Inhibition plays important roles in modulating the neural activities of sensory and motor systems at different levels from synapses to brain regions. To achieve coordinated movement, motor systems produce alternating contraction of antagonist muscles, whether along the body axis or within and among limbs, which often involves direct or indirect cross-inhibitory pathways. In the nematode C. elegans, a small network involving excitatory cholinergic and inhibitory GABAergic motoneurons generates the dorsoventral alternation of body-wall muscles that supports undulatory locomotion. Inhibition has been suggested to be necessary for backward undulation because mutants that are defective in GABA transmission exhibit a shrinking phenotype in response to a harsh touch to the head, whereas wild-type animals produce a backward escape response. Here, we demonstrate that the shrinking phenotype is exhibited by wildtype as well as mutant animals in response to harsh touch to the head or tail, but only GABA transmission mutants show slow locomotion after stimulation. Impairment of GABA transmission, either genetically or optogenetically, induces lower undulation frequency and lower translocation speed during crawling and swimming in both directions. The activity patterns of GABAergic motoneurons are different during low and high frequency undulation. During low frequency undulation, GABAergic VD and DD motoneurons show correlated activity patterns, while during high frequency undulation, their activity alternates. The experimental results suggest at least three non-mutually exclusive roles for inhibition that could underlie fast undulatory locomotion in C. elegans, which we tested with computational models: cross-inhibition or disinhibition of body-wall muscles, or inhibitory reset. Significance StatementInhibition serves multiple roles in the generation, maintenance, and modulation of the locomotive program and supports the alternating activation of antagonistic muscles. To better understand the role of inhibition in locomotion, we used C. elegans as an animal model, and challenged a prevalent hypothesis that cross-inhibition supports the dorsoventral alternation only during backward locomotion. We find that inhibition is not necessary for muscle alternation during slow undulation in either forward or backward locomotion; however, it is crucial to sustain rapid dorsoventral alternation. We combined behavior analysis and calcium imaging of motoneurons and muscle cells with computational models to test hypotheses for the role of inhibition in locomotion.
239, Introduction 651, Discussion 1500• Conflict of interest statementThe authors declare no conflicts of interest.• Acknowledgments LD thanks her thesis committee: Farzan Nadim, Daphne Soares, Andrew Leifer, and Eric Fortune for useful discussions, encouragement, and support. JED and NC thank Thomas Ranner for useful and critical discussions. Some strains were provided by the CGC, which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440).We also thank the National Bioresource Project of Japan, and the Takagi and Nakai Laboratories for providing strains. NC was funded by EPSRC (EP/J004057/1). Abstract 1Inhibition plays important roles in modulating the neural activities of sensory and motor systems 2 at different levels from synapses to brain regions. To achieve coordinated movement, motor 3 systems produce alternating contraction of antagonist muscles, whether along the body axis or 4 within and among limbs. In the nematode C. elegans, a small network involving excitatory 5 cholinergic and inhibitory GABAergic motoneurons generates the dorsoventral alternation of 6 body-wall muscles that supports undulatory locomotion. Inhibition has been suggested to be 7 necessary for backward undulation because mutants that are defective in GABA transmission 8 exhibit a shrinking phenotype in response to a harsh touch to the head, whereas wild-type animals 9 produce a backward escape response. Here, we demonstrate that the shrinking phenotype is exhibited 10 by wild-type as well as mutant animals in response to harsh touch to the head or tail, but only GABA 11 transmission mutants show slow locomotion after stimulation. Impairment of GABA transmission, 12 either genetically or optogenetically, induces lower undulation frequency and lower translocation 13 speed during crawling and swimming in both directions. The activity patterns of GABAergic 14 motoneurons are different during low and high undulation frequencies. During low undulation 15 frequency, GABAergic VD and DD motoneurons show similar activity patterns, while during high 16 undulation frequency, their activity alternate. The experimental results suggest at least three non-17 mutually exclusive roles for inhibition that could underlie fast undulatory locomotion in C. elegans, 18 which we tested with computational models: cross-inhibition or disinhibition of body-wall muscles, or 19 inhibitory reset. 20 21Significance Statement 22Inhibition serves multiple roles in the generation, maintenance, and modulation of the locomotive 23 program and supports the alternating activation of antagonistic muscles. When the locomotor 24 frequency increases, more inhibition is required. To better understand the role of inhibition in 25 locomotion, we used C. elegans as an animal model, and challenged a prevalent hypothesis that 26 cross-inhibition supports the dorsoventral alternation. We demonstrate via behavior analysis that 27 inhibition is related to speed rather than the direction of locomotion and that it is unnecessary for 28 muscle alternation during...
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