Hypothalamic Sleep-Wake Neuron Defects in Alzheimer’s disease

作为阿尔茨海默病(AD)的一个特征，睡眠障碍通常在严重记忆和 认知缺陷与阿尔茨海默病的临床阶段相关数十年。据估计，它会影响30-66%的AD 它的影响是虚弱的，对患者和照顾者都是有压力的。然而，神经 睡眠和阿尔茨海默病之间联系的潜在机制仍然知之甚少。快速眼动 (REM)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，在 在学习和记忆的调节中起着重要作用。它的干扰表现为快速眼动睡眠减少 AD患者持续时间和REM潜伏期延长与认知功能损害呈正相关 病人。黑色素浓缩激素(MCH)神经元仅位于下丘脑外侧 (Lh)，并广泛投射到整个大脑。他们被认为在这一代人和 维持快速眼动睡眠，并在此状态下最大限度地活跃。值得注意的是，这些快速眼动活动的妇幼保健 神经元也通过投射到海马区CA1区来调节记忆损伤。在临床阶段 AD的tau病理改变，神经原纤维缠结，可在黄体生成素中观察到。此外，母婴健康水平是 AD患者脑脊液显著升高，并与脑脊液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， MCH神经元在AD神经病理中的作用在提议的项目中，我们将检验以下中心假设： 阿尔茨海默病时，神经元功能紊乱。因此，使用活体显微内窥镜 钙成像，体外切片记录和PS19小鼠模型，我们将确定是否和 Tau病理如何影响Aim 1中睡眠-觉醒周期中MCH神经元的放电模式。 化学遗传学的方法，我们将进一步确定他们的神经活动的操纵是否改善 在目标2中，睡眠质量和提高认知表现。这个项目的结果应该有助于打开大门 对AD相关睡眠障碍和认知障碍的基于电路的治疗干预的发展 减损。

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.