Experimental And Computational Analyses Of Locomotor Rhythm Generation And Modulation In Caenorhabditis Elegans

Neural circuits coordinate with muscles and sensory feedback to generate motor behaviors appropriate to its natural environment. Studying mechanisms underlying complex organism locomotion has been challenging, partly due to the complexity of their nervous systems. Here, I used the roundworm C. elegans to understand the locomotor circuit. With its well-mapped nervous system, easily-measurable movements, genetic manipulability, and many human homologous genes, C. elegans has been commonly used as a model organism for dissecting the circuit, cellular, and molecular principles of locomotion. My work introduces two separate approaches to probe the mechanisms by which the C. elegans motor circuit generates and modulates undulations. First, I quantified C. elegans movements during free locomotion and during transient muscle inhibition. Undulations were asymmetrical with respect to the duration of bending and unbending per cycle. Phase response curves induced by brief optogenetic head muscle inhibitions showed gradual increases and rapid decreases as a function of phase at which the perturbation was applied. A relaxation oscillator model was developed based on proprioceptive thresholds that switch the active muscle moment. It quantitatively agrees with data from free movement, phase responses, and previous results for gait adaptation to mechanical loads. Next, I characterized a proprioception-mediated compensatory behavior during C. elegans forward locomotion: the anterior body bending amplitude compensates for the change in midbody bending amplitude by an opposing homeostatic response. I demonstrated that curvature compensation requires dopamine signaling driven by PDE neurons. Calcium imaging experiments suggested a proprioceptive functionality for PDE in sensing midbody curvature. Downstream of PDE dopamine signaling, curvature compensation requires D2-like dopamine receptor DOP-3 in the interneurons AVK. FMRFamide-like neuropeptide FLP-1, released by AVK, regulates SMB motor neurons via receptor NPR-6 to modulate anterior bending amplitude. These results revealed a mechanism whereby proprioception works with dopamine and neuropeptide signaling to mediate homeostatic locomotor control. Together, through a consolidation of experimental and computational approaches, I found C. elegans utilizes its circuitry not only to act motor behaviors but to adjust/correct its ongoing behaviors in its natural contexts.