Controlling oscillations to treat Alzheimers disease targeting the basal forebrain parvalbuminsystem

控制振荡以治疗针对基底前脑小清蛋白系统的阿尔茨海默病

• 批准号: 10383690
• 负责人: Felipe Lopes Schiffino
• 金额: $ 12.68万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383690
• 关键词: 3xTg-AD mouse; Acute; Affect; Aftercare; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid beta-Protein; Amyloidosis; Area; Attention; Award; Behavioral; Boston; Career Mobility; Chronic; Cognition; Communication; Coupling; Data; Dementia; Disease; Dorsal; Education; Electroencephalography; Funding; Goals; Hippocampus (Brain); Impaired cognition; Impairment; Institution; Interneurons; Ipsilateral; J20 mouse; Lasers; Learning; Massachusetts; Measures; Medial; Mediating; Memory; Memory impairment; Mentors; Mentorship; Methods; Modeling; Motivation; Mus; Neurons; Paper; Parietal Lobe; Parvalbumins; Pathogenesis; Pathologic; Pathology; Pathway interactions; Pharmacology; Phase; Physiologic pulse; Prefrontal Cortex; Property; Psychological reinforcement; Recovery of Function; Regulation; Research; Research Personnel; Same-sex; Short-Term Memory; Task Performances; Tauopathies; Techniques; Testing; Therapeutic; Training; Treatment Efficacy; Universities; Visual; Visual Cortex; abeta deposition; abuse liability; basal forebrain; behavioral outcome; classical conditioning; cognitive enhancement; comparative efficacy; education research; experimental study; improved; improved outcome; innovation; medical schools; member; mouse model; neuroprotection; optogenetics; pre-clinical; preclinical study; prevent; professor; programs; relating to nervous system; repaired; sensory stimulus; side effect; synergism; treatment strategy

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.

阿尔茨海默病（Alzheimer's disease，AD）是一种以β-淀粉样蛋白早期沉积为特征的神经退行性疾病 蛋白（Aβ），随后是tau蛋白病和认知受损。需要创新的治疗策略。最近 在淀粉样变性和tau蛋白病模型小鼠中的研究表明，使用 感觉刺激（GENUS）改善病理和行为结果。然而，这些令人兴奋的研究 尚未独立复制，减少伽马夹带病理的最佳方法是 未知因此，在这里，我们测试非胆碱能基底前脑小白蛋白的光遗传学激发是否 神经元（BF PV）能够广泛控制整个皮层和海马体的伽马振荡， 治疗淀粉样变性/tau蛋白病并恢复支持记忆的大脑皮层振荡功能。 该提案的指导（K99）阶段将使用5XFAD小鼠来测试40 Hz光遗传学BF的益处 PV兴奋预防淀粉样变所有实验均记录同侧内侧皮层局部场电位（LFP）。 前额叶皮层（mPFC）和海马（HPC）。第一个实验直接比较了40 Hz的功效 针对GENUS的BF PV激发治疗减少斑块病理。第二个实验使用 化学遗传学来模拟BF PV的靶向性，并测试化学遗传学BF PV是否 兴奋和GENUS协同作用以改善结果。第三个实验评估的假设， 慢性40 Hz BF PV激发修复海马和皮质中的伽马产生机制，以恢复 振荡通信和救援工作记忆。第四个实验将使用一个闭环 在海马θ相位的峰或谷处递送两个短暂（10 ms）的激光脉冲以 评估BF PV激励的θ相特定定时是否重要。 独立（R 00）阶段研究将在K99阶段学到的方法应用于3xTg 淀粉样变性/tau蛋白病模型小鼠加强BF PV靶向治疗的情况下，中度至重度 AD.在3xTg小鼠中进行的这些研究拟定了与上述相同的四项实验。此外，重要 临床前行为实验将评估BF PV激发可用于增强 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。 该奖项的培训计划包括来自哈佛医学院专家团队的指导 教授专门从事大脑皮层振荡和认知的BF调节。广告导向培训将 由波士顿大学导师团队的其他成员提供，并通过候选人的 参与马萨诸塞州广告研究中心的研究教育组成部分计划。的 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 申请人的目标是成为研究AD临床前治疗的独立研究者。