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 A 与阿尔茨海默氏病记忆功能障碍之间的关系 仍然是一个基本目标。尽管阿尔茨海默病的动物模型过度表达 淀粉样蛋白前体蛋白显示单个神经元中的钙受到干扰，记忆力下降 从根本上讲，这是完整海马体的神经系统特性，以及 A 如何影响 功能海马体中神经系统钙活性的完整性尚不清楚。期间 探索行为，神经元将空间表示为位置场，协调它们的行动 海马 theta 振荡的电位，一种依赖于乙酰胆碱能 (ACh) 的节律 来自内侧隔膜的输入；但在安静清醒和慢波睡眠期间，乙酰胆碱水平 下降和θ被生理状态所取代，其中神经元以尖锐的方式放电 波涟漪事件。鉴于 ACh 对海马功能的贡献延伸至 阿尔茨海默病，乙酰胆碱酯酶抑制剂提供了主要治疗方法，并与 记忆力显着改善，我们假设胆碱能系统影响 A 沉积的神经生理学影响，例如 A 对动态钙活性的影响 海马体的功能取决于海马体的状态和胆碱能张力 睡眠-觉醒周期。此外，由于细胞质钙的波动可能来源于 神经元去极化和钙诱导的钙释放，钙活性可能是 电生理活动的不完美替代品。为了解决这些问题，我们将研究（1） 神经元钙活性与海马电生理的关系 行为正常的动物，(2) 在两种阿尔茨海默氏病中，A如何影响这种关系 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，我们将把慢性电生理学技术与新的技术相结合。 可用的微型显微镜成像技术（Inscopix 头戴式微型显微镜） 以及强大的基因编码钙荧光团 (GCAMP6f)。我们将收购当地油田 电位连同海马神经元的单个单元记录和钙成像 A 过度表达的小鼠和同窝对照小鼠执行一项行为任务并跨越其 睡眠-觉醒周期。我们将尝试用 -分泌酶 1 来挽救 A 相关异常 抑制剂现已进入临床试验，我们将利用药理学来评估 ACh 的影响 A 对海马生理学的影响。这些努力共同将产生以下效果： A关于整个睡眠-觉醒周期的神经元动作电位活动和钙活动， 提供有关阿尔茨海默病的重要见解并确定其治疗的新目标。