Decoding brain circuit underlying metabolic regulation of sleep-wake behavior

项目总结/摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种神经退行性疾病，也是最常见的痴呆症 在老年人群中，目前还没有可用于AD的疾病改善疗法。除了衰老， 肥胖和睡眠质量差也会大大增加患AD和AD的风险， 相关性痴呆（ADRD）肥胖通常与瘦素抵抗和瘦素缺乏性肥胖有关 据报道，ob/ob和db/db小鼠不仅表现出严重的睡眠片段化和睡眠质量差， 而且还恶化了AD样病理和认知障碍，这提出了一个重要的问题， 瘦素缺乏增加AD风险是由于瘦素信号本身缺陷或睡眠质量差引起的， 肥胖和瘦素缺乏。因此，本AD补充申请的主要目的是测试 一个新的想法，即改善睡眠质量足以改善AD样病理和认知障碍， 肥胖的瘦素缺陷小鼠。这一想法源于新的遗传小鼠模型的发展， 条件性瘦素缺乏症是通过父母资助的研究R 01 HL 153274和几个 这些小鼠模型中的重要观察结果。在Parent Grant的研究中，我们发现瘦素 下丘脑外侧区（LHA）是一个历史上被称为“进食中心”的大脑区域， 在睡眠-觉醒调节中起关键作用，而不会严重影响体重动态平衡。具体来说，我们发现 选择性地恢复肥胖LepR缺失小鼠LHA中的LepR信号传导足以 正常化严重的睡眠碎片和改善整体睡眠质量，而选择性删除LepRs， LHA破坏正常的睡眠-觉醒周期，而体重没有显著变化。根据文献 支持脑LepR信号在AD/ADRD发病机制中起保护作用，睡眠质量差 加剧这些病理条件，在本研究补充，我们建议测试的假设， 脑瘦素信号传导对AD/ADRD的保护作用是由LHA LepR信号传导介导的， 睡眠质量与肥胖的关系将通过以下两个具体目标来检验这一假设： 确定LHA瘦素信号的选择性恢复是否改善AD样病理和记忆 与肥胖LepR缺失小鼠中的衰老相关的损伤和2）确定LHA瘦素的选择性损失是否 3xTg-AD突变小鼠中的信号传导加剧了AD样病理和记忆障碍。拟议 这项研究意义重大，因为它不仅有望澄清睡眠质量差在介导肥胖中的作用， 与AD样病变相关的风险，但也确定了一个关键的大脑区域， 改善AD样病理学，这可能有助于开发一种有效的策略来管理或预防肥胖- AD风险。

Project Summary / Abstract Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder and the most common form of dementia in elderly population, yet no disease modifying therapies are currently available for AD. In addition to aging, obesity and poor sleep quality have also been known to greatly increase the risk of developing AD and AD- related dementia (ADRD). Obesity is commonly associated with leptin resistance and leptin deficient obese ob/ob and db/db mice have been reported to exhibit not only severe sleep fragmentation and poor sleep quality but also worsened AD-like pathology and cognitive impairment, which raise an important question whether increased AD risk in leptin deficiency is due to defect in leptin signaling per se or poor sleep quality caused by obesity and leptin deficiency. The main objective of this AD supplement application is therefore to test the novel idea that improving sleep quality is sufficient to ameliorate AD-like pathology and cognitive impairment in obese leptin deficient mice. This idea stems from the development of novel genetic mouse models with conditional leptin deficiencies made through research funded by the parent grant R01 HL 153274 and several important observations in these mouse models. In research proposed in parent grant, we found that leptin signaling in the lateral hypothalamic area (LHA), a brain region historically known as “feeding center”, plays a key role in sleep-wake regulation without drastically affecting body weight homeostasis. Specifically, we found that selectively restoring leptin receptor (LepR) signaling in the LHA of obese LepR-null mice is sufficient to normalize severe sleep fragmentations and improve overall sleep quality, while selective deletion of LepRs in the LHA disrupts normal sleep-wake cycle without significant change in body weight. Given the literature support that brain LepR signaling play protective role in AD/ADRD pathogenesis, and that poor sleep quality exacerbate these pathological conditions, in this research supplement we propose to test the hypothesis that protective effect of brain leptin signaling against AD/ADRD is mediated by LHA LepR signaling which improve sleep quality in the context of obesity. This hypothesis will be tested by pursuing following two specific aims: determine if selective restoration of LHA leptin signaling ameliorate AD-like pathology and memory impairments associated with aging in obese LepR-null mice and 2) determine if selective loss of LHA leptin signaling in 3xTg-AD mutant mice exacerbate AD-like pathology and memory impairments. The proposed research is significant as it is not only expected to clarify the role of poor sleep quality in mediating obesity- associated risk of developing AD-like pathology but also identify a key brain region whereby leptin signaling ameliorate AD-like pathology, which may help to develop an effective strategy to manage or prevent obesity- associated AD risk.