Alteration of sleep and cortical parvalbumin interneurons in mouse model of Alzheimers disease

阿尔茨海默病(AD)是一种高度流行的痴呆症，是公共卫生面临的最大挑战之一 全世界。因此，制定预防或延缓AD进展的早期干预措施至关重要。神经元网络 功能障碍是阿尔茨海默病的早期特征，观察到有发展这种疾病的风险的人，并已 与含有皮质小白蛋白(PV)的中间神经元的异常活动有关。又一次早早 阿尔茨海默病的特征是睡眠异常，在认知障碍开始前几年就观察到了。而当 这两个问题都是在AD的早期阶段发展起来的，都是加剧后续AD的潜在因素 发病机制中，PV神经元活动异常与睡眠障碍的关系尚不清楚 调查过了。这里最重要的假设是，在早期，PV神经元的异常兴奋性 阿尔茨海默病阶段导致睡眠振荡受损，淀粉样蛋白-β(Aβ)进一步堆积，并受损 认知力。因此，早期干预、纠正PV异常可预防睡眠障碍、延缓睡眠 Aβ积聚，并防止AD记忆缺陷。拟议的实验利用了公认的AD 小鼠模型(APP/PS1和5XFAD)，并关注内侧前额叶皮质(MPFC)，这是 非快速眼动慢波的产生和最早积累Aβ的区域之一， 以及对学习和记忆至关重要的海马体(HPC)，它在AD时会发生变化。先前的体外研究 使用这些AD小鼠模型，报告了关于PV异常的发现，这似乎与 其他的。因此，该提案的目标1将使用最先进的光纤光度测量技术，以及局域 活体电位记录纵向描述PV神经元和锥体神经元的活动 神经元的变化，以及从早期到后期，PV中间神经元的变化与睡眠振荡的关系 在两种不同病程的小鼠模型中观察AD的病理变化。Aim 2将评估治疗方法 通过化学遗传学持续操作PV神经元对睡眠振荡异常的益处，Aβ 级别和行为(HPC依赖的内存)。如果成功，这项工作将确定AD相关的时间 破坏皮质网络活动、睡眠振荡生物标志物，并为早期干预策略提供信息 防止或延缓AD进展。该奖项的培训计划包括来自以下专家团队的指导 哈佛医学院/退伍军人事务部波士顿分校专门从事睡眠研究、皮质振荡、神经解剖学、 和AD。来自波士顿大学/弗吉尼亚州波士顿分校和马萨诸塞州阿尔茨海默病学院的研究人员 研究中心将提供在人类和小鼠模型上进行AD研究的全面培训。这个 拟为AD病理学提供纤维光度和组织化学分析方面的技术和概念培训，AS 以及与AD和专业发展相关的教学课程和讲习班将促进 申请者的目标是成为AD研究领域的一名独立研究员。

Alzheimer's disease (AD) is a highly prevalent form of dementia and one of the largest public health challenges worldwide. Thus, developing early interventions to prevent or delay AD progression is vital. Neuronal network dysfunction is an early characteristic of AD, observed in people at risk of developing this disorder, and has been linked to abnormal activity of cortical parvalbumin (PV) containing interneurons. Another early characteristic of AD is sleep abnormalities, observed years before the onset of cognitive impairment. While both these issues develop during early stages of AD and are potential factors that exacerbate subsequent AD pathogenesis, the relationship between abnormal PV neuron activity and sleep impairment has not been investigated. The overarching hypothesis here is that abnormal excitability of PV neurons during the early stage of AD is responsible for impaired sleep oscillations, further accumulation of amyloid-β (Aβ), and impaired cognition. Thus, early interventions, correcting PV abnormalities could prevent sleep disturbances, slow down Aβ accumulation, and prevent memory deficits in AD. The proposed experiments utilize well-established AD mouse models (APP/PS1 and 5XFAD) and focus on the medial prefrontal cortex (mPFC), an area critical for generation of non-rapid-eye-movement (NREM) slow waves and one of the earliest regions to accumulate Aβ, and the hippocampus (HPC) which is vital for learning and memory and altered in AD. Previous in vitro studies using these AD mouse models reported findings regarding PV abnormalities which appear to contradict each other. Thus, Aim 1 of this proposal will use the state-of-the-art fiber photometry technique, along with local field potential recordings in vivo to longitudinally characterize how neuronal activity in PV neurons and pyramidal neurons change, and how changes in PV interneurons relate to sleep oscillations across early to later stages of AD in the two mouse models with different timecourses of AD pathology. Aim 2 will assess the therapeutic benefit of sustained manipulation of PV neurons via chemogenetics on sleep oscillation abnormalities, Aβ level, and behavior (HPC-dependent memory). If successful, this work will identify the timing of AD-related disruption of cortical network activity, sleep oscillation biomarkers and inform early intervention strategies to prevent or delay AD progression. The training plan for this award includes mentorship from an expert team of Harvard Medical School/VA Boston faculty specializing in sleep research, cortical oscillations, neuroanatomy, and AD. Faculty investigators from Boston University/VA Boston and the Massachusetts Alzheimer's Disease Research Center will provide comprehensive training on AD research in humans and in mouse models. The proposed technical and conceptual training in fiber photometry and histochemical assay for AD pathology, as well as didactic courses and workshops relevant to AD and professional development will facilitate the applicant's goal of becoming an independent investigator in the AD research field.