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，也是最大的公共卫生挑战之一 国际吧因此，制定早期干预措施以预防或延迟AD进展至关重要。神经元网络 功能障碍是AD的早期特征，在有发展这种疾病风险的人中观察到， 与含有中间神经元的皮质小白蛋白（PV）的异常活动有关。另一个早期 AD的特征是睡眠异常，在认知障碍发作前数年观察到。而 这两个问题都在AD的早期阶段发展，并且是加重随后AD的潜在因素 发病机制，异常PV神经元活动和睡眠障碍之间的关系还没有得到证实。 研究了这里的首要假设是，PV神经元的异常兴奋性在早期 AD阶段导致睡眠振荡受损，淀粉样蛋白-β（Aβ）进一步积累， 认知.因此，早期干预，纠正PV异常可以防止睡眠障碍，减缓 Aβ蓄积，并预防AD中的记忆缺陷。拟议的实验利用完善的AD 小鼠模型（APP/PS1和5XFAD），并专注于内侧前额叶皮层（mPFC），这是一个关键区域， 非快速眼动（NREM）慢波的产生和最早积累Aβ的区域之一， 以及海马体（HPC），其对于学习和记忆至关重要并且在AD中改变。先前体外研究 使用这些AD小鼠模型，报告了关于PV异常的发现，这些发现似乎与 其他.因此，本提案的目标1将使用最先进的光纤测光技术，沿着局部场 潜在的记录在体内纵向表征如何在PV神经元和锥体神经元的神经元活动 神经元的变化，以及PV中间神经元的变化如何与早期到后期的睡眠振荡相关 在两种具有不同AD病理学时程的小鼠模型中，目标2将评估治疗 通过化学遗传学持续操作PV神经元对睡眠振荡异常Aβ的益处 水平和行为（HPC依赖的记忆）。如果成功，这项工作将确定与广告相关的时间 皮质网络活动中断，睡眠振荡生物标志物和通知早期干预策略， 预防或延缓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/弗吉尼亚州波士顿学院专门从事睡眠研究，皮层振荡，神经解剖学， 的AD。来自波士顿大学/弗吉尼亚州波士顿和马萨诸塞州阿尔茨海默病的研究人员 研究中心将提供关于人类和小鼠模型AD研究的全面培训。的 建议进行AD病理学纤维光度测定和组织化学测定的技术和概念培训， 以及与广告和专业发展相关的教学课程和研讨会将促进 申请人的目标是成为AD研究领域的独立研究者。

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.