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

父母格兰特已经表明，非侵入性的闪烁感官刺激夹带多个特定的频率 的神经活动和伽马频率的感觉刺激招募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，父母补助金正在积极调查 感官刺激对神经编码和突触的影响本提案的目标是确定哪些（如果有的话）， 感觉闪烁的模式在慢性应激后恢复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人患AD的风险增加2倍或更高。损失 突触完整性是AD患者神经精神和认知功能下降的最佳预测指标之一。应力增加 通过促进皮质边缘脑中的突触丢失而导致AD和相关神经精神症状的风险 这是由于功能失调的小胶质细胞（大脑的主要免疫细胞）增强了突触修剪。 此外，越来越多的证据表明，慢性压力加速了AD相关疾病的进展。 病理学包括聚集的淀粉样蛋白-β（Aβ）肽和淀粉样蛋白斑块的积累。因此，委员会认为， 我们将确定慢性感觉闪烁暴露是否能防止应激诱导的突触丢失，加速淀粉样蛋白 慢性应激后皮质边缘脑区小胶质细胞介导的突触重塑 在WT和5XFAD小鼠中。这项研究将是第一个确定如何应激诱导的突触损失，加速 病理学积累，并且免疫功能障碍被闪烁刺激停止。识别闪烁的影响 将揭示特定频率的神经活动对应激神经生物学的作用 并为使用这种非侵入性刺激作为一种新的治疗方法， 压力诱导的AD下降。因为个体在慢性或严重的AD后患AD的可能性是正常人的两倍， 预防应激的神经生物学效应将大大降低AD的患病率。

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.