The role of the 5-HT2A mediated neurotransmission in behaviour and neuronal dynamics during sleep and waking in mice

大脑中的5 -羟色胺能信号对多种功能都很重要——从食欲、体温调节、睡眠到焦虑、学习和记忆。研究表明，对血清素能系统的操纵可以影响不同警戒状态的数量和分布。例如，在人类和实验动物中，使用选择性血清素再摄取抑制剂治疗后，几乎完全消除了传统标准定义的快速眼动（REM）睡眠。令人惊讶的是，快速眼动睡眠的缺失似乎并没有导致任何明显的负面后果。这表明，要么快速眼动睡眠没有任何生物学功能，要么强化血清素能系统导致警觉状态的改变或混合状态的发生，从而在功能上取代真正的快速眼动睡眠。如果后者是正确的，那么血清素能系统的关键作用是控制特定睡眠状态的质量，而不是数量。本项目的目的是表征5-HT2A激动剂对自由运动小鼠皮质神经活动和行为的影响。我们选择这类化合物是因为我们的初步研究表明它们对小鼠有很强的快速眼动睡眠抑制作用。在这项研究中，我们将对自由运动小鼠的新皮层进行慢性电生理记录，并结合肌电图、加速计、位置眼动追踪和瞳孔直径，在自发觉醒和睡眠期间，以及在给予psilocin和其他5-HT2A配体期间和之后的行为任务执行。该项目将首次描述5-HT2A激动剂对睡眠和觉醒数量和质量的影响，根据3Rs建立行为唤醒及其电生理相关的新指标，并解决快速眼动睡眠和注意力表现之间的关系。

Serotonergic signalling in the brain is important for a broad range of functions - from appetite, thermoregulation, and sleep to anxiety, learning and memory. Studies suggest that manipulations of the serotonergic system can impact the amount and distribution of different vigilance states. For example, a nearly complete elimination of rapid eye movement (REM) sleep, as defined using conventional criteria, was observed after treatment with selective serotonin reuptake inhibitors in both humans and laboratory animals. Surprisingly, the loss of REM sleep does not appear to lead to any overt negative consequences. This suggests either that REM sleep does not have any biological function, or that potentiating serotonergic system results in an occurrence of altered or hybrid states of vigilance that can functionally replace the bona fide REM sleep. If the latter were true, then a key role of the serotonergic system is in controlling the quality, rather than quantity of specific sleep states. The aim of this project is to characterise the effects of 5-HT2A agonists on cortical neural activity and behaviour in freely moving mice. This class of compounds was selected because our preliminary studies suggest their strong REM sleep - suppressing effects in mice. In this study we shall perform chronic electrophysiological recordings from the neocortex in freely moving mice, combined with EMG, accelerometery, positional eye tracking and pupil diameter across spontaneous wakefulness and sleep, as well as during behavioural task performance during and after administration of psilocin and other 5-HT2A ligands. This project will for the first time characterise the effects of 5-HT2A agonists on both sleep and wake quantity and quality, establish novel metrics of behavioural arousal and its electrophysiological correlates in freely behaving mice in accordance with the 3Rs, and address the relationship between REM sleep and attentional performance.