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.
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.
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