Determining Functions of a Brainstem Pre-motor Module In Masticatory Jaw Movement

描述(申请人提供)：咀嚼是一种复杂的感觉-运动行为，是准备吞咽食物所必需的。下巴的运动对食物的分解起着至关重要的作用。下颌运动异常表现为几种神经疾病，如磨牙症、颞下颌关节紊乱病和口腔下颌骨张力障碍。因此，了解咀嚼运动的神经控制对于未来有效和有针对性地治疗这些疾病是至关重要的。已知三叉神经运动神经元(MOV)是颌骨肌肉的主要运动控制区。然而，向MOV提供直接输入从而控制其活动的前置马达电路仍然知之甚少。此外，对被认为是皮质咀嚼区(CMA)的颌骨运动皮质的一个子区域施加紧张性刺激可以激活下颌有节奏的运动。然而，运动皮质是否与MOVS形成直接联系尚不清楚。将皮质指令传递给MOV的运动前神经元的关键群组尚未确定。在初步研究中，使用基于单突触狂犬病病毒的跨突触追踪技术发现，位于外侧巨细胞旁网状核(LPGi)的神经元与支配主要闭合肌(咬肌)的MOVS直接相连，并且随着从吮吸行为到咀嚼行为的转变，LPGi前运动神经元与咬肌MOVS的突触数量显著增加。这些发现和以前的研究一起，让我提出了一个中心假说：LPGi中的MOV运动前神经元形成了一个关键的神经模块，将皮质信号直接传递到关闭颌骨的MOVS和脑干网状网中的其他运动前神经元上，从而实现有节奏和紧张性的颌骨运动。我将使用光遗传辅助切片电生理学来确定LPGi运动前神经元和其他拟议神经元组之间的功能连接。我将使用光遗传激活和抑制来确定LPGi前运动神经元在麻醉小鼠皮质诱导的假想节律性下颌运动中的作用。最后，我将研究在清醒行为的小鼠的自然咀嚼中沉默LPGi前运动神经元的后果。这些研究有望为控制下颌运动和咀嚼行为的精确神经回路提供亟需的新见解。

DESCRIPTION (provided by applicant): Mastication is a complex sensory-motor behavior necessary for the preparation of food for swallowing. The movement of the jaw plays a critical role in the breaking down of food. Abnormal jaw movements are manifested in several neurological disorders such as bruxism, temporomandibular joint disorders, and oromandibular dystonia. Thus, understanding the neural control of masticatory movements is essential for future development of effective and targeted treatments of these diseases. It is known that trigeminal motor neurons (MoVs) provide the main motor control of jaw muscles. However, the pre-motor circuits that provide direct inputs onto MoVs and thereby control their activity remain poorly understood. Furthermore, tonic stimulation applied to a sub-region of the jaw motor cortex deemed the cortical masticatory area (CMA) can activate rhythmic jaw movements. Yet the motor cortex is not known to form a direct connection with MoVs. The key groups of pre-motor neurons that relay cortical commands to MoVs have not been determined. In preliminary studies, a monosynaptic rabies virus based transsynaptic tracing technique was used to find that neurons located in the lateral paragigantocellular reticular nucleus (LPGi) are directly connected to MoVs innervating the main jaw closing muscle, the masseter, and that the number of LPGi premotor neurons that synapse onto the masseter MoVs dramatically increases with the transition from suckling to chewing behavior. These findings, together with previous studies, lead me to propose a central hypothesis: MoV pre-motor neurons in the LPGi form a critical neural module to relay cortical signals both directly onto jaw closing MoVs and onto other pre-motor neurons in the brainstem reticular network to enable rhythmic and tonic jaw movements. I will use optogenetic-assisted slice electrophysiology to determine functional connectivity between LPGi pre-motor neurons and other proposed neuronal groups. I will use optogenetic activation and inhibition to determine the role of LPGi pre-motor neurons in cortically-induced fictive rhythmic jaw movements in anesthetized mice. Finally, I will examine the consequences of silencing LPGi pre-motor neurons in natural mastication in awake behaving mice. These studies are expected to provide much needed novel insights into the precise neural circuitry controlling jaw movement and masticatory behavior.