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

描述（由申请人提供）：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。颌的运动在食物的分解中起着关键的作用。异常的颌运动表现在几种神经系统疾病中，例如磨牙症、颞下颌关节疾病和口下颌肌张力障碍。因此，了解咀嚼运动的神经控制对于这些疾病的有效和有针对性的治疗的未来发展至关重要。已知三叉神经运动神经元（MoV）提供颌肌肉的主要运动控制。然而，提供直接输入到MoVs，从而控制其活动的前运动电路仍然知之甚少。此外，紧张刺激施加到被认为是咀嚼皮质区（CMA）的下颌运动皮层的子区域可以激活有节奏的下颌运动。然而，运动皮层并不知道与MoV形成直接联系。将皮层命令中继到MoVs的前运动神经元的关键组尚未确定。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网状核（LPGi）中的神经元直接连接到支配主要的下颌闭合肌肉（咬肌）的MoVs，并且突触到咬肌MoVs上的LPGi运动前神经元的数量随着从吮吸到咀嚼行为的过渡而显著增加。这些发现，加上以前的研究，使我提出一个中心假设：在LPGi的MoV前运动神经元形成一个关键的神经模块，以中继皮质信号直接到下巴关闭MoV和其他前运动神经元在脑干网状网络，使有节奏和紧张的下巴运动。我将使用光遗传学辅助切片电生理学来确定LPGi前运动神经元和其他拟议的神经元组之间的功能连接。我将使用光遗传学激活和抑制来确定LPGi前运动神经元在麻醉小鼠中皮质诱导的虚构节律性下颌运动中的作用。最后，我将研究在清醒行为小鼠的自然咀嚼中LPGi前运动神经元沉默的后果。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急需的新见解。

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.