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

项目概要/摘要 阿尔茨海默氏病和相关的痴呆症与昼夜节律的进行性破坏有关。 AD和相关痴呆患者的这种昼夜节律功能障碍的一个特殊特征是“日落 综合征”，一种以激越、攻击和谵妄为特征的临床现象， 在傍晚时分。这些症状对患者的生活质量有重大影响， 和他们的照顾者，往往导致决定寻求机构。日落的神经生物学 目前尚不清楚，但日落症状的时间周期性表明可能存在干扰 在主生物钟中，下丘脑的视交叉上核（SCN），或在通过 SCN调节特定的节奏。已知睡眠-觉醒和LMA的节律由以下因素调节： SCN通过其主要的突触后靶点室旁下区（SPZ）， 下丘脑背内侧核（DMH）。此外，我最近证明，行为倾向 攻击也遵循由SCN调节的每日节律，通过额外的途径， SPZ，腹内侧下丘脑（VMH）。重要的是，破坏这种SCN + SPZ + VMH途径导致了 在早期休息阶段（夜间小鼠的光照期）增加攻击性， 类似于当经历日落的AD和痴呆患者显示出增加的激动， 侵略这表明，在AD中，该回路中某些结构的功能可能受到损害 和痴呆，并且该途径可能是治疗昼夜节律功能障碍的有希望的治疗靶点 和攻击性的症状为了验证这个新的假设，我开始研究昼夜节律， TAPP小鼠模型中的节律，该模型产生淀粉样β（α-β）斑块和tau神经元损伤。 缠结（AD神经病理学的标志），我的初步结果表明，这些小鼠表现出 在他们第一次发育后不久，增加了早期休息期的攻击性和钝化了活跃期的LMA AD相关神经病理学。在这个提议中，我将检查这些小鼠的组织， SCN、SPZ及其输出中的神经病理学标记物靶向VMH和DMH。已经 假设与日落有关的昼夜节律功能障碍是由AD相关的 干扰向昼夜节律系统提供输入的区域，如胆碱能和胆碱能 通路，我也将研究这些领域的神经病理学。此外，我还将检查激活的 星形胶质细胞在所有这些昼夜节律途径中，因为已经显示这种胶质反应与 AD中的神经炎症和神经变性，并且已知正常星形胶质细胞功能对AD的神经炎症和神经变性至关重要。 昼夜节律系统保持正确时间的能力。最后，我试图确定 操纵SPZ活性（使用化学发生激活）增加白天的攻击和钝化 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.