The contribution of synaptic adhesion systems to sleep regulation

在哺乳动物和许多非哺乳动物物种中，睡眠是生命所必需的。根据目前的模型，睡眠由两种机制编排：昼夜节律过程和动态平衡过程。在哺乳动物中，昼夜节律过程起源于位于下丘脑的生物钟，并在各种生理功能中产生约24小时的节律，如体温和警觉性等的节律变化。动态平衡过程是一种沙漏机制，它根据先前清醒的时间和质量来调节睡眠强度。它的性质还没有明确定义，过程相互作用的方式也是未知的。然而，最近的工作支持突触的参与，突触是神经细胞之间交流所需的功能结构，在体内平衡过程中。突触黏附分子将突触的两侧连接在一起，但更重要的是，这些蛋白质控制着神经元之间的交流强度。在这个项目中，将调查黏附系统对睡眠调节的贡献。首先，将在睡眠剥夺后评估动态平衡过程的标记物(即大脑皮质表面记录的脑电活动和大脑中特定基因的表达)，其中特定突触黏附分子通过RNA干扰下调。其次，将在使用RNA干扰下调突触分子的小鼠中评估昼夜节律系统的特性(例如，与环境的明/暗周期的同步性，恒定黑暗中内源性昼夜节律周期的长度，以及对光刺激的相移反应)。该项目将在未来五年内通过形成至少两名硕士研究生和5名本科实习生来实现。该项目的成果将促进我们对睡眠生理和神经功能的了解，并有助于开发治疗和干预涉及睡眠调节过程障碍的患者，包括与年龄相关的变化和失眠。

In mammals and many non-mammalian species, sleep is essential to life. According to current models, sleep is orchestrated by two mechanisms: a circadian process and a homeostatic process. In mammals, the circadian process originates from the biological clock located in the hypothalamus and generates an about 24-h rhythm in various physiological functions as the rhythmic changes in body temperature and alertness, among many others. The homeostatic process is an hourglass mechanism that regulates sleep intensity according to the duration and quality of prior wakefulness. Its nature has not been clearly defined and the way the processes interact is also unknown. However, recent work supports the involvement of synapses, the functional structure required for the communication between neuronal cells, in the homeostatic process. Synaptic adhesion molecules hold the two sides of the synapse together but, more importantly, these proteins control the strength of the communication between neurons. In this project, the contribution of adhesion systems to sleep regulation will be investigated. First, the markers of the homeostatic process (i.e. brain electrical activity recorded on the surface of the cortex and the expression of specific genes in the brain) will be evaluated after sleep deprivation in mice where specific synaptic adhesion molecules are downregulated using RNA interference. Second, the properties of the circadian timing system (e.g. the synchronization with the light/dark cycle of the environment, the length of the endogenous circadian period in constant darkness and the phase-shift response to light stimulus) will be evaluated in mice in which synaptic molecules are downregulated using RNA interference as well. This project will be achieved by the formation of at least two master students and 5 undergraduate trainees in the next five years. The results of the project will advance our understanding of sleep physiology and neuronal functions, and assist in the development of treatments and interventions for patients suffering from disorders involving disturbance in sleep regulatory processes, including age-related changes and insomnia.