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，睡眠对生命至关重要。根据目前的模型，睡眠是由两种机制协调的：昼夜节律过程和稳态过程。在哺乳动物中，昼夜节律过程起源于位于下丘脑中的生物钟，并在各种生理功能中产生约24小时的节律，如体温和警觉性的节律性变化等。自我平衡过程是一种沙漏机制，它根据先前清醒的持续时间和质量来调节睡眠强度。其性质尚未明确界定，各进程相互作用的方式也不清楚。然而，最近的工作支持参与突触，神经元细胞之间的通信所需的功能结构，在稳态过程。突触粘附分子将突触的两侧固定在一起，但更重要的是，这些蛋白质控制神经元之间的通信强度。在这个项目中，将研究粘附系统对睡眠调节的贡献。首先，在睡眠剥夺后，在使用RNA干扰下调特定突触粘附分子的小鼠中评估稳态过程的标志物（即，在皮层表面上记录的脑电活动和脑中特定基因的表达）。第二，将在小鼠中评估昼夜节律计时系统的性质（例如，与环境的光/暗周期的同步、恒定黑暗中内源性昼夜节律周期的长度和对光刺激的相移响应），其中突触分子也使用RNA干扰下调。该项目将在未来五年内至少培养两名硕士生和5名本科生。该项目的结果将促进我们对睡眠生理学和神经元功能的理解，并有助于为患有睡眠调节过程紊乱的患者开发治疗和干预措施，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.