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

确定脑干前运动模块在咀嚼颌运动中的功能

• 批准号: 8732469
• 负责人: Edward John Stanek
• 金额: $ 3.4万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732469
• 关键词: Adult; Area; Attenuated; Axon; Behavior; Behavioral; Brain Stem; Bruxism; Cell Nucleus; Chronic; Complex; Deglutition; Development; Disease; Dystonia; Electric Stimulation; Electrodes; Electrophysiology (science); Food; Future; Implant; In Situ Hybridization; Injection of therapeutic agent; Jaw; Label; Lateral; Lead; Light; Link; Location; Maps; Masseter Muscle; Mastication; Mediating; Mediator of activation protein; Motor; Motor Cortex; Motor Neurons; Movement; Movement Disorders; Mus; Muscle; Neurons; Neurotransmitters; Output; Play; Rabies; Rabies virus; Research; Role; Sensory; Signal Transduction; Slice; Subfamily lentivirinae; Symptoms; Synapses; Techniques; Temporomandibular Joint Disorders; Testing; Tetanus Toxin; Trigeminal System; Viral; Work; awake; base; feeding; food preparation; insight; jaw movement; motor control; nervous system disorder; neural circuit; neuromuscular; neuroregulation; novel; optogenetics; public health relevance; relating to nervous system

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.

描述（由申请人提供）：咀嚼是准备吞咽食物所必需的复杂的感觉运动行为。下巴的运动在食物的分解中起着至关重要的作用。异常的下颌运动表现为多种神经系统疾病，例如磨牙症、颞下颌关节紊乱和口下颌肌张力障碍。因此，了解咀嚼运动的神经控制对于未来开发这些疾病的有效和有针对性的治疗至关重要。众所周知，三叉神经运动神经元（MoV）提供下颌肌肉的主要运动控制。然而，对于向 MoV 提供直接输入并从而控制其活动的前电机电路仍然知之甚少。此外，对被视为皮质咀嚼区（CMA）的下颌运动皮层子区域施加强直刺激可以激活有节奏的下颌运动。然而，运动皮层是否与 MoV 形成直接联系尚不清楚。将皮质命令传递给 MoV 的前运动神经元的关键群体尚未确定。在初步研究中，使用基于单突触狂犬病病毒的突触示踪技术发现位于外侧副巨细胞网状核（LPGi）的神经元直接连接到支配主要下颌闭合肌（咬肌）的MoV，并且LPGi前运动的数量随着从吮吸行为到咀嚼行为的转变，突触到咬肌 MoV 的神经元急剧增加。这些发现与之前的研究一起，使我提出一个中心假设：LPGi 中的 MoV 前运动神经元形成一个关键的神经模块，将皮质信号直接传递到下颌闭合的 MoV 和脑干网状结构中的其他前运动神经元上网络以实现有节奏和强直的下巴运动。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提出的神经元群之间的功能连接。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急需的新见解。