Genetic control of a central pattern generator: rhythmic oromotor movement in mice is controlled by a major locus near Atp1a2.

John D Boughter,Kenichi Tokita,Steven J St John,Megan K Mulligan,Lu Lu,Detlef H Heck,Robert W Williams

doi:10.1371/journal.pone.0038169

John D Boughter, Kenichi Tokita + Show 5 more

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https://doi.org/10.1371/journal.pone.0038169

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Abstract

Fluid licking in mice is a rhythmic behavior that is controlled by a central pattern generator (CPG) located in a complex of brainstem nuclei. C57BL/6J (B6) and DBA/2J (D2) strains differ significantly in water-restricted licking, with a highly heritable difference in rates (h2≥0.62) and a corresponding 20% difference in interlick interval (mean ± SEM = 116.3±1 vs 95.4±1.1 ms). We systematically quantified motor output in these strains, their F1 hybrids, and a set of 64 BXD progeny strains. The mean primary interlick interval (MPI) varied continuously among progeny strains. We detected a significant quantitative trait locus (QTL) for a CPG controlling lick rate on Chr 1 (Lick1), and a suggestive locus on Chr 10 (Lick10). Linkage was verified by testing of B6.D2-1D congenic stock in which a segment of Chr 1 of the D2 strain was introgressed onto the B6 parent. The Lick1 interval on distal Chr 1 contains several strong candidate genes. One of these is a sodium/potassium pump subunit (Atp1a2) with widespread expression in astrocytes, as well as in a restricted population of neurons. Both this subunit and the entire Na+/K+-ATPase molecule have been implicated in rhythmogenesis for respiration and locomotion. Sequence variants in or near Apt1a2 strongly modulate expression of the cognate mRNA in multiple brain regions. This gene region has recently been sequenced exhaustively and we have cataloged over 300 non-coding and synonymous mutations segregating among BXD strains, one or more of which is likely to contribute to differences in central pattern generator tempo.

Highlights

Rhythmic movements such as those controlling circulatory function, respiration, and locomotion, are fundamental for life
mean primary interlick interval (MPI) was found to vary among inbred and BXD strains in response to either water or 0.1 M sucrose in a highly heritable manner
A suggestive quantitative trait locus (QTL) for MPI was found for either stimulus on Chr 10

Summary

Introduction

Rhythmic movements such as those controlling circulatory function, respiration, and locomotion, are fundamental for life. Are rhythmic oromotor movements involved in feeding and drinking, including mastication, fluid licking or lapping, suckling, and swallowing. These movements are thought to be controlled by one or more ‘‘central pattern generators’’ (CPGs), intrinsic neuronal circuits in the brainstem or spinal cord that produce rhythmic output [1,2,3,4,5,6,7]. In rodents, licking from a tube may be thought of as a surrogate for a more natural lapping behavior (drinking from an open surface of water), the tongue movements are not exactly the same [8]. Licking involves a pattern of alternating tongue protrusion and retraction, predominantly controlled by extrinsic tongue muscles. The specific neurons, their connectivity, and mechanisms responsible for licking pattern generation are unknown

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