延长觉醒对小脑间位核theta振荡和运动信息反馈的影响及机制研究

Prolonged wakefulness (e.g. insomnia and sleep deprivation) is a common phenomenon in the current society, which can result in the impairment of motor learning. However, the mechanisms underlying this impairment remain unclear. It has been demonstrated that the cerebellum is a brain region critical for motor learning. Motor feedback from the cerebellar interpositus nucleus to the cerebral cortical areas is currently thought as the fundamental basis for motor learning. Based on our preliminary findings that theta（5-10 Hz）oscillations in the interpositus nucleus are directly regulated by the endogenous orexins and are associated with the performance of adaptive motor learning behavior, the present study aims to determine whether the impairment of motor learning aroused from abnormal theta oscillations in the interpositus nucleus during the prolonged wakefulness. We will explore the mechanisms underlying the prolonged wakefulness- induced abnormal theta oscillations in the interpositus nucleus. In addition, its influence on motor feedback from the cerebellum to cerebral cortex will be investigated. To this end, several techniques are utilized, including multiple units recording and optogenetics. Finally, we will determine whether the abnormal theta oscillations in the interpositus nucleus and impaired motor learning can be compensatory rescued by the potentiation of wakefulness-promoting system under the prolonged wakefulness conditions. The outcomes from this project will provide new insights into relieving the impairment of motor learning induced by the prolonged wakefulness.

以失眠和睡眠剥夺为代表的延长觉醒是现今社会的常见现象。在延长觉醒状态下，运动性学习的精确发生能力显著降低，但其机制仍不清楚。小脑是运动性学习发生的关键脑区，其间位核向大脑皮层的运动状态信息反馈是运动性学习精确发生的重要基础。本项目拟在前期发现“间位核theta频带（5-10 Hz）振荡受内源性促醒肽orexins的直接调控，并与运动性学习的精确发生密切相关”的基础上，以间位核theta振荡作为研究对象，采用在体多通道记录和光遗传学等技术，研究延长觉醒是否通过影响间位核theta振荡来损害运动性学习的精确发生，并深入探讨延长觉醒影响间位核theta振荡的机制及其对小脑-大脑皮层运动状态信息反馈的影响，最终明确延长觉醒条件下增强特定促觉醒系统活动是否可以代偿性维持间位核theta振荡和运动性学习的精确发生能力，为缓解延长觉醒致运动性学习功能减退症状提供重要的新思路。

小脑是运动性学习发生的关键脑区，其间位核向大脑皮层的运动状态信息反馈是运动性学习精确发生的基础。本项目以眨眼条件反射为运动学习记忆的行为模型，发现（1）学习后的睡眠剥夺会显著降低运动记忆的巩固能力。（2）运动学习记忆过程中条件刺激可以诱发小脑间位核产生明显的theta频带（5-10 Hz）振荡。而通过阻断促觉醒系统内源性递质（如orexin）对小脑间位核的兴奋效应，模拟觉醒水平的降低，会干扰小脑间位核与前额叶皮层之间的theta振荡同步化，并引起运动记忆行为适应性表现的异常。提示小脑间位核theta频带振荡可能受内源性促醒肽orexin的直接调控，并与运动记忆学习的精确发生密切相关。（3）进一步，我们研究了缺乏运动反馈信息的条件下，小脑间位核theta振荡的变化。结果显示：延迟性眨眼条件反射在缺乏运动反馈信息的条件下会逐渐消失。但行为学分析显示，在条件反射消退的过程中，会出现显著的自发恢复现象。且自发恢复与小脑间位核theta振荡呈现出明显负相关效应，即自发恢复越明显，间位核theta振荡越弱。因此，条件刺激诱发的间位核theta振荡强弱，可以预测自发恢复的强度。（4）我们开发了一种重复可使用的轻便型光纤电极。利用该电极，结合光纤成像和光遗传学等技术，深入探索了MECII-DG通路在空间导航中的作用。这一体系的形成，为后期进一步地研究延长觉醒对小脑间位核运动反馈信息的编码奠定了技术基础。