Hypothalamic Sleep-Wake Neuron Defects in Alzheimer’s disease

作为阿尔茨海默病（AD）的标志，睡眠中断通常先于严重记忆和 与AD的临床阶段相关的认知缺陷。据估计，它会影响30-66%的AD 患者，并且其影响对患者和护理者都是使人衰弱和紧张的。然而，神经 睡眠和AD之间的潜在联系机制仍然知之甚少。快速眼动 (REM)睡眠是一种与生动的梦境和明显的认知过程有关的睡眠状态， 在调节学习和记忆中的重要作用。它的紊乱表现为快速眼动睡眠减少 持续时间和REM潜伏期增加，并与AD患者的认知功能受损呈正相关 患者黑色素浓集激素（MCH）神经元专门位于外侧下丘脑 (LH)并广泛投射到整个大脑。他们被认为在这一代人中发挥着关键作用， 保持快速眼动睡眠，并在此状态下最大限度地活跃。值得注意的是，这些快速眼动活跃的MCH 神经元还通过它们向海马CA 1区的投射来介导记忆损伤。期临床 AD、tau病理学、神经元缠结可在LH中观察到。此外，妇幼保健水平 在AD患者脑脊液中显著升高，并与CSF tau蛋白呈正相关 水平，REM睡眠中断和认知障碍的严重程度。这些证据表明 MCH神经元在AD神经病理学中的作用在拟议的项目中，我们将测试中心假设，即LH MCH 神经元在AD的tau蛋白病状态中变得功能障碍。因此，使用体内显微内窥镜 钙成像，离体切片记录和tau蛋白病的PS19小鼠模型，我们将确定是否和 tau病理学如何影响Aim 1中MCH神经元在睡眠-觉醒周期中的放电模式。使用 化学遗传学方法，我们将进一步确定是否操纵他们的神经元活动改善 睡眠质量和提高目标2中的认知能力。这个项目的结果应该有助于打开大门 开发基于回路的治疗干预措施，用于AD相关的睡眠障碍和认知功能障碍。 损伤

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.