Coordination of orofacial and respiratory movements

描述(申请人提供)：摄入食物和液体和呼吸氧气一样是生存不可或缺的一部分，并不令人惊讶的是，口腔和呼吸运动的神经控制底物都在脑干的模式产生电路中组织起来。这些有节奏的运动的持续协调是必不可少的，协调口面部和呼吸运动的缺陷与人类健康状况有关，如婴儿猝死综合征(SID)、吞咽障碍(吞咽困难)和言语障碍(构音障碍)。长期以来，小脑一直被认为与身体动作和姿势的协调有关。临床证据也将小脑功能障碍与小儿麻痹症、吞咽困难和构音障碍联系在一起，但小脑控制或协调呼吸和口面部运动的神经机制尚未确定。我们开发了一种新的实验范式，允许我们同时测量清醒行为小鼠的口面部(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。对于小脑运动协调的研究来说，高度刻板的舔和揉动作在许多方面都是理想的模型行为。它们是大量自发进行的自然行为，易于测量和量化。我们对清醒行为正常和共济失调小鼠的初步实验表明，在正常小鼠中，呼吸与搅拌和舔很好地协调，但在共济失调小鼠中则不然。在这里，我们建议确定在清醒行为的小鼠中，舔、揉和呼吸运动是如何协调的，小脑在这一任务中扮演了什么角色，以及什么神经电路参与了这一控制。我们假设，小脑协调脑干模式发生器的活动，从而产生呼吸和有节奏的口面部运动。三个特定的目标将验证这一假设：目标1：测试患有小脑性共济失调的小鼠的口面部和呼吸运动之间精确的时间协调被破坏的假设。在正常小鼠、共济失调小鼠和正常小鼠小脑深核(DCN)可逆失活期间，通过注射蝇草醇，将在不同的行为条件下确定口面部和呼吸运动的协调性。目的2：验证小脑和小脑深核神经元活动与口面部和呼吸运动高度协调的假说。我们将使用细胞外记录来定位不同行为条件下正常小鼠和感觉去传入小鼠小脑和小脑深核口面部和呼吸运动的神经元表示。目的：验证一种假说，即小脑通过DCN的顶核，通过向多个脑干CPG的侧支投射来协调控制有节奏的口面部和呼吸运动。初步数据显示，浦肯野细胞投射到顶核(FN)代表多个口面部运动，FN神经元投射到多个脑干模式生成器。脑干示踪剂注射将用于确定小脑到脑干模式发生器的投影。与公共健康相关：呼吸运动必须与其他影响气流的运动相协调，如说话、咳嗽、打喷嚏或吞咽，但神经系统如何完成呼吸与其他口腔面部运动相协调的重要任务，人们知之甚少。我们已经获得了初步数据，表明小脑参与了这一任务，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)。拟议的研究将提高我们对小脑功能的总体了解，特别是它参与协调呼吸和其他影响气流运动的重要任务。

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.