Circadian behavior circuits, Alzheimer’s pathology, chemogenetic output and input

昼夜节律行为回路、阿尔茨海默病病理学、化学遗传学输出和输入

• 批准号: 10214051
• 负责人: William David Todd
• 金额: $ 20.18万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10214051
• 关键词: Affect; Age; Aggressive behavior; Agitation; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-Protein; Area; Behavior; Behavioral; Biology; Caregivers; Cells; Centers of Research Excellence; Circadian Dysregulation; Circadian Rhythms; Clinical; Delirium; Exhibits; Hour; Hypothalamic structure; Light; Motor Activity; Mus; Neurobiology; Neurons; Output; Pathway interactions; Patients; Pattern; Periodicity; Phase; Photosensitivity; Quality of life; Rest; Resting Phase; Retina; Retinal Ganglion Cells; Sensory; Sleep; Structure; Symptoms; Syndrome; System; Testing; Work; Wyoming; brain tissue; cholinergic; circadian; circadian pacemaker; experience; improved; male; melanopsin; neuropathology; novel; postsynaptic; suprachiasmatic nucleus; tau Proteins; tau aggregation; tetra-4-amidinophenoxypropane; therapeutic target

Alzheimer’s disease (AD) and related dementias are associated with progressive disruption of circadian rhythms. One particular feature of 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. The neurobiology of sundowning remains unknown, however the temporal periodicity of it 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. Intrinsically photosensitive retinal ganglion cells (RGCs), that express the photopigment melanopsin, project to the SCN via the retinohypothalamic tract (RHT) and entrain its activity the daily lightdark cycle. Dr. Clifford Saper’s lab has shown that sleep-wake and locomotor activity (LMA) rhythms are regulated by the SCN via a pathway through its major postsynaptic target, the subparaventricular zone (SPZ), to the dorsomedial hypothalamus (DMH). More recently, my work postdoctoral work in Dr. Saper’s lab revealed that aggression propensity in male mice also follows a daily rhythm that is regulated by GABAergic SPZ neurons. This work further demonstrated that these SPZGABA neurons receive functional input from the SCN, are active in a phase-dependent manner, and project to neurons within the ventromedial hypothalamus (VMH) that drive attack behavior, altogether suggesting a novel pathway by which the central circadian clock gates aggression propensity across the 24h day. Importantly, I found that disrupting the 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 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 related dementias, and that this pathway may be a promising therapeutic target for treating circadian dysfunction and aggression in patients who display sundowning. I began testing this hypothesis by examining circadian rhythms in TAPP mice (also known as APPSwe-Tau), which develop amyloid-beta (a-beta) plaques and tau neurofibrillary tangles (both hallmarks of AD neuropathology). I found that these mice exhibit increased early resting period aggression and blunted active period LMA at ages shortly after they are known to develop AD-related neuropathology. In this proposal, I seek to expand on this work by examining brain tissue from these mice for a-beta and tau in the SCN, the SPZ, and their output targets the VMH and the DMH. It has been hypothesized that circadian dysfunction associated with sundowning may instead result from AD-related disturbances to areas that provide input to the circadian system, such as serotoninergic and cholinergic pathways, and I will also examine AD-related neuropathology in such areas. I will also assess cell loss in all of these pathways, as well as in the retina (specifically RGCs that project to and entrain the SCN). Finally, I seek to determine the effects of manipulating SPZ and RGC activity (using chemogenetic activation) on increased aggression and blunted circadian sleep-wake rhythms in TAPP mice, and on the patterns of AD neuropathology. While sundowning is an important clinical problem, there has been little work focused on how the circadian system effects agitation and aggression, and almost none on how such circuits are affected by AD. Interrogating such circuits, and determining whether manipulation of their neuronal activity can ameliorate AD-related behavioral disturbances in mice, may point to an eventual therapy that could greatly improve quality of life for AD patients and their caregivers.

阿尔茨海默氏病（AD）和相关痴呆症与昼夜节律的进行性破坏有关。昼夜节律功能障碍在AD和相关痴呆症患者中的一个特征是“日落综合征”，这是一种鲜为人知的临床现象，其特征是在傍晚傍晚时分搅动，侵略和妄想。日落的神经生物学仍然未知，但是IT症状的暂时周期性表明，昼夜节律钟表，下丘脑的核上核核（SCN）或SCN调节特定节奏的途径。表达光化黑色素蛋白的本质上光敏性视网膜神经节细胞（RGC）通过视网膜丘脑图（RHT）投射到SCN，并在每日Lightdark循环中进入其活性。克利福德·萨珀（Clifford Saper）博士的实验室表明，睡眠效果和运动活性（LMA）节奏通过SCN通过途径通过其主要突触后靶向区域（SPZ）来调节，向背侧中型下丘脑（DMH）调节。最近，我在Saper博士实验室的博士后工作表明，雄性小鼠的侵略性承诺也遵循每日的节奏，该节奏受GABA能SPZ神经元的调节。这项工作进一步表明，这些SPZGABA神经元从SCN接收功能输入，以相位依赖性的方式活跃，并将其投影到腹膜下丘脑（VMH）内的神经元，从而驱动攻击行为，从而驱动攻击行为，这表明了一种新颖的途径，这是一种新的途径，中央昼夜节律的循环钟进行了24小时的侵略性。 Importantly, I found that disrupting the SCN SPZ VMH pathway led to increased aggressiveness during the early resting phase (the light period for nocturnal mice), This suggests that the function of certain structures within this circuit may be compromised in AD and related dementias, and that this pathway may be a promising therapeutic target for treating circadian dysfunction and aggressive in patients who display sundown.我开始通过检查TAPP小鼠（也称为Appswe-tau）中的昼夜节律来检验这一假设，这些小鼠会发展出淀粉样蛋白β（A-BETA）斑块和Tau神经纤维纤维缠结（AD Neuroparoparology的标志）。我发现，这些小鼠在众所周知，这些小鼠在发展与广告相关的神经病理学后不久，在年龄段就增加了早期休息期。在此提案中，我试图通过检查SCN，SPZ中的A-Beta和Tau的这些小鼠的脑组织来扩展这项工作，而SPZ及其输出靶向VMH和DMH。据推测，与日落降落相关的昼夜节律功能障碍可能是由于广告相关的灾难而引起的，这些灾难是为昼夜节律系统提供输入的区域，例如5-羟色胺能和胆碱能途径，我还将检查这些领域中与广告相关的神经病理学。我还将评估所有这些途径以及视网膜中的细胞损失（特别是投射到SCN的RGC）。最后，我试图确定操纵SPZ和RGC活性（使用化学激活）对TAPP小鼠中攻击性和蓝色昼夜节律睡眠节奏的影响以及AD神经病理学的模式。尽管日落是一个重要的临床问题，但很少有工作重点是昼夜节律如何影响搅动和攻击性，几乎没有任何事情都涉及该电路如何受到AD的影响。询问此类电路，并确定对其神经元活性的操纵是否可以改善小鼠与广告相关的行为障碍，这可能指出事件疗法可以极大地改善AD患者及其护理人员的生活质量。