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背后的电路机制 阿尔茨海默病 (AD) 和阿尔茨海默病的功能障碍和相关行为障碍 相关痴呆症（ADRD）。 AD/ADRD 与昼夜节律的逐渐破坏有关， 与健康年龄匹配的人相比，包括体温、运动活动和其他节律 控制。这表明 AD 相关的病理学改变了主要昼夜节律起搏器（ 下丘脑的视交叉上核（SCN），使这种节律与日常明暗周期同步。 大约 20% 的 AD/ADRD 患者存在一种特殊形式的昼夜节律功能障碍，即“日落”，其特征是 下午晚些时候和傍晚早些时候，由于烦躁、攻击性和徘徊。神经生物学 日落仍然未知，但我们的实验室已经开发了一个工作模型来解释昼夜节律如何被破坏 小鼠体内的通路可能会导致与日落相关的时间紊乱。众所周知，SCN 可以调节 体温和运动活动节律通过通过其主要突触后目标的途径来调节 室旁区（SPZ）。我们最近表明，小鼠的攻击倾向也遵循每日行为 SCN 和 SPZ 通过单独的下游途径调节节律。重要的是，破坏这个 途径增加了围绕活动到休息阶段转变的攻击性，这在时间上类似于 当日落时，患者表现出焦躁和攻击性。 AD 相关的 SCN、SPZ 或它们的中断 输入途径，可能因此导致体温、运动活动的紊乱（以 徘徊），以及与日落相关的攻击行为。解决之间潜在的机械联系 AD相关的病理学和昼夜节律功能，我们进行了行为和神经解剖学分析 AD的TAPP小鼠模型。我们确定脑干中的外侧臂旁核（LPB）是一个主要的 pTau 站点，发现 LPB 投射到 SCN 和 SPZ，并揭示了强有力的证据表明 LPB pTau 在 AD 相关昼夜节律功能障碍和攻击行为中的作用。在这里，我们将检验我们的假设 LPBàSCN/SPZ 通路是正常昼夜节律功能所必需的，该通路中的 pTau 是 AD-的基础 相关的昼夜节律功能障碍和日落相关的行为障碍。我们将使用逆行递送 来自 SCN 和 SPZ 的 Cre 重组酶以及 LPB 中的 Cre 依赖性载体来特异性操作 LPBàSCN/SPZ 神经元。我们将确定 LPBàSCN/SPZ 神经元的化学遗传学操作是否会严重影响 改善或加剧 TAPP 小鼠的昼夜节律功能障碍并增加攻击性。我们也会表达 P301L 突变（以及随后的 pTau）仅存在于野生型小鼠和患有此病的小鼠的 LPBàSCN/SPZ 神经元中 高水平的 a-β 来检查该通路中 pTau 和 a-β 之间的相互作用。最后，我们将使用 Cre-小鼠系针对特定的 LPB 亚群，这些亚群差异性地投射到昼夜节律系统，以 确定它们在正常昼夜节律功能和 pTau 相关昼夜节律功能障碍中各自的作用。