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.

阿尔茨海默病 (AD) 和相关痴呆症与昼夜节律的逐渐破坏有关。 AD 和相关痴呆症患者昼夜节律功能障碍的一个特殊特征是“日落综合症”，这是一种人们知之甚少的临床现象，其特征是傍晚时分的烦躁、攻击性和谵妄。日落的神经生物学仍然未知，但其症状的时间周期性表明主生物钟、下丘脑的视交叉上核 (SCN) 或 SCN 调节特定节律的途径可能出现紊乱。本质上感光的视网膜神经节细胞 (RGC) 表达感光色素黑视蛋白，通过视网膜下丘脑束 (RHT) 投射到 SCN，并在每日明暗周期中带动其活动。 Clifford Saper 博士的实验室表明，睡眠-觉醒和运动活动 (LMA) 节律由 SCN 通过其主要突触后目标室旁区 (SPZ) 到达下丘脑背内侧 (DMH) 的通路进行调节。最近，我在 Saper 博士实验室的博士后工作表明，雄性小鼠的攻击倾向也遵循由 GABA 能 SPZ 神经元调节的日常节律。这项工作进一步证明，这些 SPZGABA 神经元接收来自 SCN 的功能输入，以相位依赖的方式活跃，并投射到下丘脑腹内侧 (VMH) 内驱动攻击行为的神经元，这完全表明了中央生物钟在 24 小时内控制攻击倾向的新途径。重要的是，我发现扰乱 SCN·SPZ·VMH 通路会导致早期休息阶段（夜间活动的小鼠的光照期）的攻击性增加，这在时间上类似于经历日落的患者表现出增加的激动和攻击性。这表明该回路内某些结构的功能可能在 AD 和相关痴呆症中受到损害，并且该通路可能是治疗昼夜节律功能障碍和表现出日落的患者攻击性的有希望的治疗靶点。我开始通过检查 TAPP 小鼠（也称为 APPSwe-Tau）的昼夜节律来检验这一假设，这些小鼠会形成淀粉样β (a-beta) 斑块和 tau 神经原纤维缠结（这都是 AD 神经病理学的标志）。我发现这些小鼠在已知患有 AD 相关神经病理学后不久，就表现出早期休息期攻击性增加和活跃期 LMA 减弱。在本提案中，我试图通过检查这些小鼠的脑组织 SCN、SPZ 中的 a-beta 和 tau 蛋白来扩展这项工作，并且它们的输出针对 VMH 和 DMH。据推测，与日落相关的昼夜节律功能障碍可能是由于与 AD 相关的对昼夜节律系统提供输入的区域（例如血清素能和胆碱能通路）的干扰所致，我还将检查这些区域中与 AD 相关的神经病理学。我还将评估所有这些途径以及视网膜（特别是投射到并夹带 SCN 的 RGC）中的细胞损失。最后，我试图确定操纵 SPZ 和 RGC 活性（使用化学遗传学激活）对 TAPP 小鼠攻击性增加和昼夜节律睡眠-觉醒节律减弱以及 AD 神经病理学模式的影响。虽然日落是一个重要的临床问题，但很少有研究关注昼夜节律系统如何影响躁动和攻击性，而且几乎没有研究关注这种回路如何受到 AD 的影响。探究这些回路，并确定操纵其神经元活动是否可以改善小鼠中 AD 相关的行为障碍，可能会指出一种最终的治疗方法，可以极大地改善 AD 患者及其护理人员的生活质量。