Optogenetic interrogation of sleep circuits during aging

衰老过程中睡眠回路的光遗传学询问

• 批准号: 8712037
• 负责人: Luis De Lecea
• 金额: $ 36.76万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712037
• 关键词: Acetylcholine; Affect; Age; Aging; Aging-Related Process; Alzheimer' s Disease; Animals; Architecture; Blood; Cardiovascular system; Caregivers; Cells; Chronic; Cognition; Cognitive; Complex; Data; Deterioration; Drosophila genus; Elderly; Electric Stimulation; Electroencephalography; Environment; Frequencies; Genetic; Health; Human; Hypothalamic structure; Impaired cognition; Individual; Injection of therapeutic agent; Institutionalization; Lateral; Lead; Memory; Methods; Mus; Neuromodulator; Neurons; Neurotransmitters; Norepinephrine; Operative Surgical Procedures; Parabiosis; Pathology; Performance; Personal Satisfaction; Physiological; Plasma; Quality of life; Rodent; Role; Sleep; Sleep Architecture; Sleep Fragmentations; Sleep Wake Cycle; Specificity; System; Testing; Thalamic structure; Therapeutic Intervention; Time; Wakefulness; Work; aged; alertness; basal forebrain; cell type; cholinergic; cholinergic neuron; cognitive function; extracellular; hypocretin; improved; innovation; juvenile animal; locus ceruleus structure; noradrenergic; novel; object recognition; optogenetics; public health relevance; research study

DESCRIPTION (provided by applicant): Aging leads to a functional deterioration of multiple physiological systems, including those underlying sleep and wakefulness. Older individuals tend to have reduced sleep amounts and changes in sleep composition and distribution, decreased alertness, increased fragmentation, reduced nocturnal sleep and amplitude of delta EEG frequency. Sleep disruptions in the elderly also severely affect the health and well-being of their caregivers to the point that, in pathologies such as Alzheimer's disease, sleep fragmentation is the main cause of institutionalization. The underlying mechanisms of these changes in sleep architecture and efficiency during aging are unknown. In this proposal, we will use optogenetics to interrogate the role of specific neuronal cell types and circuits in the decline of sleep qualit and cognition during aging. Optogenetics is an ideal method to study sleep/wake mechanisms in rodents because pharmacological approaches far exceed the short time scale of sleep/wake cycles (in the order of minutes), and electrical stimulations cannot provide cellular specificity. n particular we propose to determine whether the ability of three neurotransmitters (Hcrt/orexin, norepinephrine and acetylcholine) to facilitate wakefulness is reduced in old mice. In aim 2, we will determine whether specific features of sleep quality driven by these three transmitters are relevant for the cognitive decline observed during aging. In a third aim we will test whether a young systemic environment is able to improve sleep composition and distribution in an old mouse using plasma transfer and parabiosis experiments. The data obtained from these experiments may lead to selective therapeutic interventions to improve the quality of life of the elderly and their caregivers.

描述（由申请人提供）：衰老会导致多个生理系统的功能退化，包括那些潜在的睡眠和觉醒系统。老年人往往睡眠量减少，睡眠成分和分布发生变化，警觉性降低，碎片化增加，夜间睡眠和δ脑电图频率幅度减少。老年人的睡眠中断也严重影响他们的健康和福祉 护理人员认为，在阿尔茨海默病等疾病中，睡眠碎片化是导致住院的主要原因。衰老过程中睡眠结构和效率变化的潜在机制尚不清楚。在本提案中，我们将利用光遗传学来探究特定神经元细胞类型和回路在衰老过程中睡眠质量和认知能力下降中的作用。光遗传学是研究啮齿类动物睡眠/觉醒机制的理想方法，因为药理学方法远远超出了睡眠/觉醒周期的短时间范围（以分钟为单位），而电刺激无法提供细胞特异性。特别是，我们建议确定老年小鼠中三种神经递质（Hcrt/食欲素、去甲肾上腺素和乙酰胆碱）促进觉醒的能力是否降低。在目标 2 中，我们将确定这三种发射器驱动的睡眠质量的具体特征是否与衰老过程中观察到的认知能力下降有关。第三个目标是，我们将使用血浆转移和联体共生实验来测试年轻的全身环境是否能够改善年老小鼠的睡眠成分和分布。从这些实验中获得的数据可能会导致选择性的治疗干预措施，以改善老年人及其护理人员的生活质量。