Excitatory motor neurons are local oscillators for backward locomotion

Abstract

Cell- or network-driven oscillators underlie motor rhythmicity. The identity of C. elegans oscillators remains unknown. Through cell ablation, electrophysiology, and calcium imaging, we show: (1) forward and backward locomotion is driven by different oscillators; (2) the cholinergic and excitatory A-class motor neurons exhibit intrinsic and oscillatory activity that is sufficient to drive backward locomotion in the absence of premotor interneurons; (3) the UNC-2 P/Q/N high-voltage-activated calcium current underlies A motor neuron’s oscillation; (4) descending premotor interneurons AVA, via an evolutionarily conserved, mixed gap junction and chemical synapse configuration, exert state-dependent inhibition and potentiation of A motor neuron’s intrinsic activity to regulate backward locomotion. Thus, motor neurons themselves derive rhythms, which are dually regulated by the descending interneurons to control the reversal motor state. These and previous findings exemplify compression: essential circuit properties are conserved but executed by fewer numbers and layers of neurons in a small locomotor network.

Whole integration of neural connectomics, dynamics and bio-mechanics for identification of behavioral sensorimotor pathways in Caenorhabditis elegans

“…How the information from stimuli is translated to movements and how movements shape neural responses is a fundamental question in neuroscience. Although Central Pattern Generator (CPG) networks, responsible for generating rhythmic neural activity and motor behavior, were found in various organisms, e.g., the locust, the lamprey, and recently in C. elegans, many details of sensorimotor integration and functional pathways guiding neural activity and movements are still to be resolved (1)(2)(3) .…”

Gain-of-function mutations in the UNC-2/CaV2α channel lead to hyperactivity and excitation-dominant synaptic transmission in Caenorhabditis elegans

“…unc-2 (Schafer and Kenyon, 1995). UNC-2/CaV2α is exclusively expressed in the nervous system (Mathews et al, 2003) and localizes to presynaptic zones, at synaptic vesicle release sites (Saheki and Bargmann, 2009), as well as at the plasma membrane of neural somas (Gao et al, 2018). Behaviorally, unc-2 loss-of-function (lf) mutants are sluggish and uncoordinated (Mathews et al, 2003).…”

“…Behaviorally, unc-2 loss-of-function (lf) mutants are sluggish and uncoordinated (Mathews et al, 2003). Furthermore, unc-2(lf) mutants have a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs) (Richmond et al, 2001), and reduced intrinsic neuronal calcium oscillations (Gao et al, 2018).…”

“…These findings suggest that FHM1 mutations cause a dysregulation of cortical excitatory-inhibitory balance (Vecchia and Pietrobon, 2012) but the mechanisms that underlie this excitatory/inhibitory (E/I) imbalance in the nervous system remain poorly understood.The genome of the nematode Caenorhabditis elegans encodes a single CaV2α subunit gene:unc-2 (Schafer and Kenyon, 1995). UNC-2/CaV2α is exclusively expressed in the nervous system (Mathews et al, 2003) and localizes to presynaptic zones, at synaptic vesicle release sites (Saheki and Bargmann, 2009), as well as at the plasma membrane of neural somas (Gao et al, 2018). Behaviorally, unc-2 loss-of-function (lf) mutants are sluggish and uncoordinated (Mathews et al, 2003).…”

“…Behaviorally, unc-2 loss-of-function (lf) mutants are sluggish and uncoordinated (Mathews et al, 2003). Furthermore, unc-2(lf) mutants have a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs) (Richmond et al, 2001), and reduced intrinsic neuronal calcium oscillations (Gao et al, 2018).In this study, we characterize a novel unc-2/CaV2α gain-of-function (gf) mutant, which, in sharp contrast to the loss-of-function mutant, exhibits hyperactive-as well as seizure-Iike motor behaviors.We show that the expression of an unc-2 gene carrying FHM1 mutations results in a similar hyperactive behavioral phenotype, while the intragenic suppressor alleles of unc-2(gf) resemble EA2 mutations and are lethargic. We reveal that the unc-2(gf) mutation shifts the E/I balance towards excitatory transmission, and an increased excitatory signaling leads to the destabilization of GABAergic synapses in a TAX-6/calcineurin-dependent manner.…”