咀嚼运动的中枢去抑制调节环路

The trigeminal motor nucleus (“Mo5”) is the main motor nucleus controlling the jaw musculature that drives mastication. However, the exact mechanisms by which the central nervous system controls Mo5 remain unknown, which precludes a better understanding of orofacial pathologies such as bruxism. The aim of this project is to characterize the neural circuitry underlying the pathological functioning of masticatory muscles during wakefulness and sleep. Specifically, the project will test the hypothesis that the central nucleus of the amygdala (“CeA”), a brain center that regulates behavioral responses to stress, acts to disinhibit Mo5 via its projections to the premotor region of the parvocellular reticular formation (“PCRt”). In this model, CeA neurons, which release the inhibitory neurotransmitter GABA, respond to stress by halting the activity of inhibitory PCRt premotor neurons. This therefore causes the inappropriate release of Mo5 neurons, particularly during sleep. Strong preliminary data supports the hypothesis that stress acts in CeA to activate craniofacial muscles via a CeA (GABA) ->PCRt (GABA) ->Mo5 disinhibitory pathway. The project involves the use of interdisciplinary, cutting-edge tools that include optogenetics, multi-muscle simultaneous electromyograms, genetically encoded neural tracing, design-receptor neurotransmission, and in vivo electrophysiology. The outcome of this project will establish for the first time that a stress-related brain nucleus is a major controller of craniofacial muscles. These findings will thus demonstrate mechanistically how physiological stress alters jaw function. From a clinical standpoint, these studies should significantly expand our understanding of the neural mechanisms of bruxism and related orofacial disorders.

脑干以及高级中枢对三叉神经运动核团Mo5的神经调控环路，以及咀嚼相关的疾病，如磨牙症的神经病理机制，一直不甚明确。该领域作为口腔医学与神经生理学的交叉领域，相关研究者较少。本课题组根据神经科学最新理论，以及前期翔实数据提出：脑干小细胞网状核前部PCRtA内的抑制性神经元是调控咀嚼运动和睡眠节律的关键脑区。中央杏仁核CeA作为高级中枢的压力感受核团，是压力诱发磨牙症的潜在目标脑区。“CeA->PCRtA->Mo5”通过“抑制->去抑制->运动输出”的环路机制调节咀嚼功能。本课题结合尖端的神经示踪、光遗传和药物遗传在体刺激，肌电和脑电在体记录等技术，通过小鼠模型，研究咀嚼运动的神经生理病理机制。本课题的顺利开展，不仅将填补咀嚼运动发生环路的这一基础理论研究空白，还将为磨牙症等咀嚼相关疾病的临床诊疗，提供全新的思路，具有非常确实的应用价值。

本课题结合尖端的神经肌肉示踪、肌电脑电记录、脑片膜片钳技术、在体光遗传和药物遗传学刺激抑制等技术，证明以下关键理论：.1）头颈部的运动调控是通过抑制中央杏仁去抑制脑干小细胞网状核内的抑制性神经元，从而进步激活运动输出核团内胆碱能初级运动神经的方式来调节最终运动输出的，即通过“制动”机制调节咀嚼运动。在临床上，该环路也参与焦虑情绪对磨牙症的影响。.2）中央杏仁核向中脑导水管周围灰质的投射参与猎食行为。选择性刺激中央杏仁核向中脑导水管周围灰质的投射，可以显著增加小鼠的猎食动力以及四肢行动速度。而通过激活导水管周围灰质内的兴奋性神经元则可以完全诘抗中央杏仁核的激活效应。.3）通过对于张口肌群和闭口肌群在中枢的初级运动神经元和肌肉本体感受神经元的精细示踪，本研究发现三叉神经运动核包含所有张口肌和闭口肌的初级运动神经元；而脑桥三叉神经中脑核只含有颧肌、咬肌和少量颞肌的初级本体感受神经元。进一步的深入研究显示：牙髓的感觉神经环路和张口肌的运动神经环路在脑干水平没有重叠。但是，两者的神经环路在下丘脑、边缘系统和运动皮层有部分细胞重叠。因此，牙髓痛引发的伤害性张口反射的环路发生于前脑，而非脑干。通过张口肌电生理分析，损伤前脑外侧下丘脑的PSTn后，张口肌介导的伤害反射明显延迟。.4）临床上，焦虑情绪会诱发对磨牙症，CeA向PCRtA的投射环路是介导睡眠时相与磨牙症的关键脑区。小鼠在压力环境下的情绪反应需要CeA的参与，压力应激后小鼠睡眠时间延长，深睡眠时程增长。咀嚼活动可以部分逆转小鼠清醒状态下的应激反应，同时改善睡眠模式.本课题的深入开展，不仅将加深对于咀嚼运动神经生理调控这一基础理论问题的了解，更为磨牙症压力应激引发咬合功能紊乱等口腔颌面相关疾病的临床诊疗，提供全新的思路，具有非常确实的应用价值。