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.

脑深部成像方法（显微内窥镜）是一种高通量方法， 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与患病的大脑。为了验证这个假设，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）的一部分神经元活动进行成像 阿尔茨海默病模型（正常与纯合子同窝仔）。我们创造了一个促进者- 驱动钙传感器，驱动红移钙指标jRGECO进入食欲素唤醒 神经元将使用GABA睡眠神经元中的单独钙传感器（GCaMP 6 m）作为比较。 用两种不同的波长对神经元成像的优点是，它允许比较神经元的 当大脑在清醒和睡眠之间转换时，唤醒和睡眠神经元。我们会想象 在正常的清醒-睡眠发作期间和6小时睡眠丧失后，含有jRGECO和GCaMP的神经元。我们 假设在从尾流过渡期间存在异常的荧光时间模式 在5xFAD小鼠的大脑中睡眠，并且随着疾病的进展而恶化。这可以解释 阿尔茨海默病患者睡眠-觉醒模式紊乱的原因。我们假设异常活动 在大脑深处控制睡眠的回路是疾病的前兆。这个小预算的总体影响 该项目的目的是，它将确定两个不同的并列神经元在清醒，NREM和 野生型REM睡眠与疾病模型的比较，这将有助于理解小簇的REM睡眠是如何发生的。 神经元的行为就像清醒的大脑福尔斯入睡一样。