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）的标志，睡眠干扰通常是在严重记忆和 数十年来，与AD的临床阶段相关的认知缺陷。估计会影响AD的30-66％ 患者及其影响对患者和护理人员都令人衰弱和压力。但是，中立 睡眠与AD之间关联的机制仍然很少了解。快速眼动 （REM）睡眠状态，与生动的梦和明显的认知处理有关的睡眠状态 在学习和记忆的调节中的重要作用。它的灾难表现为减少REM睡眠 持续时间和增加的REM潜伏期，并与AD中认知功能受损呈正相关 患者。黑色素浓缩马酮（MCH）神经元专门位于下丘脑 （LH）和整个大脑的投影。他们被认为在这一代人中起着至关重要的作用 维持REM睡眠，在此状态下最高活跃。值得注意的是，这些持久的MCH 神经元还通过其项目介导海马CA1区域的记忆障碍。在临床阶段 在LH中可以观察到AD，TAU病理学，神经纤维缠结。此外，MCH水平是 AD患者的脑脊髓液（CSF）显着升高，并与CSF TAU呈正相关 水平，REM睡眠中断和认知障碍的严重程度。这些证据表明了 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 在AD的tauopathy状态下，神经元变得功能失调。根据体内微观镜检查 钙成像，离体切片记录和tauopathy的PS19小鼠模型，我们将确定是否和 tau病理如何影响AIM 1中的睡眠效果周期的MCH神经元的发射模式。 化学发生方法，我们将进一步确定对其神经元活动的操纵是否有所改善 AIM 2中的睡眠质量并提高认知表现。该项目的结果应有助于打开大门 开发基于电路的治疗干预措施，用于与广告相关的睡眠障碍和认知能力 障碍。