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

解析痴呆症和阿尔茨海默病中昼夜节律功能障碍和日落相关行为攻击的途径

• 批准号: 10076507
• 负责人: William David Todd
• 金额: $ 14.45万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10076507
• 关键词: Affect; Age; Aggressive behavior; Agitation; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-Protein; Area; Astrocytes; Behavior; Behavioral; Caregivers; Cells; Circadian Dysregulation; Circadian Rhythms; Clinical; Delirium; Dementia; Exhibits; Female; Functional disorder; Glial Fibrillary Acidic Protein; Hour; Hypothalamic structure; Immunohistochemistry; Injections; Institutionalization; Lead; Ligands; Light; Measures; Motor Activity; Mus; Nerve Degeneration; Neurobiology; Neurons; Output; Pathway interactions; Patients; Pattern; Periodicity; Peripheral; Phase; Postdoctoral Fellow; Quality of life; Rest; Resting Phase; Sleep; Structure; Symptoms; Syndrome; System; Testing; Time; Tissues; Viral Vector; Work; brain pathway; cholinergic; circadian; circadian pacemaker; experience; immunohistochemical markers; improved; male; mouse model; neuroinflammation; neuropathology; novel; postsynaptic; relating to nervous system; response; suprachiasmatic nucleus; tau Proteins; tau aggregation; tetra-4-amidinophenoxypropane; therapeutic target

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.

项目总结/文摘