Coordination of orofacial and respiratory movements

描述（由申请人提供）：食物和液体的摄入与呼吸氧气一样是生存的组成部分，并且用于口面和呼吸运动的神经控制基底在脑干中的模式生成回路内组织并不奇怪。这些节律性运动的持续协调是必不可少的，并且协调口面和呼吸运动的缺陷与人类健康状况有关，例如婴儿猝死综合征（SIDS）、吞咽功能障碍（吞咽困难）和言语障碍（构音障碍）。小脑长期以来一直与身体运动和姿势的协调有关。临床证据也将小脑功能障碍与SIDS、吞咽困难和构音障碍联系起来，但小脑控制或协调呼吸和口面运动的神经元机制尚未确定。我们开发了一种新的实验范式，使我们能够同时测量清醒行为小鼠的orofacial（搅拌和舔）和呼吸运动，同时记录小脑和脑干中的神经元活动。高度刻板的舔和拂动动作在许多方面都是研究小脑运动协调的理想模型行为。它们是大量自发进行的自然行为，易于测量和量化。我们在清醒行为正常和共济失调小鼠中的初步实验表明，正常小鼠的呼吸与搅拌和舔是协调一致的，但共济失调小鼠则不然。在这里，我们建议，以确定如何舔，搅拌和呼吸运动是协调清醒的行为小鼠，小脑在这项任务中扮演什么样的角色，什么样的神经回路参与这种控制。我们假设小脑协调脑干模式发生器的活动，这些发生器产生呼吸和有节奏的口面运动。三个具体的目标将测试这一假设：目标1：测试的假设，精确的时间协调之间的口面和呼吸运动被破坏的小鼠与小脑共济失调。将在正常和共济失调小鼠以及在通过蝇蕈醇注射的小脑深核（DCN）可逆失活期间的正常小鼠中的不同行为条件下确定口面和呼吸运动的协调。目标二：验证小脑和小脑深核神经元活动与口面和呼吸运动高度协调的假设。我们将使用细胞外记录映射在不同的行为条件下，在正常和感觉传入的小鼠的小脑和小脑深部核的口面和呼吸运动的神经元表示。目标3：验证以下假设：小脑通过DCN的顶核，通过向多个脑干CPG的侧支投射协调控制有节奏的口面和呼吸运动。初步数据表明，浦肯野细胞投射到顶核（FN）代表多个orofacial运动和FN神经元项目多个脑干模式发生器。脑干示踪剂注射将用于确定小脑到脑干模式发生器的投射。公共卫生相关性：呼吸运动必须与影响气流的其他运动协调，如讲话，咳嗽，打喷嚏或吞咽，但神经系统如何实现协调呼吸与其他口面运动的重要任务却知之甚少。我们已经获得的初步数据表明，小脑是关键参与这项任务，这可以解释为什么小脑患者患有语言障碍（构音障碍）和吞咽困难（吞咽困难）。这些研究将提高我们对小脑功能的总体理解，特别是它参与协调呼吸与其他气流影响运动的重要任务。

DESCRIPTION (provided by applicant): Ingestion of food and fluids are as integral to survival as is breathing oxygen, and it is not surprising that neural control substrates for both orofacial and respiratory movements are organized within pattern generating circuits in the brainstem. Constant coordination of these rhythmic movements is essential, and deficits in coordinating orofacial and respiratory movements are implicated in human health conditions such as sudden infant death syndrome (SIDS), swallowing dysfunction (dysphagia) and speech disorders (dysarthria). The cerebellum has long been implicated in the coordination of body movements and posture. Clinical evidence has also linked cerebellar dysfunction to SIDS, dysphagia and dysarthria but the neuronal mechanisms through which the cerebellum controls or coordinates respiratory and orofacial movements has yet to be determined. We have developed a new experimental paradigm that allows us to simultaneously measure orofacial (whisking and licking) and respiratory movements in awake behaving mice while recording neuronal activity in the cerebellum and brainstem. The highly stereotyped licking and whisking movements are in many respects ideal model behaviors for the study of cerebellar motor coordination. They are natural behaviors spontaneously performed in large numbers and easy to measure and quantify. Our preliminary experiments in awake behaving normal and ataxic mice show that respiration is well coordinated with whisking and licking in normal but not in ataxic mice. Here we propose to determine how licking, whisking and respiratory movements are coordinated in awake behaving mice, what role the cerebellum plays in this task and what neural circuitry is involved in this control. We hypothesize that the cerebellum coordinates the activities of brainstem pattern generators which generate respiratory and rhythmic orofacial movements. Three specific aims will test this hypothesis: Aim 1: Test the hypothesis that the precise temporal coordination between orofacial and respiratory movements is disrupted in mice with cerebellar ataxia. The coordination of orofacial and respiratory movements will be determined under different behavioral conditions in normal and ataxic mice and in normal mice during reversible inactivation of the deep cerebellar nuclei (DCN) through muscimol injections. Aim 2: Test the hypothesis that cerebellum and deep cerebellar nuclei neuronal activity is highly coordinated with orofacial and respiratory movements. We will use extracelluar recordings to map the neuronal representation of orofacial and respiratory movements in the cerebellum and deep cerebellar nuclei in normal and sensory deafferented mice under different behavioral conditions. Aim 3: Test the hypothesis that the cerebellum, via the fastigial nucleus of the DCN, coordinately controls rhythmic orofacial and respiratory movements via collateralized projections to multiple brainstem CPGs. Preliminary data show that Purkinje cells projecting to the fastigial nucleus (FN) represent multiple orofacial movements and that FN neurons project to multiple brain stem pattern generators. Brainstem tracer injections will be used to determine cerebellar to brainstem pattern generator projections. PUBLIC HEALTH RELEVANCE: Respiratory movements must be coordinated with other movements affecting airflow like speech, coughing, sneezing or swallowing, but how the nervous system achieves the important task of coordinating respiration with other orofacial movements is poorly understood. We have obtained preliminary data suggesting that the cerebellum is critically involved in this task, which could explain why cerebellar patients suffer from speech disorders (dysarthria) and difficulties in swallowing (dysphagia). The proposed studies will improve our general understanding of cerebellar function and particularly its involvement in the important task of coordinating respiration with other airflow-affecting movements.