Impact of Amyloid Beta on Hippocampal Neurophysiology and Calcium Activity across the Sleep-Wake Cycle

β 淀粉样蛋白对睡眠-觉醒周期中海马神经生理学和钙活性的影响

• 批准号: 9381672
• 负责人: Stephen N. Gomperts
• 金额: $ 41.63万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381672
• 关键词: Accounting; Acetylcholine; Action Potentials; Address; Affect; Alpha Rhythm; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Animals; Behavioral; Brain; Calcium; Cholinergic Receptors; Chronic; Circadian Rhythms; Clinical; Clinical Trials; Coupling; Data; Deposition; Electrophysiology (science); Event; Exploratory Behavior; FDA approved; Fire - disasters; Functional disorder; Goals; Grant; Head; Hippocampus (Brain); Image; Imaging technology; In Vitro; Individual; Interdisciplinary Study; Knowledge; Medial; Memory; Memory impairment; Microscope; Mus; Muscarinics; Neurons; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Play; Process; Property; Receptor Activation; Research; Research Personnel; Rest; Role; Services; Sleep; Sleep Wake Cycle; Slow-Wave Sleep; Symptoms; System; Techniques; Testing; Theta Rhythm; Wakefulness; beta-site APP cleaving enzyme 1; cholinergic; esterase; esterase inhibitor; experience; experimental study; falls; fluorophore; improved; in vivo; inhibitor/antagonist; insight; memory consolidation; memory encoding; microscopic imaging; mouse model; neurophysiology; new therapeutic target; overexpression; place fields; relating to nervous system

Understanding the relationship between A and memory dysfunction in Alzheimer’s disease remains an essential objective. Although animal models of Alzheimer’s that over-express the amyloid precursor protein show perturbed calcium in individual neurons, memory is fundamentally a neural systems property of the intact hippocampus, and how A impacts the integrity of neural systems calcium activity in the functioning hippocampus is unknown. During exploratory behavior, neurons represent space as place fields, coordinating their action potentials with the hippocampal theta oscillation, a rhythm dependent on acetylcholinergic (ACh) inputs from the medial septum; but during quiet wakefulness and slow wave sleep, ACh levels fall and theta is replaced with a physiological state in which neurons fire instead with sharp- wave ripple events. Given that ACh’s contribution to hippocampal function extends to Alzheimer’s, with ACh esterase inhibitors providing the mainstay of therapy and associated with significant improvements in memory, we hypothesize that the cholinergic system impacts the neurophysiological effects of A deposition, such that A’s effects on dynamic calcium activity in the functioning hippocampus will depend on hippocampal state and cholinergic tone across the sleep-wake cycle. In addition, since fluctuations in cytoplasmic calcium may derive both from neuronal depolarization and from calcium-induced calcium release, calcium activity may be an imperfect surrogate for electrophysiological activity. To address these issues, we will study (1) the relationship between neuronal calcium activity and hippocampal electrophysiology in freely behaving normal animals, (2) how this relationship is impacted by Ain two Alzheimer’s disease mouse models, and (3) how ACh impacts A's effects on calcium activity and action potentials. To investigate these aims, we will combine chronic electrophysiological techniques with newly available miniature microscope imaging technologies (Inscopix head mounted mini-microscope) and robust, genetically encoded calcium fluorophores (GCAMP6f). We will acquire local field potentials together with single unit recordings and calcium imaging of hippocampal neurons as A over-expressing mice and littermate controls perform a behavioral task and across their sleep-wake cycles. We will attempt to rescue A-associated abnormalities with a -secretase1 inhibitor now in clinical trials, and we will employ pharmacology to evaluate the impact of ACh on A’s effects on hippocampal physiology. Together, these efforts will establish the effects of Aon neuronal action potential activity and calcium activity across the sleep-wake cycle, providing key insights into Alzheimer’s disease and identifying new targets for its treatment.

了解阿尔茨海默氏病中A与记忆功能障碍之间的关系 仍然是一个基本的目标。尽管阿尔茨海默氏症的动物模型过表达 淀粉样蛋白前体蛋白在单个神经元中表现出钙的钙，记忆是 从根本上讲，完整海马的神经学特性，以及A如何影响 神经元系统钙活性在功能海马中的完整性尚不清楚。期间 探索性行为，神经元表示空间作为位置，协调其作用 海马theta振荡的电势，依赖于乙酰胆碱能的节奏（ACH） 内侧隔膜的输入；但是在安静的清醒和缓慢的睡眠期间，ACH水平 秋天和theta被一个物理状态所取代，在这种状态下，神经元以尖锐的形式开火 波浪连冠事件。鉴于ACH对海马功能的贡献扩展到 阿尔茨海默氏症，带有ACH酯酶抑制剂提供治疗的中流 记忆的显着改善，我们假设胆碱能系统影响 A沉积的神经生理作用，使A对动态钙活性的影响 功能性海马将取决于海马状态和胆碱能的张力 睡眠唤醒周期。另外，由于细胞质钙的波动可能从 神经元沉积和钙诱导的钙释放，钙活性可能是一种 电生理活性不完善的替代物。为了解决这些问题，我们将研究（1） 自由的神经元钙活性与海马电生理学之间的关系 表现正常的动物，（2）在两个阿尔茨海默氏病中，这种关系如何受到A的影响 小鼠模型，以及（3）ACH如何影响A对钙活性和动作电位的影响。 为了研究这些目标，我们将将慢性电生理技术与新的 可用的微型显微镜成像技术（Inscopix头安装的迷你微镜） 强大的，一般编码的钙荧光团（GCAMP6F）。我们将获得当地领域 电势以及海马神经元的单个单位记录和钙成像作为 A过表达的小鼠和同窝室控制执行行为任务，并跨越其 睡眠唤醒周期。我们将尝试用-分泌酶挽救与A相关的异常 抑制剂现在正在临床试验中，我们将采用药理学来评估ACH的影响 关于A对海马生理的影响。这些努力将共同确定 在整个睡眠效果周期中，在神经元动作的潜在活性和钙活性中， 提供有关阿尔茨海默氏病的关键见解，并确定其治疗的新目标。