Neuronal Activity in Sleep & Wake in Alzheimer's Disease Mice

睡眠中的神经元活动

• 批准号: 10723302
• 负责人: Priyattam J. Shiromani
• 金额: $ 15.75万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723302
• 关键词: Acetylcholine; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Area; Arousal; Behavior; Binding; Brain; Brain Diseases; Brain imaging; Budgets; Calcium; Cells; Color; Cre driver; Data; Disease; Disease Progression; Disease model; Dopamine; Female; Fluorescence; Funding; Goals; Histamine; Hypothalamic structure; Image; Lateral; Methods; Monitor; Mus; Neurons; Neurosciences; Norepinephrine; Pattern; Phenotype; Population; Positioning Attribute; REM Sleep; Research Personnel; Serotonin; Sleep; Sleep Deprivation; Sleep disturbances; Technical Expertise; Testing; Time; awake; brain cell; calcium indicator; design; falls; gamma-Aminobutyric Acid; hypocretin; imaging approach; male; microendoscopy; mouse model; network models; neural; neuronal patterning; new technology; non rapid eye movement; promoter; redshift; response; sensor; virtual; zona incerta

The deep-brain imaging approach (microendoscopy) is a high throughput method that identifies the temporal and spatial pattern of activity in specific phenotypes of neurons. We have hypothesized that activity in small networks can identify normal versus diseased brains. To test this hypothesis, we will use the two-wavelength miniscope to image activity of a subset of neurons in 5xFAD mice, a validated animal model of Alzheimer’s disease (normal versus the homozygous littermates). We have created promoter- driven calcium sensor that drives the red-shifted calcium indicator, jRGECO, into orexin-arousal neurons. A separate calcium sensor (GCaMP6m) in GABA sleep neurons will be used as comparison. The advantage of imaging neurons with two different wavelengths is that it allows for comparison of arousal versus sleep neurons as the brain transitions between wake and sleep. We will image activity of neurons that contain jRGECO and GCaMP during normal wake-sleep bouts and after 6h sleep loss. We hypothesize that there is an abnormal temporal pattern of fluorescence during the transition from wake to sleep in the brains of 5xFAD mice, and it worsens with progression of disease. This may explain the cause of the disrupted sleep-wake patterns in Alzheimer’s disease. We hypothesize that abnormal activity in deep brain circuits regulating sleep is a harbinger of disease. The overall impact of this small budget project is that it will identify activity of two different juxtapositioned neurons during wake, NREM and REM sleep in wildtype versus a disease model, which will aid in understanding how small clusters of neurons behave as the waking brain falls asleep.

深部脑成像方法（显微内窥镜检查）是一种高通量方法，可识别 神经元特定表型活动的时间和空间模式。我们假设 小网络中的活动可以识别正常大脑和患病大脑。为了检验这个假设，我们将使用 双波长微型显微镜对 5xFAD 小鼠（一种经过验证的动物）神经元子集的活动进行成像 阿尔茨海默病模型（正常与纯合同窝仔鼠）。我们创建了发起人- 驱动钙传感器，驱动红移钙指示剂 jRGECO 进入食欲素唤醒状态 神经元。 GABA 睡眠神经元中的单独钙传感器 (GCaMP6m) 将用作比较。 使用两种不同波长对神经元进行成像的优点是可以比较 当大脑在清醒和睡眠之间转换时，唤醒神经元与睡眠神经元的关系。我们将形象活动 正常觉醒-睡眠期间和 6 小时睡眠缺失后含有 jRGECO 和 GCaMP 的神经元。我们 假设从尾流过渡期间存在异常的荧光时间模式 5xFAD 小鼠大脑中的睡眠状态会随着疾病的进展而恶化。这可以解释 阿尔茨海默病睡眠-觉醒模式紊乱的原因。我们假设异常活动 在大脑深层回路中调节睡眠是疾病的先兆。这个小预算的总体影响 该项目的目的是识别清醒、NREM 和 NREM 期间两个不同并置神经元的活动 野生型与疾病模型中的快速眼动睡眠，这将有助于了解小簇如何 神经元的行为就像清醒的大脑进入睡眠状态一样。