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.

了解阿尔茨海默病中A β与记忆功能障碍的关系 仍然是一个重要目标。尽管阿尔茨海默氏症的动物模型过度表达了 淀粉样蛋白前体蛋白在单个神经元中显示出钙的扰动，记忆是 从根本上说，这是完整海马体的神经系统特性，以及海马体如何影响神经系统。 神经系统的完整性功能海马体中的钙活性是未知的。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θ振荡的电位，一种依赖于乙酰胆碱能（ACh）的节律 输入从内侧隔;但在安静的觉醒和慢波睡眠，ACh水平 下降和θ被一种生理状态所取代，在这种状态下，神经元以尖锐的- 波浪涟漪事件考虑到乙酰胆碱对海马功能的贡献， 阿尔茨海默氏症，乙酰胆碱酯酶抑制剂提供了治疗的主要手段， 记忆力的显著改善，我们假设胆碱能系统影响了 A β沉积的神经生理学效应，例如A β对动态钙活性的影响， 海马体的功能将取决于海马体的状态和整个大脑中的胆碱能张力。 睡眠-觉醒周期此外，由于细胞质钙的波动可能来自于 神经元去极化和钙诱导的钙释放，钙活性可能是一个 电生理活动的不完美替代物。为了解决这些问题，我们将研究（1） 海马神经元钙活性与海马电生理关系 行为正常的动物，（2）这种关系是如何影响在两个阿尔茨海默病的A β （3）ACh如何影响A β对钙活性和动作电位的影响。 为了研究这些目标，我们将联合收割机慢性电生理技术与新的 可用的微型显微镜成像技术（Insopix头戴式微型显微镜） 和鲁棒的、遗传编码的钙荧光团（GCAMP 6 f）。我们将收购当地油田 电位与单个单位记录和海马神经元钙成像， 一个过表达的小鼠和同窝对照小鼠执行一项行为任务，并在其整个实验过程中， 睡眠-觉醒周期我们将尝试用β-分泌酶来挽救A β相关的异常。 现在在临床试验中，我们将采用药理学来评估ACh的影响 对海马体生理学的影响总之，这些努力将建立以下效果： 一项关于睡眠-觉醒周期中神经元动作电位活动和钙活动的研究， 为阿尔茨海默病提供关键的见解，并确定其治疗的新靶点。