Parsing the pathways of circadian dysfunction and sundowning-related behavioral aggression in dementia and Alzheimer's disease

项目摘要/摘要 阿尔茨海默病和相关的痴呆症与进行性的昼夜节律紊乱有关。 阿尔茨海默病和相关痴呆症患者的这种昼夜节律紊乱的一个特殊特征是“日落” 综合征“，一种鲜为人知的临床现象，以激越、攻击性和精神错乱为特征 在傍晚时分。这些症状对两位患者的生活质量都有重大影响 以及他们的照顾者，往往导致他们决定寻求机构安置。日落的神经生物学 尚不清楚，但日落症状的时间周期表明可能存在干扰 在昼夜节律主钟中，下丘脑的视交叉上核(SCN)或通过 其中SCN调节特定的节奏。众所周知，睡眠-觉醒和LMA的节律受 SCN通过其主要突触后靶点--室旁区(SPZ)到达 背内侧下丘脑(DMH)。此外，我最近证明了行为倾向 攻击性也遵循由SCN调节的日常节律，通过额外的途径通过 下丘脑腹内侧核(VMH)。重要的是，破坏SCNSPZVMH途径导致 在早期休眠阶段(夜间小鼠的光照阶段)，攻击性增加，这是暂时的 类似于当经历日落的AD和痴呆症患者表现出更多的焦虑和 攻击性。这表明在AD中，该回路内的某些结构的功能可能受到损害 这一途径可能是治疗昼夜节律紊乱的一个有前途的治疗靶点。 以及表现出日落的病人的攻击性。为了验证这一新颖的假设，我开始研究昼夜节律。 TAPP小鼠模型的节律，该模型形成淀粉样β蛋白(a-beta)斑块和tau神经原纤维 唐尔斯(AD神经病理学的两个特征)，我的初步结果表明，这些小鼠表现出 初发年龄早期静止期攻击性和钝化活动期LMA增加 与AD相关的神经病理学。在这项提案中，我将检查这些小鼠的组织是否与AD有关 SCN、SPZ及其输出的神经病理标记物以VMH和DMH为靶点。一直以来 假设昼夜节律失调与日落有关，而不是与AD相关 对为昼夜节律系统提供输入的区域的干扰，如5-羟色胺能和胆碱能 路径，我还将研究这些区域的神经病理学。此外，我还将检查已激活 星形胶质细胞在所有这些昼夜节律的通路中，因为这种神经胶质反应已经被证明与 阿尔茨海默病的神经炎症和神经变性，以及正常的星形胶质细胞功能被认为是至关重要的 昼夜节律系统维持适当时间的能力。最后，我试图确定 控制SPZ的活动(使用化学激活)应对日间攻击和钝化的增加 TAPP小鼠的昼夜睡眠-觉醒节律，以及神经病理学和星形胶质细胞反应的模式。

Project Summary/Abstract Alzheimer's disease and related dementias are associated with progressive disruption of circadian rhythms. One particular feature of such circadian dysfunction in patients with AD and related dementias is “sundowning syndrome”, a poorly understood clinical phenomenon characterized by agitation, aggression, and delirium during the early evening hours. Such symptoms have a major impact on the quality of life for both the patient and their caregivers and often lead to the decision to seek institutionalization. The neurobiology of sundowning remains unknown, however the temporal periodicity of sundowning symptoms suggests a possible disturbance in the master circadian clock, the suprachiasmatic nucleus (SCN) of the hypothalamus, or in the pathways by which the SCN modulates particular rhythms. Rhythms of sleep-wake and LMA are known to be regulated by the SCN via a pathway through its major postsynaptic target, the subparaventricular zone (SPZ), to the dorsomedial hypothalamus (DMH). Additionally, I recently demonstrated that the propensity for behavioral aggression also follows a daily rhythm that is regulated by the SCN, via an additional pathway through the SPZ, to the ventromedial hypothalamus (VMH). Importantly, disrupting this SCNSPZVMH pathway led to increased aggression during the early resting phase (the light period for nocturnal mice), which is temporally analogous to when AD and dementia patients who experience sundowning display increased agitation and aggression. This suggests that the function of certain structures within this circuit may be compromised in AD and dementia, and that this pathway may be a promising therapeutic target for treating circadian dysfunction and aggression in patients who display sundowning. To test this novel hypothesis, I began examining circadian rhythms in the TAPP mouse model, which develops amyloid-beta (a-beta) plaques and tau neurofibrillary tangles (both hallmarks of AD neuropathology), and my preliminary results suggest that these mice exhibit increased early resting period aggression and blunted active period LMA at ages shortly after they first develop AD-related neuropathology. In this proposal, I will examine tissue from these mice for AD-related neuropathological markers in the SCN, the SPZ and its output targets the VMH and the DMH. It has been hypothesized that circadian dysfunction associated with sundowning results instead from AD-related disturbances to areas that provide input to the circadian system, such as serotoninergic and cholinergic pathways, and I will also examine neuropathology in such areas. Additionally, I will also examine activated astrocytes in all of these circadian pathways, as such glial responses have been show to be associated with neuroinflammation and neurodegeneration in AD, and normal astrocyte functioning is known to be critical to the circadian system's ability to maintain proper time-keeping. Finally, I seek to determine the effects of manipulating SPZ activity (using chemogenetic activation) on the increased daytime aggression and blunted circadian sleep-wake rhythms in TAPP mice, and on the patterns of neuropathology and astrocyte responses.