Optogenetic interrogation of sleep circuits during aging

描述(申请人提供)：衰老导致多种生理系统的功能退化，包括那些潜在的睡眠和清醒。老年人往往睡眠时间减少，睡眠组成和分布发生变化，警觉性降低，碎片化程度增加，夜间睡眠减少，脑电增量频率幅度减少。老年人的睡眠障碍也严重影响他们的健康和福祉 照顾者认为，在阿尔茨海默病等病理疾病中，睡眠不完整是导致住院的主要原因。这些睡眠结构和效率在衰老过程中发生变化的潜在机制尚不清楚。在这个方案中，我们将使用光遗传学来询问特定的神经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动物睡眠/觉醒机制的理想方法，因为药理学方法远远超过睡眠/觉醒周期的短时间尺度(几分钟)，而电刺激不能提供细胞特异性。特别是，我们建议确定三种神经递质(Hcrt/增食欲素、去甲肾上腺素和乙酰胆碱)促进老年小鼠觉醒的能力是否降低。在目标2中，我们将确定由这三种递质驱动的睡眠质量的特定特征是否与在衰老过程中观察到的认知下降有关。在第三个目标中，我们将通过血浆转移和异生实验来测试年轻的全身环境是否能够改善老年小鼠的睡眠组成和分布。从这些实验中获得的数据可能导致有选择的治疗干预，以改善老年人及其照顾者的生活质量。

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.