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: 9916679
• 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/9916679
• 关键词: Accounting; Acetylcholine; Action Potentials; Address; Affect; Alpha Rhythm; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Animals; Behavioral; Brain; Calcium; Cholinergic Receptors; Chronic; Clinical; Clinical Trials; Coupling; Data; Deposition; Diurnal Rhythm; 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; 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与阿尔茨海默病记忆功能障碍之间的关系