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

家长的资助表明，非侵入性的闪光感官刺激具有多种特定频率 神经活动和伽马频率的感觉刺激招募免疫信号和细胞吞噬小胶质细胞 阿尔茨海默病小鼠模型中的致病蛋白。此外，家长赠款正在积极调查 神经编码和突触上的感觉刺激。这项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了健康的突触和小胶质细胞的功能。个人 遭受慢性或严重压力的人患AD的风险增加2倍或更多。损失 突触完整性是预测阿尔茨海默病患者神经精神和认知功能下降的最佳指标之一。压力增加 促进皮质边缘脑突触丢失的AD风险及相关神经精神症状 由于功能失调的小胶质细胞加强突触修剪的区域，小胶质细胞是大脑的主要免疫细胞。 此外，越来越多的证据表明，慢性压力会加速AD相关疾病的进展 病理包括聚集的淀粉样蛋白(Aβ，Aβ)多肽和淀粉样斑块。因此， 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，加速的淀粉样蛋白 慢性应激后皮质边缘脑区小胶质细胞介导的突触重构及蓄积 在WT和5XFAD小鼠中。这项研究将首次确定应激诱导的突触丢失、加速 病理堆积和免疫功能障碍通过闪烁刺激而停止。确定闪烁的影响 关于应激诱导的病理学将揭示特定频率的神经活动在应激神经生物学中的作用 并为使用这种非侵入性刺激作为一种新的治疗方法来预防 应激导致AD的下降。因为个人患AD的可能性是慢性或重度AD的两倍 应激，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.