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: 10455467
• 负责人: Susan T Nguyen
• 金额: $ 4.68万
• 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/10455467
• 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.); Control Animal; 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.

项目概要/摘要 Toll 样受体 4 (TLR4) 是一种先天免疫受体，在脑损伤后增强，与 调节海马齿状回的兴奋性。我们发现脑损伤后抑制 TLR4 降低癫痫易感性和记忆缺陷，但在对照中具有相反的效果。在试点研究中， TLR4 信号传导增加了对照组对齿状颗粒细胞的突触抑制，同时在 TBI 后减少了突触抑制， 表明抑制可能是控制大脑和受伤大脑中 TLR4 差异效应的核心。 TLR4 是 定位于齿状肺门神经元，并与生长抑素共定位，而不是小清蛋白中间神经元。自从TLR4 对抑制的影响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TLR4调节调节齿状兴奋性和记忆 加工。使用单/双膜片钳记录，细胞特异性图案化光遗传学神经元激活 和啮齿动物脑损伤模型中的药理学，我将解决 SOM+ 突触输入的 TLR4 调节问题 和PV+神经元到对照和受伤动物的颗粒细胞。具有细胞特异性 TLR4 缺失的小鼠将 遭受脑损伤并使用新型体外时间模式探究 TLR4 对网络功能的调节 分离测定和行为模式分离任务。该研究将增进免疫基础知识 调节兴奋性和记忆处理，并确定限制创伤后变化的潜在目标 神经元活动。