Cellular Mechanism underlying emotional problems of Alzheimer's disease

摘要 调节情绪的能力是我们适应性功能的一个重要方面。异常情绪引起的 调节，神经精神症状（NPS）-激动，攻击，冷漠，抑郁等，是第一 阿尔茨海默病（AD）的“非认知”症状的组成部分，这给患者带来了巨大的负担 并显著降低AD患者的质量。到目前为止，还没有安全有效的药物， 这些情绪问题的非药物管理。精神科药物目前 由于其独特的脑病理学和不清楚的潜在机制，现有的治疗方法可能对AD无效。 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 在AD中介导NPSs的关键位点。然而，涉及的电路和细胞异常还没有被发现。 确定，这是开发AD的NPSs治疗策略的重要知识。与此同时， “日落”是AD的一个特征，描述了晚上焦虑行为的增加，表明睡眠 中断与AD中不良的情绪处理密切相关。我们的总体假设是 直接由AD病理导致的特定AMY或PFC神经元的低活性或高活性， 间接导致AD的NPSs。增加睡眠可以对抗这些异常，从而减轻NPSs 的AD。为了验证这一点，我们建议探测单个GABA能或谷氨酸能神经元的活动动力学 在自由活动的AD小鼠中使用脑深部钙成像工具。基因工程AD小鼠模型（VGAT-100） Cre/APP/PS1和VGLUT 2-Cre/APP/PS1）在我们的设施中已经准备好靶向这些神经元。冷漠（巢 建设，梳理，并暴露于异性同种），侵略（居民入侵者范式）， 和抑郁（尾部悬挂）行为将被测试以显示NPS。此外，我们将研究 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 AD认知缺陷的新兴生物标志物。睡眠正在成为减少AD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的NPSs的功能生物标志物。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NPS。该提案的结果将 加深了对AD的NPSs的神经基质的理解，因此，激发了新的 治疗。

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.