Functional and Structural Diversity in Hypoglossal Motoneurons

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PROJECT SUMMARY/ABSTRACT Tongue muscles, which are innervated by hypoglossal motoneurons (XIIMNs), are critical for survival given their role in suckling, swallowing, mastication, breathing and more advanced functions such as human speech. The hypoglossal motor nucleus is a bilateral collection of seven separate motoneuron pools, with motoneurons in each pool innervating one of the seven different tongue muscles. We recently showed that XIIMNs innervating the superior longitudinalis and genioglossus tongue muscles of neonatal rats have significantly different resting membrane potentials, action potential firing thresholds, and f-I curves, i.e., the change in firing rate as a function of injected current. These findings raise three very important questions: 1) what is the extent and nature of phenotypic diversity both within and between individual XIIMN pools? 2) what are the anatomic and ionic mechanisms that underlie this phenotypic diversity? 3) do structural and functional differences among XIIMNs in each pool map to unique gene expression profiles? We propose a rational and robust approach to address these questions: specifically, to describe the morphology, intrinsic membrane properties, and the transcriptome of muscle specific XIIMNs. Our initial targets are XIIMNs innervating the genioglossus, hyoglossus and superior longitudinalis muscles, as each muscle has different effects on tongue movement. Muscle-specific XIIMNs will be identified by injecting each of the muscles with a retrograde tracer conjugated to a fluorescent reporter. All experiments use brain tissue from neonatal rats 5-12 days of age. Key techniques include neuroanatomic tracing to define neuron morphology, immunohistochemistry, whole cell patch clamp electrophysiology and next- generation RNA sequencing. These basic science studies will identify unique molecular targets associated with functional and/or structural differences between the motoneuron pools. Without this fundamental information, interventions aimed at stimulating or inhibiting the activity of specific tongue muscles will be imprecise and may result in unintended outcomes. In contrast, specific knowledge of unique molecular targets will focus the development of therapeutic approaches aimed at stimulation and/or inhibition of specific tongue muscles. Preliminary data show several pool-specific differences in motoneuron function and gene expression, strongly suggesting that the proposed work will provide truly novel data on the anatomic, physiologic, and molecular underpinnings of phenotypic diversity within and between muscle-specific hypoglossal motoneuron pools. This, in turn, will lead to a major leap in our understanding of how the tongue muscles perform complex, coordinated behaviors such as suckling, swallowing, and defense of the upper airway during sleep, and will lay the foundation for the development of therapies aimed at controlling the activity of specific tongue muscles.