Non-Invasive Methods to Drive Neural Activity with Millisecond Precision and to Recruit the Brain’s Immune Cells

以毫秒精度驱动神经活动并招募大脑免疫细胞的非侵入性方法

基本信息

批准号：
10301791
负责人：
Annabelle Catherine Singer
金额：
$ 11.08万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10301791
关键词：
3-Dimensional Acceleration Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Amendment Amygdaloid structure Amyloid Amyloid beta-Protein Animal Model Animals Brain Brain region Cells Cellular Structures Chronic Chronic stress Code DLG4 gene Development Enzyme-Linked Immunosorbent Assay Female Foundations Frequencies Functional disorder Genes Goals Hippocampus (Brain)Hour Human Immune Immune System Diseases Immune signaling Immunohistochemistry Impaired cognition Individual Life Light Mediating Mental disorders Methods Microglia Molecular Morphology Mus Neurobiology Neurodegenerative Disorders Neurons Nucleus Accumbens Pathogenicity Pathologic Pathology Pattern Phagocytosis Prefrontal Cortex Prevalence Prevention Proteins Proteomics Research Risk Role Senile Plaques Sensory Stress Structure Synapses Synaptophysin Time Vertebral column Visual abeta accumulation aged amyloid pathology beta amyloid pathology brain cell brain tissue density experience immune function millisecond mouse model neuropsychiatric symptom neuropsychiatry novel therapeutic intervention parent grant preservation prevent psychological stressor psychosocial stressors reconstruction recruit relating to nervous system sound stressor synaptic function synaptic pruning transcriptomics treatment response

项目摘要

The parent grant has shown that non-invasive flickering sensory stimulation entrains multiple specific frequencies of neural activity and gamma frequency sensory stimulation recruits immune signals and cells microglia to engulf pathogenic proteins in mouse models for AD. In addition, the parent grant is actively investigating the effects of sensory stimulation on neural codes and synapses. The goal of this proposal is to determine which, if any, patterns of sensory flicker restore healthy synaptic and microglia functions following chronic stress. Individuals that have suffered from chronic or severe stress have a 2-fold or greater increased risk of developing AD. Loss of synaptic integrity is one of the best predictors of neuropsychiatric and cognitive decline in AD. Stress increases the risk of AD and associated neuropsychiatric symptoms by promoting synapses loss in corticolimbic brain regions due to enhanced synaptic pruning by dysfunctional microglia, the primary immune cells of the brain. Furthermore, mounting evidence suggests that chronic stress accelerates the progression of AD-associated pathology including the accumulation of aggregated amyloid-β (Aβ) peptide and amyloid plaques. Accordingly, we will determine if chronic sensory flicker exposure prevents stress-induced synaptic loss, accelerated amyloid accumulation, and microglia-mediated synapse remodeling in corticolimbic brain regions following chronic stress in WT and 5XFAD mice. This research will be the first to identify how stress-induced synaptic loss, accelerated pathology accumulation, and immune dysfunction is halted by flicker stimulation. Identifying the effects of flicker on stress-induced pathology will reveal a role for specific frequencies of neural activity on stress neurobiology and provide the foundation for using this non-invasive stimulation as a novel therapeutic approach to prevent stress-induced decline in AD. Because individuals are twice as likely to develop AD following chronic or severe stress, prevention of the neurobiological effects of stress would severely reduce the prevalence of AD.

父授予的赠款表明，非侵入性闪烁的感觉模拟进入多个特定频率神经活动和伽马频率感觉刺激报告的免疫信号和细胞小胶质细胞吞噬 AD小鼠模型中的致病蛋白。此外，父母赠款正在积极调查神经元代码和突触的感觉模拟。该提案的目的是确定哪个（如果有）感觉闪烁的模式恢复了慢性应激后健康的突触和小胶质细胞功能。个人患有慢性或严重压力的患者的发展风险增加了2倍或更大。损失突触完整性是AD神经精神病和认知能力下降的最佳预测指标之一。压力增加通过促进Corticolimbic大脑的突触损失，AD和相关神经精神症状的风险由于大脑的原发性免疫细胞的功能失调的小胶质细胞增强了突触修剪而引起的区域。此外，越来越多的证据表明，慢性应力加速了AD相关的发展病理学，包括聚集的淀粉样蛋白β（Aβ）果皮和淀粉样斑块的积累。因此，我们将确定慢性感觉闪烁是否会阻止应力引起的突触损失，加速淀粉样蛋白在慢性应激之后，累积和小胶质细胞介导的突触重建在WT和5XFAD小鼠中。这项研究将是第一个确定压力引起的合成损失，加速如何加速的一项研究。病理积累和免疫功能障碍会因闪烁刺激而停止。识别闪烁的影响关于应激诱导的病理学，将揭示神经活性特定频率在压力神经生物学上的作用并为使用这种非侵入性刺激作为一种新型治疗方法提供基础压力引起的AD下降。因为个人在慢性或严重之后发展广告的可能性是压力，预防压力的神经生物学作用将严重降低AD的流行率。