Controlling oscillations to treat Alzheimers disease targeting the basal forebrain parvalbuminsystem

阿尔茨海默病(AD)是一种以早期淀粉样β蛋白沉积为特征的神经发生疾病 蛋白质(Aβ)，紧随其后的是紧张症和认知障碍。需要创新的治疗策略。近期 对淀粉样变性和自发性疾病模型小鼠的研究表明，慢性40赫兹伽玛夹带使用 感觉刺激(属)可改善病理和行为结果。然而，这些令人兴奋的研究 尚未被独立复制，通过伽马携带减少病理的最佳方法是 未知。因此，在这里，我们测试了非胆碱能基底前脑小白蛋白的光遗传兴奋 神经元(BF PV)能够广泛控制整个大脑皮层和海马区的伽马振荡 治疗淀粉样变性/肌萎缩侧索硬化症，恢复支持记忆的海马皮层振荡功能。 该计划的指导(K99)阶段将使用5XFAD小鼠来测试40赫兹光遗传BF的益处 PV激发在预防淀粉样变性中的作用。所有实验均记录到内侧同侧局部场电位(LFP) 前额叶皮质(MPFC)和海马区(HPC)。第一个实验直接比较了40赫兹的疗效。 BF PV激发抗菌治疗在减少斑块病理中的作用。第二个实验使用 用化学遗传学模拟BF PV的药理靶向，并测试BF PV是否发生化学作用 激励和类协同作用，以改善结果。第三个实验评估了假设 慢性40 HzBF PV激发修复海马区和大脑皮层的伽马产生机制以恢复 振荡交流与救援工作记忆。第四个实验将使用闭环系统 在海马theta相的波峰或波谷发出两个短(10ms)激光脉冲的刺激方法 评估高炉风电励磁的theta相特定时间是否重要。 独立(R00)阶段的研究将把在K99阶段学到的方法应用于3xTg 淀粉样变性/结肠炎模型小鼠加强对BF PV中重度靶向治疗的研究 广告。建议在3xTg小鼠身上进行上述四个相同的实验。此外，更重要的是 临床前行为学实验将评估BF PV兴奋可用于增强 在不影响动机(潜在副作用)或强化(滥用潜力)的情况下，3xTg小鼠的认知能力。 该奖项的培训计划包括哈佛医学院专家团队的指导 专门研究大脑皮层振荡和认知的BF调节的教授。广告定向培训将是 由波士顿大学导师团队的其他成员提供，并通过候选人的 参加马萨诸塞州广告研究中心研究教育组成部分计划。这个 拟议的AD研究和教学活动以及关于神经振荡研究的培训将促进 申请者的目标是成为一名研究AD临床前治疗的独立研究员。

Alzheimer's disease (AD) is a neurogenerative disorder characterized by early deposition of amyloid-beta protein (Aβ) followed by tauopathy and impaired cognition. Innovative treatment strategies are needed. Recent studies in amyloidosis and tauopathy model mice have shown that chronic 40Hz gamma entrainment using sensory stimuli (GENUS) improves pathological and behavioral outcomes. However, these exciting studies have not been independently replicated and optimal methods to reduce pathology by gamma entrainment are unknown. Thus, here, we test whether optogenetic excitation of non-cholinergic basal forebrain parvalbumin neurons (BF PV) enables widespread control of gamma oscillations throughout cortex and hippocampus to treat amyloidosis/tauopathy and restore hippocampal-cortical oscillatory functions that support memory. The mentored (K99) phase of this proposal will use 5XFAD mice to test benefits of 40Hz optogenetic BF PV excitation in preventing amyloidosis. All experiments record ipsilateral local field potentials (LFP) in medial prefrontal cortex (mPFC) and hippocampus (HPC). The first experiment directly compares the efficacy of 40Hz BF PV excitation treatment against GENUS in reducing plaque pathology. The second experiment uses chemogenetics to model pharmacologically targeting of BF PV and tests whether chemogenetic BF PV excitation and GENUS synergize to improve outcome. The third experiment assesses the hypothesis that chronic 40Hz BF PV excitation repairs gamma generating mechanisms in hippocampus and cortex to restore oscillatory communication and rescue working memory. The fourth experiment will use a closed-loop stimulation method to deliver two brief (10ms) laser pulses at the peak or trough of hippocampal theta phase to assess whether theta-phase specific timing of BF PV excitation matters. The independent (R00) phase studies will apply methods learned during the K99 phase to 3xTg amyloidosis/tauopathy model mice to strengthen the case for BF PV targeted treatments of moderate to severe AD. The same four experiments as above are proposed for these studies in 3xTg mice. Further, important preclinical behavioral experiments will assess the hypothesis that BF PV excitation can be used to enhance cognition in 3xTg mice without affecting motivation (a potential side effect) or reinforcement (abuse potential). The training plan for this award includes mentorship from an expert team of Harvard Medical School professors specializing in BF regulation of cortical oscillations and cognition. AD-directed training will be provided by additional members of the mentorship team from Boston University and through the candidate's participation in the Massachusetts AD Research Center Research Education Component program. The proposed AD research and didactic activities and training on the study of neural oscillations will facilitate the applicant's goal of becoming an independent investigator studying preclinical treatments for AD.