The circuit basis of sundowning-related circadian dysfunction in Alzheimer's disease and Alzheimer's disease-related dementias

阿尔茨海默病和阿尔茨海默病相关痴呆中日落相关昼夜节律功能障碍的回路基础

• 批准号: 10807621
• 负责人: William David Todd
• 金额: $ 35.18万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10807621
• 关键词: Ablation; Acute; Address; Aggressive behavior; Aging; Agitation; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Model; Area; Behavioral; Body Temperature; Brain Stem; Caregivers; Cholecystokinin; Circadian Dysregulation; Circadian Rhythms; Clinical; Darkness; Dynorphins; Enterobacteria phage P1 Cre recombinase; Female; Functional disorder; Goals; Hypothalamic structure; Institutionalization; Lateral; Lead; Light; Modeling; Motor Activity; Mus; Mutation; Nerve Degeneration; Neural Pathways; Neuroanatomy; Neurobehavioral Manifestations; Neurobiology; Neurons; Pathology; Pathway interactions; Patients; Phase; Phase Transition; Physiological; Population; Quality of life; Research Project Grants; Resting Phase; Role; Site; Symptoms; Syndrome; System; Testing; Time; Transgenic Mice; Wild Type Mouse; aged; circadian; circadian pacemaker; comorbidity; genetic manipulation; hyperphosphorylated tau; improved; male; mouse model; novel; parabrachial nucleus; postsynaptic; pre-clinical; suprachiasmatic nucleus; tetra-4-amidinophenoxypropane; therapeutic target; vector

The long-term goal of this project is to gain an understanding of the circuit mechanisms underlying circadian dysfunction and associated behavioral disturbances in Alzheimer’s disease (AD) and Alzheimer’s disease related dementias (ADRD). AD/ADRD are associated with progressive disruption of circadian rhythms, including body temperature, locomotor activity, and other rhythms, compared to healthy aged-matched controls. This suggests that AD-related pathology alters the ability of the master circadian pacemaker (the suprachiasmatic nucleus of the hypothalamus, SCN), to synchronize such rhythms to the daily light-dark cycle. A particular form of circadian dysfunction in around 20% of AD/ADRD patients is “sundowning”, characterized by agitation, aggression, and wandering during the late afternoon and early evening. The neurobiology of sundowning remains unknown, but our lab has developed a working model for how disruption of circadian pathways in mice may lead to temporal disturbances relevant to sundowning. The SCN is known to regulate body temperature and locomotor activity rhythms by a pathway through its major postsynaptic target, the subparaventricular zone (SPZ). We recently showed that aggression propensity in mice also follows a daily rhythm regulated by the SCN and SPZ through a separate downstream pathway. Importantly, disrupting this pathway increases aggression around the active-to-rest phase transition, which is temporally analogous to when sundowning patients show agitation and aggression. AD-associated disruptions to the SCN, SPZ, or their input pathways, may thus lead to disturbances in body temperature, locomotor activity (in the form of wandering), and also sundowning-related aggression. To address potential mechanistic connections between AD-related pathology and circadian function, we conducted behavioral and neuroanatomical analyses in the TAPP mouse model of AD. We identified the lateral parabrachial nucleus (LPB) in the brainstem as a major site of pTau, found that the LPB projects to both the SCN and SPZ, and reveal strong evidence of a role for LPB pTau in AD-related circadian dysfunction and aggression. Here, we will test our hypotheses that the LPBàSCN/SPZ pathway is required for normal circadian function and that pTau in this pathway underlies AD- related circadian dysfunction and sundowning-related behavioral disturbances. We will use retrograde delivery of Cre recombinase from the SCN and SPZ, and Cre-dependent vectors in the LPB to specifically manipulate LPBàSCN/SPZ neurons. We will determine if chemogenetic manipulations of LPBàSCN/SPZ neurons acutely ameliorate or exacerbate circadian dysfunction and increased aggression in TAPP mice. We will also express the P301L mutation (and subsequently pTau) in only LPBàSCN/SPZ neurons in wild-type mice and in mice with high levels of a-beta to examine interactions between pTau and a-beta in this pathway. Finally, we will use Cre-mouse lines to target specific LPB subpopulations that differentially project to the circadian system to determine their respective roles in normal circadian function and pTau-related circadian dysfunction.

该项目的长期目标是了解昼夜节律的电路机制 阿尔茨海默氏病（AD）和阿尔茨海默氏病的功能障碍和相关的行为障碍 相关痴呆症（ADRD）。 ADRD与昼夜节律的进行性破坏有关， 与健康的老年匹配相比，包括体温，运动活性和其他节奏 控件。这表明与广告相关的病理改变了大师昼夜节奏起搏器的能力（ 下丘脑的核核，SCN），将这种节奏同步到每日的光黑暗周期。 大约20％的AD/ADRD患者中，昼夜节律功能障碍的一种特殊形式是“日落” 通过躁动，侵略和在午后和早期徘徊。神经生物学 日落仍然未知，但是我们的实验室已经开发了一个工作模型，以造成昼夜节律的破坏 小鼠的途径可能导致与日落有关的暂时灾难。已知SCN调节 通过其主要突触后靶标的途径，体温和运动活性节奏 子室内区（SPZ）。我们最近表明，小鼠的侵略性倾向也遵循每日 由SCN和SPZ通过单独的下游途径调节的节奏。重要的是，破坏了这一点 途径周围围绕活性到验证的相位跃迁提高了侵略性，这暂时类似于 日落时，患者表现出躁动和攻击。与SCN，SPZ或其相关的AD相关干扰 因此，输入途径可能会导致体温，运动活性的干扰（以 徘徊），以及与日落有关的侵略性。解决之间的潜在机械连接 与广告相关的病理学和昼夜节律功能，我们在行为和神经解剖学分析中进行了 AD的Tapp鼠标模型。我们确定脑干中的侧侧核核（LPB）是主要的 PTAU的现场发现，LPB向SCN和SPZ投射，并揭示了有力的作用证据 LPB PTAU与广告相关的昼夜节律功能障碍和侵略性。在这里，我们将测试我们的假设 正常的昼夜节律功能需要LPBàscn/spz途径，并且该途径中的PTAU是AD的基础 相关的昼夜节律功能障碍和与日落有关的行为灾难。我们将使用逆行交货 来自SCN和SPZ的CRE重组酶，以及LPB中CRE依赖的向量，以专门操纵 lpbàscn/spz神经元。我们将确定LPBàscn/spz神经元的化学发生操作是否敏锐 TAPP小鼠的改善或加重昼夜节律功能障碍并增加了侵略性。我们还将表达 仅在野生型小鼠中的LPBàscn/spz神经元中的P301L突变（以及随后的PTAU），在带有的小鼠中 高水平的A-beta检查该途径中PTAU和A-BETA之间的相互作用。最后，我们将使用 Cre-Mouse线以针对特定的LPB亚群，这些亚群将昼夜节律的指向不同 确定它们在正常的昼夜节律功能和与PTAU相关的昼夜节律功能障碍中的作用。