The molecular pathways and neuronal circuits that underpin the effect of neuropeptide galanin on sleep homeostasis.

支持神经肽甘丙肽对睡眠稳态影响的分子途径和神经元回路。

• 批准号: 2249890
• 金额: --
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2249890
• 关键词: molecular; pathways; neuronal; circuits; underpin

Sleep pressure increases as a function of wakefulness. Prolonged sleep deprivation causes homeostatic rebound sleep. Homeostasis is fundamental component of sleep regulation and has been tightly conserved across evolution from invertebrates to man. Yet, little is known about the molecular pathways and circuitry which underpins homeostatic sleep regulation. Previously, the Rihel laboratory has demonstrated a role for the neuropeptide galanin in homeostatic sleep regulation in zebrafish larvae. Galanin-expressing neurons were shown to be active during rebound sleep, induction of galanin transcripts was predictive of total rebound sleep, and galanin mutants lack rebound sleep following elevated neural activity and sleep deprivation. This project will continue this work using zebrafish (Danio Rerio) as a model organism. Zebrafish are small, fast-developing and diurnal. They show behavioral, physiological, and pharmacological characteristics of mammalian sleep. Optical transparency at the larval stage make visualisation of neuron activity, at single cell resolution, possible using intracellular fluorescent markers of calcium responses. Zebrafish are an established model system for the genetic dissection of sleep, facilitated by advanced, well-annotated genetic maps. This model also has the additional benefit of allowing large scale genetic screens.Within this model, the project will investigate the molecular pathways and neuronal circuits which underpin the observed effect of neuropeptide galanin on sleep homeostasis. Initially the focus of the project will be on the downstream signaling pathway and neuron circuitry. The circuitry downstream of galanin-expressing neurons will be investigated using imaging techniques. Molecular techniques, including genetic knock down, will be used to establish the receptor downstream of galanin signaling. There is scope within this project to investigate the upstream effectors of galanin-mediated sleep homeostasis. Preliminary data from the Rihel laboratory suggests a role for glia upstream of galanin-expressing neurons which requires further investigation.

睡眠压力随着清醒程度的增加而增加。长期睡眠不足会导致体内平衡恢复睡眠。动态平衡是睡眠调节的基本组成部分，在从无脊椎动物到人类的进化过程中一直被严格保守。然而，人们对支持稳态睡眠调节的分子通路和电路知之甚少。此前，Rihel实验室已经证明神经肽Galanin在斑马鱼幼体的动态平衡睡眠调节中发挥了作用。甘丙素表达的神经元在反弹睡眠中表现出活跃，甘丙素转录本的诱导预示着总的反弹睡眠，而甘丙肽突变体在神经活动增加和睡眠剥夺后缺乏反弹睡眠。该项目将使用斑马鱼(Danio Rerio)作为模式生物来继续这项工作。斑马鱼体型小，发育迅速，白天活动。它们表现出哺乳动物睡眠的行为、生理和药理学特征。幼虫阶段的光学透明使使用细胞内钙反应的荧光标记物在单细胞分辨率下可视化神经元活动成为可能。斑马鱼是一个已建立的睡眠遗传解剖的模型系统，通过先进的、注释良好的遗传图谱来促进。这个模型还有一个额外的好处，那就是可以进行大规模的基因筛查。在这个模型中，该项目将研究神经肽甘丙肽对睡眠稳态的影响所依据的分子通路和神经元电路。最初，该项目的重点将放在下游信号通路和神经元电路上。甘丙肽表达神经元的下游电路将使用成像技术进行研究。分子技术，包括基因敲除，将被用来建立甘丙素信号下游的受体。在这个项目中，有机会研究甘丙素介导的睡眠稳态的上游效应器。来自Rihel实验室的初步数据表明，胶质细胞在甘丙素表达神经元的上游发挥了作用，这需要进一步的研究。