛋白中间神经元共定位。由于TLR 4 抑制效应与齿状兴奋性和记忆结果相关，我认为细胞类型特异性 GABA能突触的损伤状态依赖性TLR 4调节调节齿状兴奋性和记忆 处理.使用单/双膜片钳记录，细胞特异性模式化光遗传神经元激活 和药理学在啮齿动物模型的脑损伤，我将解决TLR 4调节突触输入从SOM+ 对照组和损伤组PV+神经元向颗粒细胞转化。具有TLR 4的细胞特异性缺失的小鼠将被 并使用一种新的体外时间模式探索TLR 4对网络功能的调节 分离测定和行为模式分离任务。这项研究将促进免疫的基础知识 调节兴奋性和记忆处理，并确定潜在的目标，以限制创伤后的变化， 神经元活动