Hypothalamic Sleep-Wake Neuron Defects in Alzheimer’s disease

阿尔茨海默病中的下丘脑睡眠-觉醒神经元缺陷

• 批准号: 10731103
• 负责人: Peng Zhong
• 金额: $ 30.6万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731103
• 关键词: Hypothalamic; Sleep; Wake; Neuron; Defects

As a hallmark of Alzheimer’s Disease (AD), sleep disruption often precedes the onset of the severe memory and cognitive deficits associated with the clinical phase of AD by decades. It is estimated to affect 30-66% of AD patients, and its effects are debilitating and stressful for both the patient and the caregiver. However, the neural mechanisms underlying the association between sleep and AD are still poorly understood. Rapid eye movement (REM) sleep, a sleep state that is associated with vivid dreaming and obvious cognitive processing, plays an important role in the regulation of learning and memory. Its disturbances manifest as decreased REM sleep duration and increased REM latency and are positively correlated with impaired cognitive functions in AD patients. Melanin-concentrating hormone (MCH) neurons are exclusively located in the lateral hypothalamus (LH) and project broadly throughout the brain. They are thought to play a critical role in the generation and maintenance of REM sleep and are maximally active during this state. Remarkably, these REM-active MCH neurons also mediate memory impairment by their projections to the hippocampus CA1 region. In clinical phase of AD, tau pathology, neurofibrillary tangles, can be observed in the LH. Furthermore, MCH levels are significantly elevated in the cerebral spinal fluid (CSF) of AD patients and are positively correlated to CSF tau level, REM sleep disruption and severity of cognitive impairment. These pieces of evidence suggest a role for MCH neurons in neuropathology of AD. In the proposed project, we will test the central hypothesis that LH MCH neurons become dysfunctional in the tauopathy condition of AD. Accordingly, using in vivo microendoscopic calcium imaging, ex vivo slice recording and PS19 mouse model of tauopathy, we will determine whether and how tau pathology affects the firing patterns of MCH neurons across the sleep-wake cycles in Aim 1. Using chemogenetic approaches, we will further determine whether manipulation of their neuronal activities improves sleep quality and enhances cognitive performance in Aim 2. The results of this project should help open the door to the development of circuit-based therapeutic interventions for AD-related sleep disorders and cognitive impairments.

作为阿尔茨海默氏病 (AD) 的一个标志，睡眠中断通常先于严重的记忆力和记忆力下降之前出现。 据估计，认知缺陷会影响 30-66% 的 AD 患者。 然而，它的影响使患者和护理人员都感到虚弱和压力。 睡眠与 AD 之间关联的机制仍知之甚少。 （快速眼动睡眠）是一种与生动的梦境和明显的认知处理相关的睡眠状态，起着 它在学习和记忆的调节中发挥着重要作用，其障碍表现为快速眼动睡眠减少。 持续时间和 REM 潜伏期增加，与 AD 认知功能受损呈正相关 黑色素浓缩激素（MCH）神经元仅位于外侧下丘脑。 (LH) 并广泛投射到整个大脑中，它们被认为在生成和发育过程中发挥着关键作用。 REM 睡眠的维持，并且在该状态下处于最大活跃状态。值得注意的是，这些 REM 活跃的 MCH。 在临床阶段，神经元还通过投射到海马 CA1 区域来介导记忆障碍。 AD、tau 病理学、神经原纤维缠结，可以在 LH 中观察到。此外，MCH 水平也是如此。 AD患者脑脊液（CSF）中的tau蛋白升高，并与CSF tau呈正相关 水平、快速眼动睡眠中断和认知障碍的严重程度这些证据表明， AD 神经病理学中的 MCH 神经元 在拟议的项目中，我们将测试 LH MCH 的中心假设。 因此，使用体内显微内窥镜，神经元在 AD 的 tau 蛋白病状态下变得功能障碍。 钙成像、离体切片记录和 PS19 tau 蛋白病小鼠模型，我们将确定是否和 目标 1 中 tau 病理学如何影响睡眠-觉醒周期中 MCH 神经元的放电模式。 化学遗传学方法，我们将进一步确定对其神经活动的操纵是否会改善 睡眠质量并提高目标 2 中的认知表现。该项目的结果应该有助于打开大门 开发针对 AD 相关睡眠障碍和认知障碍的基于回路的治疗干预措施 损伤。