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Riddle DL, Blumenthal T, Meyer BJ, et al., editors. C. elegans II. 2nd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 1997.

Cover of C. elegans II

C. elegans II. 2nd edition.

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Section IIntroduction: the Neural Circuit For Locomotion

Diverse mechanical stimuli are likely to be encountered constantly in Caenorhabditis elegans' normal habitat, the soil. Therefore, it is not surprising that C. elegans utilizes mechanosensory neurons to regulate many of its behaviors. Touch regulates locomotion, foraging, egg laying, pharyngeal pumping, and defecation. Mechanosensory inputs not only give rise to simple reflexive avoidance behaviors, but also appear to control the overall activity of the animal. In this chapter, we describe the neural circuits for locomotion, foraging, and touch avoidance, their genetic analysis, and a molecular model for mechanosensory transduction. Since understanding regulation of locomotion by mechanical stimuli requires knowledge of the neural circuit for locomotion, we first describe this circuit with a focus on three key questions: How is the sinusoidal pattern of body bends generated? How are the antagonistic behaviors of forward and backward locomotion coordinated? How is the sinusoidal wave propagated along the body axis?

A. Musculature and Motor Neuron Innervation

The anatomy of the body wall muscles and of their synaptic inputs restricts locomotion to dorsal and ventral turns of the body. Locomotion consists of a sinusoidal pattern of alternating ventral and dorsal turns of the body musculature. The body wall muscles are organized into two dorsal rows and two ventral rows. Each row consists of 23 or 24 diploid mononucleate muscle cells arranged in an interleaved pattern (Sulston and Horvitz 1977). Dorsal and ventral body muscles are controlled by distinct classes of motor neurons. Five types of ventral cord motor neurons (A, B, D, AS, and VC) are defined by similarities in axonal morphologies and patterns of synaptic connectivities (White et al. 1986). Motor neuron processes have presynaptic regions, which form neuromuscular junctions and provide input to other neurons, and postsynaptic regions, which receive input from other neurons. Some classes of neurons (VA, VB, VC, and VD) form neuromuscular junctions with the ventral body muscles, whereas others (AS, DA, DB, and DD) innervate the dorsal muscles. Each motor neuron class is composed of multiple members, which are arrayed along the length of the ventral cord in repeating units (e.g., VA1−VA6). Equivalent motor neuron classes are found in the nervous system of Ascaris suum (Stretton et al. 1978; Johnson and Stretton 1980). Unlike C. elegans neurons, Ascaris neurons are large and amenable to electrophysiological study. Since the nervous systems of these two nematodes are largely homologous, neurophysiological properties of C. elegans neurons can be inferred from analyses in Ascaris.

To generate the sinusoidal pattern of movement, the contraction of the dorsal and ventral body muscles must be out of phase. For example, to turn the body dorsally, the dorsal muscles contract while the opposing ventral muscles relax. A pattern of alternating dorsal and ventral contractions is produced by interactions between excitatory and inhibitory motor neurons. The A, B, and AS motor neurons utilize the neurotransmitter acetylcholine (J. Duerr and J. Rand, unpubl.) and are likely to be excitatory. Consistent with this are physiological measurements showing that the analogous Ascaris motor neurons are both cholinergic and excitatory (Johnson and Stretton 1985; Walrond et al. 1985a). The D-type neurons are inhibitory and utilize GABA as their transmitter (McIntire et al. 1993b).

The A- and B-type neuromuscular junctions are organized into characteristic dyadic complexes in which an A or B synaptic terminus is apposed to two distinct postsynaptic elements, a body wall muscle and a D neuron dendrite (White et al. 1986). The pattern of these dyadic synapses is highly asymmetric. The VD neurons receive input at the dorsal A- and B-type neuromuscular junctions (and hence are likely to be active during dorsal muscle contractions), and they form neuromuscular junctions ventrally that appear to relax the ventral muscles. The converse set of connections obtain for the DD neurons. This pattern of connectivities led to the proposal that the D neurons act as cross-inhibitors that prevent the simultaneous contraction of the dorsal and ventral muscles (White et al. 1986).

This model for cross-inhibition is supported by genetic analysis and cell ablations in C. elegans and by physiological studies in Ascaris. In C. elegans, mutations in the unc-25 gene, which encodes the GABA biosynthetic enzyme glutamic acid decarboxylase (Y. Jin and R. Horvitz, unpubl.), or killing the D neurons with a laser microbeam causes the simultaneous contraction of the dorsal and ventral muscles so that animals shrink along their body axis (Brenner 1974; McIntire et al. 1993a,b). In Ascaris, the excitatory cholinergic motor neurons activate the inhibitory GABAergic motor neurons, which in turn relax the opposing muscles (Walrond and Stretton 1985b). Together, these results strongly support the model that synaptic interactions between excitatory (A and B) and inhibitory (D) motor neurons prevent simultaneous contraction of dorsal and ventral muscles.

The unc-25 phenotype suggested a second function for the D-type neurons. When at rest, unc-25 mutants have a straight rather than sinusoidal posture, and when moving, they generate a wave with greatly reduced amplitude (McIntire et al. 1993b), implicating the D neurons in the regulation of wave amplitude. In Ascaris, the FMRFamide peptide AF1 modulates the activity of the cross-inhibitors, greatly reducing the domain of muscle relaxation (Cowden et al., 1989). The D-type neurons of C. elegans may also be modulated in this manner, since they are postsynaptic to the VC neurons that express FMRF-like immunoreactivity (White et al. 1986; Li and Chalfie 1990; Schinkmann and Li 1992).

How does this circuit create the rhythmic pattern of locomotory movement? In several cases in other organisms, networks of neurons have been shown to control rhythmic behaviors, and specific cells in these networks have intrinsic oscillating activity that engenders the observed rhythm. These oscillating cells have been termed pattern generators (for review, see Getting 1988). In the case of C. elegans locomotion, relatively little is known about how the rhythmicity is engendered. In Ascaris, the GABA-containing ventral cord motor neurons (equivalent to the D-type motor neurons of C. elegans) have an oscillating pattern of electrical activity, leading to the speculation that the GABA motor neurons act as the pattern generator for locomotion (Angstadt and Stretton 1989; Davis and Stretton 1989). A similar pattern-generating mechanism seems unlikely in the case of C. elegans because unc-25 and unc-30 mutants that lack functional D neurons still generate rhythmic sinusoidal movement, albeit with a reduced amplitude. Given the recent success in obtaining electrophysiological recordings from C. elegans neurons (L. Avery et al., pers. comm.), the pattern-generating activity of the locomotory circuit should be elucidated in the near future.

B. Circuits for Forward and Backward Locomotion

Forward locomotion and backward locomotion are antagonistic behaviors, controlled by distinct neural circuits (Fig. 1). Four bilaterally symmetric interneuron pairs (AVA, AVB, AVD, and PVC) have large-diameter axons that run the entire length of the ventral nerve cord and provide input to the ventral cord motor neurons (White et al. 1976). These interneurons have distinct patterns of connectivities. AVA and AVD provide input to the A-type motor neurons, whereas AVB and PVC provide input to the B-type motor neurons. Cell-killing experiments have shown that the ventral cord interneurons and motor neurons can be subdivided according to their function in forward or backward movement (Chalfie et al. 1985). The circuit comprising AVB, PVC, and the B motor neurons drives forward locomotion, whereas the circuit comprising AVA, AVD, and the A motor neurons drives backward movement. The phenotype of unc-4 mutants also supports the specific function of AVA, AVD, and the A-type neurons in backward movement. The UNC-4 homeodomain protein is expressed in the A-type neurons (Miller et al. 1992; Miller and Niemeyer 1995; see Ruvkun, this volume). In unc-4 mutants, type-A neurons have synaptic inputs characteristic of the B motor neurons, and defective backward movement results (White et al. 1992).

Figure 1. Locomotory circuitry.

Figure 1

Locomotory circuitry. (Inverted triangles) Representatives of the six major motor neuron classes; (rectangles) interneurons. Only one of each motor neuron class is shown, (more...)

Although to a first approximation forward and backward locomotion reflects the activities of competing circuits, there are several indications that these circuits functionally interact. First, disabling either circuit with a laser microbeam also causes mild defects in the opposing behavior (J. Kaplan; B. Sawin; both unpubl.). Second, mosaic analysis of GLR-1 glutamate receptors, which are expressed in the locomotory interneurons, suggests that both the forward and backward interneurons play a part in backward movement (Hart et al. 1995). Third, simultaneous activation of the forward and backward circuits with a diffuse mechanical stimulus (tap, described below) reveals that these circuits functionally inhibit each other (Wicks and Rankin 1995; see Jorgensen and Rankin, this volume). Interaction between these opposing circuits may be mediated by the unusual connectivities of the ventral cord interneurons. The forward and backward interneurons have multiple reciprocal connections, which could mediate coordination of opposing circuits (White et al. 1986).

C. Propagation of the Sinusoidal Wave

Relatively little is known about how the sinusoidal wave is propagated along the body axis. Adjacent muscle cells are electrically coupled via gap junctions, which could couple excitation of adjacent body muscles. Alternatively, ventral cord motor neurons could promote wave propagation since adjacent motor neurons of a given class are connected by gap junctions (White et al. 1986). A third possibility is that motor neurons could themselves act as stretch receptors so that contraction of body muscles could regulate adjacent motor neuron activities, thereby propagating the wave. This model (originally proposed by R.L. Russell and L. Byerly and described in White et al. 1986) was inspired by subtle morphological features of the ventral cord motor neurons. Both A and B motor neurons have long undifferentiated processes distal to the regions containing their neuromuscular junctions (White et al. 1976). These terminal, undifferentiated processes have been proposed to be stretch-sensitive. Interestingly, the anterior-posterior polarity of motor neuron processes correlates with function in either forward or backward movement. A-type neurons, required for backward movement (i.e., anteriorly propagated waves), have anteriorly directed processes, whereas B neurons drive forward movement (i.e., posteriorly propagated waves) and have posteriorly directed processes (White et al. 1986). It is not known whether motor neurons are actually stretch-sensitive, nor is the relationship between motor neuron function and axonal polarity understood.

Copyright © 1997, Cold Spring Harbor Laboratory Press.
Bookshelf ID: NBK19982

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