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

了解A-与阿尔茨海默病记忆功能障碍的关系 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 淀粉样前体蛋白显示单个神经元中钙离子被扰乱，记忆是 从根本上说，这是完整海马体的神经系统特性，以及如何影响 神经系统在正常工作的海马体中钙活动的完整性尚不清楚。在.期间 探索行为，神经元将空间表示为位场，协调它们的行动 海马theta振荡的电位，这是一种依赖于乙酰胆碱能(ACh)的节律 从内侧隔传入；但在安静觉醒和慢波睡眠时，ACh水平 坠落和theta被一种生理状态取代，在这种状态下，神经元用尖锐的- 波纹事件。鉴于ACh对海马区功能的贡献延伸到 阿尔茨海默氏症，乙酰胆碱酯酶抑制剂是治疗的主要药物，与 记忆的显著改善，我们假设胆碱能系统影响 A沉积的神经生理效应，如A‘S对大鼠心肌细胞动态钙活动的影响 海马体的功能将取决于海马区的状态和胆碱能张力。 睡眠-觉醒循环。此外，由于细胞质钙的波动可能源于 神经元去极化和钙诱导的钙释放，钙活动可能是一种 电生理活动的替代物不完美。为了解决这些问题，我们将研究(1) 大鼠海马神经元钙活动与电生理的关系 表现正常的动物，(2)在两个阿尔茨海默病患者中，这种关系如何受到的影响 (3)ACh如何影响A的S对钙活性和动作电位的影响。 为了研究这些目标，我们将结合慢性电生理技术和新的 可用的微型显微镜成像技术(Inscope ix头戴式微型显微镜) 和强大的，基因编码的钙荧光团(GCAMP6f)。我们将收购当地的油田 海马神经元的电位结合单位记录和钙成像 过表达的小鼠和产仔对照组执行行为任务，并跨越它们的 睡眠-觉醒周期。我们将尝试用-Secrease1挽救相关异常 抑制剂目前正在进行临床试验，我们将利用药理学来评估ACh的影响 论A‘S对海马区生理的影响。综合起来，这些努力将建立起 关于睡眠-觉醒周期中神经元动作电位活动和钙活动的， 为阿尔茨海默病提供关键的见解，并为其治疗确定新的靶点。

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.