Cellular Mechanism underlying emotional problems of Alzheimer's disease

阿尔茨海默病情绪问题的细胞机制

• 批准号: 10159839
• 负责人: Meng Liu
• 金额: $ 18.69万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159839
• 关键词: APP-PS1; Affect; Age; Aggressive behavior; Agitation; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amygdaloid structure; Animal Disease Models; Behavior; Behavioral; Biological Markers; Brain; Brain Pathology; Calcium; Caregiver Burden; Cells; Characteristics; Chemosensitization; Clinical Research; Cognitive deficits; Control Groups; Custom; Data; Data Analyses; Dementia; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Distress; Emotional; Emotions; Exposure to; Functional Magnetic Resonance Imaging; Future; Generations; Genetic; Genetic Engineering; Glutamates; Goals; Grooming; Hyperactivity; Image; Imaging Device; Impaired cognition; Impairment; Individual; Information Networks; Intervention; Knowledge; Life; Link; Mediating; Memory Loss; Mental Depression; Mus; Neurons; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Phenotype; Positron-Emission Tomography; Prefrontal Cortex; Protocols documentation; REM Sleep; Regulation; Research; Resolution; Role; Severities; Site; Sleep; Sleep Deprivation; Sleep disturbances; Structure; Symptoms; Tail Suspension; Testing; Therapeutic; Therapeutic Effect; base; behavior test; care giving burden; crosslink; effective therapy; emotion regulation; emotional symptom; experience; feasibility testing; hypocretin; improved; in vivo; mouse model; neuromechanism; neuropathology; neuropsychiatric symptom; neuropsychiatry; non rapid eye movement; novel; psychological symptom; real-time images; receptor; relating to nervous system; response; sensor; sex; spectrograph; tool; vector

Abstract The ability to regulate emotions is a critical aspect of our adaptive functioning. Caused by abnormal emotional regulation, neuropsychiatric symptoms (NPSs)--agitation, aggression, apathy, depression, etc., are the primary component of the “non-cognitive” symptoms of Alzheimer’s Disease (AD), which bring colossal caregiving burden and significantly reduce the quality of AD patients. So far, there is no safe and effective pharmacological nor non-pharmacological management for these emotional problems. Prescribed psychiatric drugs currently available may not work in AD because of its unique brain pathology and the unclear underlying mechanism. Substantial clinical studies suggested that the amygdala (AMY) and the prefrontal cortex (PFC) might be two pivotal sites mediating NPSs in AD. However, the circuitry and cellular abnormalities involved have yet to be determined, which are vital knowledge for developing therapeutic strategies for AD’s NPSs. In the meantime, “sundowning,” a feature of AD describing an increase in agitated behavior in the evening, indicates that sleep disruption is closely related to poor emotion processing in AD. Our overall hypothesis is that the abnormal hypo- or hyper-activity of specific AMY or PFC neurons resulting from AD pathology directly or indirectly, causes NPSs in AD. Increasing sleep can antagonize these abnormalities, thus alleviate NPSs of AD. To test it, we propose to probe the activity dynamic from individual GABAergic or glutamatergic neurons in freely moving AD mice with deep-brain calcium imaging tools. Genetically engineered AD mice models (VGAT- Cre/APP/PS1 and VGLUT2-Cre/APP/PS1) are ready in our facility for targeting these neurons. Apathy (nest construction, grooming, and exposure to opposite-sex conspecifics), aggression (resident-intruder paradigm), and depression (tail suspension) behavior will be tested to manifest NPSs. Furthermore, we will examine the effect of sleep potentiation on NPSs severity and neuronal activities. Neuronal hyperactivity is becoming an emerging biomarker of AD cognitive deficit. Sleep is becoming a promising intervention to reduce AD neuropathology. Our first goal is to identify the functional biomarker of NPSs of AD. Our second goal is to determine if increasing sleep could improve NPSs by affecting these biomarkers. Results from this proposal will deepen the understanding of the neural substrate underlying NPSs of AD, and therefore, inspire novel treatments.

摘要 调节情绪的能力是我们适应能力的一个关键方面。情绪异常所致 规则，神经精神症状(NPSS)--激越、攻击、冷漠、抑郁等是主要的 阿尔茨海默病(AD)“非认知”症状的组成部分，会带来巨大的护理负担 并显著降低AD患者的素质。到目前为止，还没有安全有效的药理或药物 对于这些情绪问题的非药物治疗。现时处方的精神科药物 由于其独特的大脑病理和不清楚的潜在机制，可用药可能在AD中不起作用。 大量的临床研究表明，杏仁核(AMY)和前额叶皮质(PFC)可能是两个 AD中调节NPSS的关键部位。然而，所涉及的电路和细胞异常尚未得到证实。 这些知识对于开发AD的NPSS的治疗策略是至关重要的。与此同时， “日落”是AD的一个特征，描述的是晚上烦躁不安的行为增加，这表明睡眠 阿尔茨海默病患者的情绪障碍与情绪加工不良密切相关。我们的总体假设是，反常的 直接或间接由AD病理引起的特异性AMY或PFC神经元的低或高活动 间接导致AD中的NPSS。增加睡眠可以对抗这些异常，从而缓解NPSS 公元一代的。为了测试它，我们建议探索单个GABA能或谷氨酸能神经元的活动动态 在自由活动的阿尔茨海默病小鼠中使用脑深部钙成像工具。遗传工程AD小鼠模型(VGAT- Cre/APP/PS1和VGLUT2-CRE/APP/PS1)已经准备好在我们的设施中靶向这些神经元。冷漠(巢) 构建、修饰和接触异性同种特质)、攻击性(居民-入侵者范式)、 并将测试抑郁(尾部悬挂)行为，以体现NPSS。此外，我们还将研究 睡眠增强对NPSS严重程度和神经元活动的影响。神经元过度活跃正在成为一种 阿尔茨海默病认知缺陷的新兴生物标志物。睡眠正在成为减少阿尔茨海默病的一种有希望的干预措施 神经病理学。我们的第一个目标是确定AD患者NPSS的功能生物标记物。我们的第二个目标是 确定增加睡眠是否可以通过影响这些生物标志物来改善NPSS。这项提案的结果将是 加深对阿尔茨海默病NPSS的神经基础的理解，从而启发小说 治疗。