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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS060887-04
Application #
8230734
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Chen, Daofen
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$317,275
Indirect Cost
$102,900
Name
University of Tennessee Health Science Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Lang, Eric J; Apps, Richard; Bengtsson, Fredrik et al. (2016) The Roles of the Olivocerebellar Pathway in Motor Learning and Motor Control. A Consensus Paper. Cerebellum :
Ito, J; Roy, S; Liu, Y et al. (2014) Whisker barrel cortex delta oscillations and gamma power in the awake mouse are linked to respiration. Nat Commun 5:3572
Qiao, Shuhong; Kim, Sun-Hong; Heck, Detlef et al. (2013) Dab2IP GTPase activating protein regulates dendrite development and synapse number in cerebellum. PLoS One 8:e53635
Lu, Lianyi; Cao, Ying; Tokita, Kenichi et al. (2013) Medial cerebellar nuclear projections and activity patterns link cerebellar output to orofacial and respiratory behavior. Front Neural Circuits 7:56
Heck, Detlef H; De Zeeuw, Chris I; Jaeger, Dieter et al. (2013) The neuronal code(s) of the cerebellum. J Neurosci 33:17603-9
LeDoux, Mark S (2012) Exome sequencing for gene discovery: time does not stand still. Ann Neurol 72:628-9
Roy, Snigdha; Watkins, Nick; Heck, Detlef (2012) Comprehensive analysis of ultrasonic vocalizations in a mouse model of fragile X syndrome reveals limited, call type specific deficits. PLoS One 7:e44816
Heck, Detlef H; Lu, Lu (2012) The social life of neurons: synaptic communication deficits as a common denominator of autism, schizophrenia, and other cognitive disorders. Biol Psychiatry 72:173-4
Cao, Ying; Roy, Snigdha; Sachdev, Robert N S et al. (2012) Dynamic correlation between whisking and breathing rhythms in mice. J Neurosci 32:1653-9
Boughter Jr, John D; Mulligan, Megan K; St John, Steven J et al. (2012) Genetic control of a central pattern generator: rhythmic oromotor movement in mice is controlled by a major locus near Atp1a2. PLoS One 7:e38169

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