The adult C. elegans hermaphrodite has 302 neurons that belong to two distinct and independent nervous systems: a large somatic nervous system (282 neurons) and a small pharyngeal nervous system (20 neurons). These systems communicate through a single pair of RIP interneurons (NeuroFIG 1) (Ward et al., 1975; Sulston and Horvitz, 1977; Sulston et al., 1983; White et al., 1986). (For a discussion of the pharyngeal nervous system, see Alimentary System - Pharynx ) The two nervous systems differ in their topologies. In the somatic nervous system, the neurons and their processes are generally positioned between the hypodermis and the body wall muscle and share a basal lamina with the hypodermis that isolates them from the muscles (NeuroFIG 2). In contrast, the pharyngeal neurons lie directly among the pharyngeal muscles and are not separated from their muscle targets by a basal lamina. The neurons in the hermaphrodite have been assigned to 118 distinct classes according to their topology and synaptic connection patterns (White et al., 1986). Cell bodies of most neurons are clustered in ganglia in the head or tail (NeuroFIG 1). C. elegans has 56 neuronal support cells (including the GLR cells; see Muscle System - GLR Cells), which are associated only with the somatic nervous system. The neurons communicate through approximately 6400 chemical synapses, 900 gap junctions, and 1500 neuromuscular junctions (NMJs). Among individual animals, the location of chemical synapses is about 75% reproducible (Durbin, 1987). Every C. elegans neuron name consists of either two or three uppercase letters indicating class and in some cases a number indicating the neuron number within one class. If the neurons are radially symmetrical, each cell has a three-letter name followed by L (left), R (right), D (dorsal), or V (ventral). A complete list of C. elegans neurons, their lineage, and descriptions can be found in the Individual Neuron section of the WormAtlas.

Males have a larger nervous system with 473 cells (with an additional 79 neurons and 36 support cells). Most of these extra, male-specific cells are involved in male mating behavior and are located in the posterior body (Sulston et al., 1980; Lipton and Emmons, 2003; Emmons, 2005). The four CEM (cephalic neuron in male) neurons are an exception; they are located in the head as part of the male cephalic sensilla. The hermaphrodite has only two classes of hermaphrodite-specific neurons: HSN, which are generated in males but go through programmed cell death during early development, and VC neurons, which are derived from the P lineages that give rise to cells of the hook sensillum in males. All of the neurons in both sexes have been individually identified and their lineages described. The connectivity among the hermaphrodite neurons has been established from electron micrographs of serial thin sections, whereas the connectivity of the male nervous system has been the focus of more recent studies (Ward et al., 1975; Ware et al., 1975; White et al., 1986; Durbin, 1987; Hall and Russell, 1991; Chen et al., 2006; see also Male Anatomy.

Despite its compact nervous system, C. elegans is capable of several complex behaviors, in addition to the basics such as locomotion, foraging, feeding, and defecation (de Bono and Maricq, 2005). The animal can discriminate and move toward or away from chemicals, odorants, temperatures, and food sources. It can also detect the presence, density, and sex of nearby nematodes by short-range diffusible signals, by a pheromone, and by changes in oxygen levels (Riddle and Golden, 1982; Cheung et al., 2004; Gray et al., 2004; Jeong et al., 2005; Barr and Garcia, 2006). The animal displays social feeding behavior (de Bono, 2003). Each sex also displays sex-specific behaviors such as egg-laying in hermaphrodites and mating behavior in males (Schafer, 2005). Most of these behaviors are plastic and therefore subject to change through learning and memory (Giles et al., 2006). Additionally, food is a significant modulator of many C. elegans behaviors, including egg-laying, feeding, locomotion, and olfactory behavior, often through serotonin-dependent pathways (Zhang et al., 2005). The neuron circuits that are dedicated to each of these behaviors may communicate via interneurons to produce hierarchies in their execution. For example, in stressful environments where food is scarce, egg-laying behavior is suppressed, whereas after an encounter with food, locomotion behavior becomes suppressed in a starved animal, allowing the animal to feed properly.

Almost all C. elegans neurons have simple monopolar or bipolar morphologies with mostly unbranched processes that follow nearly identical trajectories in each animal (NeuroFIG 3). A few motor neurons, including VC4 and HSN neurons, make several simple branches as they reach their muscle targets. PVD and FLP neurons are unique in C. elegans because they branch extensively near each body muscle quadrant after early larval stages. Many neurons in the adult male tail are also more highly branched within the preanal ganglion, where some neurons can have four to eight separate branches within the neuropil (S.W. Emmons, J.E. Sulston, D.G. Albertson, M. Xu, and D.H. Hall, unpubl.). Some neuron processes may have pure sensory functions (a dendrite) or pure synaptic output functions (an axon), but many have mixed functions capable of both receiving inputs and sending outputs (a neurite or process).

Neuronal somata are among the smallest in the nematode. In transmission election microscopy (TEM) sections, they are seen as having relatively lightly staining cytoplasm, with a compact nucleus, distinctive rough endoplasmic reticulum (RER), several mitochondria, small clusters of synaptic vesicles, and one or more Golgi bodies. Most of the neuronal nucleus is filled with light-staining “euchromatin,” with a modest amount of dark “heterochromatin,” and one or more small round nucleoli. Under differential interference contrast (DIC) microscopy, neuronal nuclei can easily be distinguished as small, stippled ovals (NeuroFIG 1). The processes of individual neurons are generally very thin (100–200 nm in diameter), but show local swellings with clusters of vesicles at synaptic regions along the length of the process (White et al., 1986). Within each neurite or major side branch, a small bundle of microtubules (MTs) runs continuously along its length. In addition, each neurite contains a small tube of smooth endoplasmic reticulum (ER) and occasional mitochondria. A few small clusters of free ribosomes sometimes lie within the neurite not far from synapses, either on the presynaptic or post-synaptic side (Rolls et al., 2002). The exact position of synaptic swellings or short side branches is not identical among animals; however, the polarity, handedness, and position of a cell’s main processes are very predictable.

2.1 Nervous System Development

2.1.1 Cell Birth, Programmed Cell Death and Cell Migration

C. elegans neurons are generated at three main developmental periods. The first is during the proliferation phase of embryogenesis, the second at the late-L1 stage, and the third at the L2 stage (Sulston and Horvitz, 1977; Sulston et al., 1983). At the time of hatching, the hermaphrodite worm has 222 neurons (202 somatic, 20 pharyngeal) and most of these derive from the AB lineage (the male worm has 224 neurons at this stage). All of the glial cells arise from the AB lineage. MS (six neurons) and C (two neurons) lineages contribute only a few neurons to the nervous system. During late L1, five classes of ventral nerve cord (VNC) motor neurons are generated from P and W lineages (see Postembryonic Neurons Table). Also at this time, additional neurons are generated from Q, G1, H2, T, and K lineages. In the L2 stage, the G2 blast cell divides to give rise to the excretory socket cell and RMF neuron pair, and V5paa generates the cells of the posterior deirids on both sides (see Epithelial system - Hypodermis). In males, the additional neurons that function in male mating are born during the L3 stage (Sulston et al., 1980). As a general rule in C. elegans neurogenesis, most bilaterally symmetric pairs of neurons arise from bilaterally symmetric cell lineages, but there are exceptions to this rule.

C. elegans uses programmed cell death in two contexts during neurogenesis: to generate sexual dimorphism in certain parts of the nervous system (death of CEM cells in the hermaphrodite and HSN cells in the male) and to eliminate extra motor neuron production in the VNC. The ap daughters of P3a–P8a become VNC motor neurons, whereas the corresponding cells in the other P lineages die (see Epithelial system - Hypodermis). Similarly, P11aaap and P12aaap are eliminated instead of becoming additional VB cells (Sulston, 1976).

Developmentally, neuronal cell movements can be divided into early mass migrations and later individual cell migrations. During embryogenesis, mass neuroblast movements occur to close the ventral cleft (at ~230–290 min after first cell cleavage, dorsal and lateral neurons sink towards inside and adjacent hypodermal cells cover the ventral side). They also occur later at comma stage when anterior neuron groups move toward the tip of the head to form rudiments of the head sensilla (see Epithelial system - Hypodermis). During this time, a sensory depression forms at the tip of the head to provide more surface area for the newly forming sensilla, and later everts (Sulston et al., 1983). Cell bodies of the head sensilla neurons later migrate posteriorly, leaving their dendritic processes stretching behind as attached to the lips. Two extracellular matrix proteins , DYF-7 and DEX-1, are required to anchor these nascent dendritic processes to the lips, since in dyf-7 or dex-1 mutants dendrites remain short and stubby and are dragged along by the neuron cell bodies as they pull away (Heiman & Shaham, 2009). Additionally, the anchoring of dendrites of amphid neurons of each side is highly coordinated, since failure of one dendrite to anchor leads to the failure of attachment of the remaining dendrites of the same side. Subsequent to these events, during elongation, the head neurons are pushed aside as the pharynx grows forward through the mass of neurons surrounding the developing nerve ring (NR). By late embryogenesis, the neurons around the NR settle into their recognizable positions. In later stages, despite the mechanical force generated by body movements, the organization of cells in head ganglia is mostly maintained through homophilic and heterophilic interactions of cell adhesion molecules expressed on the surfaces of the neurons (Sasakura et al., 2005). There are some exceptions to this however; in live animals, cells can sometimes be seen to flip from one side of the anterior bulb to the other as the pharynx moves (Z. Altun, unpublished observations; White et al., 1986).

Although relative positions of cell bodies within ganglia are fairly well conserved between animals of the same developmental stage and genotype, there is still a certain amount of natural variation. These fall into four groups (Z. Altun, unpublished observations; Bargmann and Avery 1996):
1- posterior lateral ganglia neurons (e.g. AIN, RIC, AIZ, ADEso, AVD)
2- postembryonic neurons in the tail (e.g. PHC, PLN, PVN, PVW)
3- postembryonic neurons in the ventral cord (ASn, VAn, VBn, VCn, VDn)
4- the anterior socket and sheath cells in the head, such as ILsh, ILso, OLQso

The most extreme cases of variability of cell position in the head are seen around the anterior bulb of the pharynx which fits fairly tightly in the body cavity and excludes these cell bodies from its region of maximum diameter. This leads to variability in the position of cell bodies with respect to the bulb. For example, in the N2U animal, OLQsoDL lies anterior to the bulb, whereas its symmetrical partner, OLQsoDR, lies posterior to the bulb (White et al., 1986).

Most neurons are born close to their ultimate positions and need migrate only short distances. However, there are a few neurons that must migrate long distances after they are born (NeuroFIG 4A,B) (Hedgecock et al., 1987; Montell, 1999). This group includes canal-associated neurons (CAN), which move from the anterior end to a location midway along the body; HSN neurons, which move from the posterior end to close to the vulva; and anterior lateral microtubule (ALM) neurons, which move posteriorly from the anterior edge of the intestine to midway within the anterior body. QR and QL neuroblasts also migrate extensively (NeuroFIG 4). QR and QL are born about 1 hour before hatching at symmetric locations on the right and left sides of the posterior body, respectively, but after cell migrations their terminally differentiated progeny reside in nonsymmetric positions. Soon after hatching, QR migrates anteriorly, whereas QL migrates posteriorly. Their descendents continue migrating asymmetrically to anterior positions on the right side and posterior positions on the left (Salser and Kenyon, 1992). Each Q lineage produces a mechanosensory neuron (AVM/PVM), a sensory neuron (AQR/PQR), an interneuron (SDQR/L), and two programmed cell deaths.

Some neurons display delayed maturation during development. The Y cell functions as a rectal epithelial cell until early larval stages, but later becomes terminally differentiated as PDA in the hermaphrodite. The embryonically born HSN neurons develop synapses onto newly born sex muscles only in the L3 and L4 stages (White et al., 1986). Similarly, VC neurons branch onto sex muscles in the L4 stage. DD motor neurons acquire their final synaptic connection pattern at the late-L1 stage, after the birth of VD neurons, and AVM neurons become connected to the anterior touch circuit at the late-L4 stage (Chalfie and White, 1988; Walthall et al., 1993).

2.1.2 Process Outgrowth, Establishment of Process Tracts and Guidance at the Midline

The nervous system of C. elegans displays handedness at many places. First, although the majority of neurons are in pairs and localize on the right and left sides of the animal in a bilaterally symmetric manner, there are many unilaterally placed single neurons. Additionally, members of some neuron pairs, such as SDQL/SDQR and AQR/PQR, are positioned far away from one another in a nonsymmetrical manner (NeuroFIG 4). Second, the two major cords of the animal, the VNC and dorsal cord (DC), are asymmetrical in their composition or location (NeuroFIG 4 and NeuroFIG 5). The DC is located at the left side of the dorsal hypodermal ridge, whereas the VNC has a thick fascicle on the right side of the ventral hypodermal ridge and a thin fascicle on the left. Third, the neurons in the body choose the side of the body on which to send their processes; although the pair of HSN neurons extends its neurites ipsilaterally along the two VNC tracts, many neuron pairs, such as PVD and PDE, have both of their neurites in the right tract, which requires the left-sided process to cross the midline. Similarly, the VNC motor neurons, which are localized at the midline, make “choices” regarding the side on which to grow their circumferential processes, whereas all of them extend their ventral processes along the right VNC tract. The right fascicle of the VNC is further populated by some NR processes that exit the NR on the left side, but then decussate to the right to continue extending within the VNC (NeuroFIG 5, top panel right side and panel C) (White et al., 1986).

Asymmetry within the C. elegans VNC is established embryonically by pioneer neurons and midline cues provided by neuronal and nonneuronal (e.g., hypodermal and glial) tissues (NeuroFIG 4). AVG and PVT neurons mark the anterior and posterior boundaries of the VNC. AVG is the anterior guidepost neuron that pioneers the right tract of the VNC, whereas PVPR pioneers the left tract from the posterior, followed by the PVQL process (Durbin, 1987; Wadsworth and Hedgecock, 1996; Wadsworth et al., 1996). PVQ axons pioneer the lumber commissures and continue to travel alongside the PVP processes in the VNC. Although the PVPR axon is absolutely required for proper outgrowth of left-tract neurites, the AVG axon is essential for the correct outgrowth of only a subset of processes into the right tract (Hutter, 2003; Hutter et al., 2005). PVT, a single neuron in the preanal ganglion, serves as a guidepost neuron to growing axons from the lumbar ganglia in the posterior of the VNC. When PVT is ablated embryonically, these axons follow multiple routes to enter the VNC instead of making tight bundles in the two lumbar commissures (Wadsworth et al., 1996; Antebi et al., 1997; Ren et al., 1999). PVT is also required for maintenance of neurite architecture in the VNC post-embryonically, because in the absence of PVT, embryonically generated neurites are unable to maintain their positioning along the cord at the L1 stage and erroneously cross over the midline into the opposite fascicle (Aurelio et al., 2002; Hobert and Bülow, 2003). BDU processes are required for correct positioning of AVM branches in the NR (Chalfie and White, 1988). Notably, RIF neurons, which are the first processes to cross the ventral midline between the NR and the beginning of the VNC, are not essential for providing the pathway for guiding processes into the right VNC fascicle at the anterior decussation (Durbin, 1987; Hutter, 2003). The two neuron pairs, which decussate shortly after RIF, SABVs, and RIGs, are also not essential for this function.

Of the 302 neurons in the adult hermaphrodite,180 project axons/processes into the NR. In the developing embryo, these axons that form the nerve ring must navigate to the NR within commissural and longitudinal nerve bundles, recognize the region of the NR, make L/R side choices to enter the NR, make specific contacts with each other to form synapses and maintain these contacts during later growth. Additionally, head and neck muscle development has to be coordinated with the longitudinal and commissural tract and nerve ring development. Currently, little is known about the procession and control of the NR development. Based on studies of embryos at 350 min and 430 min (after first cleavage,) it has been suggested that SIBD neurons act as pioneers to might provide a substrate for the formation of early amphid commissure, while RIH and RMEV might help navigate the first axons entering the NR from the ventral side (Norris, C., Hall, D. H., Hedgecock, E. unpublished observations) (NeuroFIG 15-2). In the early neurula, head muscle cells directly surround the pharynx where the NR will form and hence may restrict the access of lateral axons to reach the NR until the muscle cells move dorsally and ventrally to the periphery to their usual positions next to the hypodermis. As they migrate, they are suggested to leave railing processes behind attached to the NR, forming the arms of the head muscles (see Somatic Muscle).

Outgrowth, branching, and shaping of neuronal processes, which are dependent on intrinsic cytoskeletal dynamics and extrinsic cues, are highly stereotyped in C. elegans. Mutant studies have uncovered several genes that seem to be involved in proper process outgrowth and suppression of excess axon branching (Altun-Gultekin et al., 2001; Knobel et al., 2001; Bülow et al., 2002). Neurons that extend commissures use the classical UNC-6/netrin and SLT-1/slit pathways, which act redundantly, as well as additional pathways that act in parallel to these, for circumferential guidance along the dorsoventral axis (for review, see Chisholm and Jin, 2005). Intrinsically, cytoskeletal rearrangements are regulated by Rac GTPases and the actin-binding protein UNC-115 (Yang and Lundquist, 2005). Extracellularly, guidance cues are modified by heparan sulfate proteoglycans, which affect neurite branching and patterning in a cellular context-dependent manner (Bülow and Hobert, 2006.) Although the mechanisms for branch-point control are still unclear, branching generally occurs under four circumstances: (1) Processes may enter midway along an existing nerve and bifurcate and grow in both directions; (2) processes are confronted with two equivalent neighborhoods, such as the entrance to the NR, and they may split and grow into both; (3) within the NR, processes may also bifurcate to enter two different neighborhoods; and finally, (4) processes in longitudinal nerves may bifurcate and grow a branch circumferentially into another nerve (Hedgecock et al., 1987).

2.1.3 Developmental Plasticity

The C. elegans nervous system exhibits various forms of plasticity as it matures. At the end of the L1 stage, post-embryonically born body wall muscles and five classes of newly born motor neurons are incorporated into the existing motor system and novel neuromuscular junctions are established, suggesting reciprocal responsiveness between the muscles and motor neurons. The end of the first larval stage also marks the rewiring of the synaptic contacts of DD motor neurons after the birth of VD motor neurons. This rewiring is intrinsically controlled and is not dependent on VD, VA, or VB neurons (White et al., 1978). Additionally, the neurons maintain similar densities of synapses during the fivefold increase in body length as the animal goes through four larval stages, suggesting that the nervous system maintains a certain level of plasticity throughout life and adjusts itself to the overall growth.

2.2 Neuron Categories

C. elegans neurons fall into four functional categories defined by their circuitry: (1) motor neurons, which make synaptic contacts onto muscle cells; (2) sensory neurons, which have obvious sensory specializations (behavioral or mutant paradigms now demonstrate defined sensory functions for most of these cells, but some cells only have inferred or yet obscure sensory capabilities; NeuroTABLE 1); (3) interneurons, which receive incoming synapses from and send outgoing synapses onto other neurons; and (4) polymodal neurons, which perform more than one of these functional modalities. A pair of pharyngeal neurons, NSML/R, have prominent secretory terminals and are classified as neurosecretory neurons (they also have motor function; see Alimentary System - Pharynx). Besides these categories, there is a small subset of neurons whose functions are yet unknown. Some of these may be more important in process guidance or maintenance than in circuitry (Durbin, 1987; Chen et al., 2006; Hall et al., 2006).

The locomotory behavior repertory of C. elegans includes "crawling" on solid surfaces and "swimming/thrashing" in liquid media. A total of 113 of the 302 C. elegans neurons belong to the motor neuron category, and they control crawling and swimming behaviors as well as the motility of the alimentary and reproductive systems. Of these 113, 75 innervate 79 body wall muscles posterior to the head (16 neck and 63 body muscles) and belong to eight distinct classes (AS, DA, DB, DD, VA, VB, VC, and VD) (NeuroFIG 6, NeuroFIG 7 and NeuroFIG 8). A- and B-type motor neurons (VA, VB, DA, DB, AS) are cholinergic and stimulatory. D-type motor neurons (VD, DD) secrete γ-aminobutyric acid (are GABAergic) and are inhibitory and strictly post-synaptic to other motor neurons. VC motor neurons express several transmitters and their primary targets are vulval muscles. VA, VB, VC, and VD classes innervate ventral muscles, whereas DA, DB, DD, and AS classes innervate the dorsal muscles by sending commissures to the dorsal side (White et al., 1976, 1986).

The VNC neurons regulate the characteristic undulatory movement of the animal, which involves alternate contraction of the dorsal and ventral longitudinal muscle rows. These motor neurons synapse onto either both dorsal or both ventral muscle quadrants, thereby restricting the body’s flexures to the dorsoventral plane, creating sinusoidal waves as the animal lies on its lateral side on the substrate. When the dorsal muscles are activated, the ventral muscles are reciprocally inhibited and vice versa. Bending against the substrate results in forward locomotion as a result of propagation of sequential contraction and relaxation waves passing backward along the body. D-type motor neurons have processes that are post-synaptic corecipients at the dyadic NMJs of stimulatory (A- or B-type) motor neurons, and the ventral D and dorsal D neurons work as reciprocal cross-inhibitors. Their GABAergic synaptic outputs are onto diametrically opposite muscles, so that when a ventral or dorsal muscle group is activated by a cholinergic motor neuron, the opposite group of muscles is inhibited and relaxed (NeuroFIG 6) (White et al., 1978; McIntire et al., 1993). D-type motor neurons are most important for resetting the animal’s posture, for example, when reversing direction or initiating rapid movement (Jorgensen and Nonet, 1995; Jorgensen, 2006). In response to a touch, an animal that lacks GABA input shrinks due to unopposed contraction of both dorsal and ventral muscles. Once an animal gets moving, GABA input does not interfere with wave propagation; however, it does affect the amplitude of the body waves.

Movement in either forward or reverse directions is regulated by signals from specific classes of command interneurons (NeuroFIG 6A). Forward motion is promoted by input from AVB and PVC interneurons onto DB and VB neurons, whereas backward motion is promoted by input from AVA, AVD, and AVE interneurons onto DA and VA neurons (NeuroFIG 6) (Chalfie and White, 1988; Driscoll and Kaplan, 1997; Von Stetina et al., 2006). Synaptic innervation of motor neurons by command interneurons occurs throughout the length of the VNC. Command interneurons establish the direction of locomotion, but are not thought to be involved in wave propagation down the length of the animal (Jorgensen and Nonet, 1995). It is currently unclear which neurons are involved in wave propagation, although proprioceptive inputs are thought to have a role. The command interneurons are not equivalent because ablation of AVA or AVB produces uncoordinated animals (after a bout of forward or backward motion, animals kink while trying to reverse their direction) that are touch responsive, whereas ablation of PVC or AVD mainly abolishes the touch-mediated locomotory responses, but does not result in any change in spontaneous locomotion (Chalfie et al. 1985).

The members of each class of body motor neurons are evenly distributed along the length of the ventral cord between the retrovesicular ganglion (RVG) and preanal ganglion (PAG). They create a longitudinal, synaptic fate map onto the body muscles (NeuroFIG 6C, NeuroFIG 7 and NeuroFIG 8). Within each class of motor neurons there is little or no overlap in the output regions of adjacent members (White et al., 1976). The cell bodies of motor neurons are covered by the hypodermal basal lamina and lie on top of the ventral hypodermal ridge or are wedged between the ridge and the processes of the right tract of the VNC.

Motor neurons are generated at two distinct developmental stages: first, around midembryogenesis and then, during the first larval stage (Sulston and Horvitz, 1977; Sulston et al., 1983). DA, DB, and DD are the only classes of motor neuron present in the VNC at hatching. They are born at midembryogenesis and simultaneously extend commissures to the DC. Command interneurons that make synapses onto them enter the VNC after motor neuron outgrowth is completed. During the L1 stage, DA and DB innervate dorsal muscles and DD innervates ventral muscles. DD dendrites receive input from DA and DB at dyadic synapses onto the dorsal muscle arms. After hatching, the other five classes (additional 56 motor neurons) are generated by 13 (W and Pn) blast cells (see Epithelial System - Hypodermis ). The anterior daughters of the first division of P cells (Pna) give rise to 53 of these (Sulston et al., 1983). The processes from these later-born cells insert themselves into the cord between existing fibers to establish contacts with appropriate command interneurons and muscle cells. After post-embryonic motor neurons are born, DD neurons reverse their synaptic polarity without undergoing any structural change in process placement (White et al., 1978). They rearrange their synaptic machinery to receive input from the nascent VA and VB motor neurons and send output to dorsal muscles. An additional excitatory class of neurons, SABVL/VR/D, innervates anterior ventral body muscles only in the L1 stage; after this stage, they function as interneurons.

Unlike the body, the head of the animal is capable of making lateral movements as well as dorsoventral flexures, especially during foraging behavior. Head and neck muscles are innervated by about 11 classes of motor neurons in the NR in a complex pattern (see Somatic Muscle). Additional nerve–muscle contacts occur along the length of the sublateral cords (J. Duerr et al., unpubl.). Most axons in these nerve cords show periodic swellings filled with synaptic vesicles and sometimes have small presynaptic densities. The post-synaptic targets of these synaptic release zones are possibly the body muscles. The specialized motor neurons of the alimentary and reproductive systems that are associated with defecation and egg-laying muscles are discussed the Alimentary System - Rectum and Anus and Reproductive System - Egg-laying apparatus sections, respectively.

2.4 Sensory Neurons

C. elegans explores its environment and moves to favorable surroundings by chemotaxis, thermotaxis, and aerotaxis and escapes from harmful and noxious stimuli by avoidance/escape behaviors. The perception of environmental cues, including mechanical stimuli, temperature, many water-soluble and volatile chemicals, noxious substances, ambient osmolarity, oxygen levels, pH, and light, is accomplished through 24 sensillar organs and various isolated sensory neurons (NeuroTABLE 1) (Bargmann, 2006; Bergamasco and Bazzicalupo, 2006). Sensillar neurons perform most of the sensory functions. However, some sensory functions, including oxygen sensation and mechanosensation, are performed by nonsensillar neurons. Each sensillum contains ciliated endings of one or more neurons and often two types of glia: the socket cells and the sheath cells. Except for posterior deirids and phasmids, all sensilla are located in the head (see Neuronal Support Cells and Introduction; IntroTABLE 1).

Through the function of these neurons, C. elegans navigates thermal, chemical, and oxygen gradients by modulating the probability of its turning behavior and speed of movement on a solid surface. Turning can be produced either by a reversal of movement followed by resumption of forward movement in a new direction or by omega turns in which the animals curl their whole body so that their heads get close to or even touch their tails before starting to move forward (NeuroFIG 6) (Pierce-Shimomura et al., 1999). Alternatively, the animal can accelerate its forward-directed movement after receiving a sensory signal.

2.4.1 Mechanosensation

Mechanical stimuli, including gentle touch along the body (e.g., with a soft hair), gentle touch to the nose, harsh touch along the body (e.g., with a wire), and tapping of the culture plate, are perceived through touch receptors and proprioceptors that fall into three classes according to their cytoskeletal specialization: (1) mechanoceptors with ciliated sensory endings; (2) touch receptor neurons containing large-diameter, 15-protofilament microtubules (also called MT cells); and (3) neurons with processes containing synapse-free stretches and undifferentiated cytoskeletons (NeuroTABLE 1) (Herman, 1995; Driscoll and Kaplan, 1997; Syntichaki and Tavernarakis, 2004; Goodman, 2006; O’Hagan and Chalfie, 2006). Mechanociliary neurons display features important for sensing any mechanical deflections over the worm’s surface; IL1, CEP, OLL, OLQ, ADE, and PDE cilia terminate embedded within the cuticle, and all of them except for IL1 are anchored in this cuticle by small electron-dense nubbins. Additionally, the distal sections of ADE, PDE, OLL, and CEP cilia contain an amorphous, dark, microtubule-associated material (TAM) that is also found in mechanocilia of other species. IL1 cilia contain a dark-membrane-attached disc at their tips. All mechanosensory stimuli lead to avoidance responses in the hermaphrodite.
Mechanosensory neurons detect force through mechanically-gated ion channels which produce touch- or stretch-evoked currents. These channels are generally formed by two protein superfamilies; the TRP channels which are nonspecific cation channels composed of subunits with six transmembrane α helices, and heterotrimeric DEG/ENaC channels which are permeable to sodium and sometimes to calcium (Arnadottir and Chalfie, 2010; Bounoutas and Chalfie, 2007; Kahn-Kirby and Bargmann, 2006). The C. elegans genome encodes 28 predicted DEG/ENaC proteins and 23 predicted TRP proteins(Goodman & Schwarz, 2003).

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ALM and PLM cells are born during embryogenesis. ALM cells migrate posteriorly, a process that is completed before the elongation stage of the embryo (Sulston et al., 1983; Chalfie, 1993). In newly hatched larvae, the processes of these touch cells are located between the lateral hypodermis and the adjacent muscle quadrant. At about 12 hours post-hatching, they become engulfed by the adjacent hypodermis (Chalfie, 1993). Two other touch receptor neurons, AVM and PVM, are born post-embryonically about 9 hours after hatching at 20°C. Their processes run anteriorly within the VNC at its extreme ventral edge (NeuroFIG 5).

Each touch neuron process is 400–500 μm long in the adult and is filled with large-diameter (30 nm), 10- to 20-μm-long, 15-protofilament MTs that overlap and bundle together through cross-links (Chalfie and Thomson, 1979, 1982). The tubulin dimers MEC-12 (α-tubulin) and MEC-7 (β-tubulin) coassemble into these 15-protofilament structures (Fukushige et al., 1999). At hatching, ALM and PLM cells contain fewer and shorter MTs. By 12 hours, MTs start to increase in number and length and, by 36–48 hours, adult levels are reached (Chalfie and Thomson, 1979, 1982).

The touch receptor neurons also transduce the plate-tap response, which is considered to involve a nonlocalized touch stimulus. In the tap response, signals from the anterior touch circuit (the producer of backward movement) tend to override those from the posterior one, causing animals to reverse direction or move backward in response to a tap to the culture plate. This preference becomes especially strong at L4–adult transition (approximately 46–51 hours post-hatching) when the late-developing AVM becomes connected to the anterior touch circuit by forming an inhibitory connection to the AVB interneurons (Chalfie and Sulston, 1981; Walthall and Chalfie, 1988; Chiba and Rankin, 1990).

Touch sensation modifies other behaviors of the animal; for example, gentle body touch regulates pharyngeal pumping and egg-laying and resets the defecation cycle. These responses may be elicited by the synapses between the touch neurons and CEPs, deirid neurons, HSN motor neurons, and RIP interneurons (Syntichaki and Tavernarakis, 2004).

Harsh (high threshold) body touch. In the absence of all touch receptor neurons, the animal still retains the ability to respond to harsh touch along the body (e.g., with a wire), and this response can be eliminated by killing the PVD cells (recent results suggest ALM neurons also sense harsh touch (Chatzigeorgiou et al., 2010)). Hence, PVD neurons, which are presynaptic to command interneurons AVA and PVC, are proposed to be the mechanoceptors for harsh body touch (Way and Chalfie, 1989). In adult animals, PVD neurons show extensive branching along the body wall, from the tail to the neck of the animal, covering dorsal and ventral territories (NeuroFIG 3 and NeuroFIG 10) (Halevi et al., 2002). Multiple short branches arise from the main branches at the level of the muscle quadrants and these branches give rise to further branches subventrally and subdorsally. The molecules needed for mechanotransduction of harsh touch are not well known (O’Hagan and Chalfie, 2006). mec-3 mutant animals, in which PVD neurons do not differentiate properly, retain the ability to respond to harsh touch to the head and tail (Way and Chalfie, 1989; Tsalik et al., 2003; O’Hagan and Chalfie, 2006). A harsh touch defect in the tail is seen in the absence of PVC neurons, which may be sensing the stimulus directly or indirectly through other neurons (NeuroFIG 10C).

Harsh (high threshold) head/nose touch. Three classes of neurons, FLP, ASH, and OLQ, form ciliated endings in the nose, which transduce head-on nose touch stimuli that results in reversal of movement (NeuroFIG 10) (Kaplan and Horvitz, 1993). FLP neurons have a similar branching pattern to PVDs in the head (topologically they complement; where PVD branches end in the neck, FLP branches start) and act together with ASH neurons to sense harsh mechanical stimuli to the head (Albeg et al., 2011; Chatzigeorgiou and Schafer, 2011). OLQs may enhance this mechanoreception (NeuroFIG 10A). ASH and FLP neurons are coupled to the locomotion circuitry via gap junctions and chemical synapses made onto AVA, AVB, and AVD interneurons.

Gentle (low threshold) nose touch. Two classes of neurons, OLQ and IL1, function in aversive head-withdrawal reflex and suppression of lateral foraging movements of the head in response to gentle touch on the ventral or dorsal tip of the nose (Hart et al., 1995). IL1 and OLQ synapse onto NR motor neurons, and IL1 makes direct synapses onto head muscles. OLQ may also function in mechanosensory feedback for foraging, as the rate and amplitude of foraging in unstimulated animals is affected in OLQ-ablated animals. FLP neurons also respond to gentle nose touch and activate an escape behavior (Chatzigeorgiou and Schafer, 2011). OLQ and CEP neurons indirectly facilitate gentle nose touch responses in the FLP head nociceptors via the RIH interneuron which acts as the integrating neuron of this circuit hub(Chatzigeorgiou and Schafer, 2011).

Texture sensation. C. elegans can sense mechanical attributes of the surface material on which it navigates through the function of dopaminergic CEP, ADE, and PDE neurons (NeuroFIG 10) (Sawin et al., 2000). The capability to distinguish texture (e.g., small, round objects) helps animals to detect food in their environment, in addition to olfactory cues, and causes slowing of locomotion (food-induced slowing response).

Proprioception. Worms may sense changes in stretch and tension within their own bodies, especially during locomotion. Some neuron processes with morphologically nonspecialized, synapse-free, bare-wire portions are thought to transduce proprioceptive stimuli. Such properties have been hypothesized for many neurons, including the A- and B-type motor neurons, PHC, some pharyngeal neurons, and male tail neurons (NeuroFIG 6) (Hall, 1977; Sulston et al., 1980; Albertson and Thomson, 1984; Hall and Russell, 1991; R. Lints and D.H. Hall, unpubl.). Some of these may function to sense the degree of bending during undulatory movement, providing sensory feedback about the worm’s body posture and coordinating the degree and timing of alternating contractions and relaxations of muscles (White et al., 1986; Tavernarakis et al., 1997). A similar proprioceptive property has been proven for the DVA neuron, in which stretch sensitivity is transduced by the trp-4 membrane channel (Li et al., 2006). The DVA axon travels from its cell body in the tail anteriorly to the NR via the VNC, but it is not known to show any specializations by TEM that mark its stretch-sensitive portion. PVD may have a role in proprioception, as ablation of PVD leads to defective posture (Albeg et al., 2011). PVD and DVA neurons are presynaptic to both forward and backing command interneurons and provide input to both anterior and posterior touch circuits to maintain overall activity of the circuits. Animals lacking these neurons respond to tap stimulus with diminished forward accelerations and reversals, and mutation of the trp-4 channel or laser ablation of DVA gives rise to animals with body bending defects (Wicks et al., 1996; Driscoll  and Kaplan, 1997; Li et al., 2006).

Body wall muscles may also sense the degree of stretch within them and modulate the contractions required for organized locomotion (Liu et al., 1996). Putative “proprioceptive” endings in the pharynx are fastened by AJs or hemi-AJs to the pharyngeal cuticle (I1, I2, I3, I6), pharyngeal muscle specializations near the lumen (M3, NSM), or a muscle cell soma (I5) (Albertson and Thomson, 1976). Physiological experiments support that a few of these pharyngeal neurons may be stretch sensitive (Avery and Thomas, 1997).

2.4.2 Nociception

Nociception is the ability to recognize toxic and harmful components in the environment that allows for avoidance and survival. For C. elegans, aversive cues include mechanical stimuli (both light and harsh touch), certain odorants and toxic chemicals, high osmotic strength, acidic pH, extremes of heat and cold (see thermonociception below), and certain light wavelengths (Culotti and Russell, 1978; Tobin and Bargmann, 2004). Many of the chemicals that are noxious for C. elegans are toxic or bitter for other animals as well, including sodium dodecyl sulfate (SDS), quinine, and heavy metals such as copper (Sambongi et al., 1999; Tobin and Bargmann, 2004). It should be noted that animals in diapause are much more stress-tolerant, including heat-shock conditions (Wittenburg and Baumeister, 1999, see Dauer chapter). ASH neurons are polymodal nociceptors that detect nose touch, high osmotic strength (high concentration of salts or sugars), acidic pH, quinine and other bitter compounds, heavy metals, and aversive odors such as 2octanone, octanol, and benzaldehyde (NeuroTABLE 1). ASH neurons have cilia exposed to the outside and generate a rapid escape response in the form of reversal and turning upon encountering noxious stimuli (NeuroFIG 6) ( et al., 1986; Troemel et al., 1997; Hart et al., 1999). All ASH-mediated sensory behaviors require the TRPV channels OSM-9 and OCR-2 (Tobin et al., 2002). The diverse array of nociceptive cues sensed by ASH neurons generate distinct amplitudes and patterns of glutamate release from these neurons onto the target command interneurons that allow separable behavioral responses (Mellem et al., 2002).

2.4.3 Chemosensation and Odorsensation

C. elegans can detect and discriminate a wide range of chemical compounds, including water-soluble chemicals (chemosensation or gustatory sensation) such as anions, cations, cyclic nucleotides, biotin, and amino acids and volatile chemicals (odorsensation or olfactory sensation) such as alcohols, aldehydes, ketones, esters, pyrazines, thiazoles, and aromatic compounds (Bargmann and Mori, 1997; Mori, 1999; Bargmann, 2006). There are 32 chemo/odorsensory neurons that fall into 14 classes. Of these, 22 are paired neurons of the amphid sensilla, four are paired neurons of the phasmid sensilla, and six are IL2 neurons of the inner labial sensilla (NeuroTABLE 1; see Neuronal Support Cells). Most of the individual amphid neurons detect either water-soluble or volatile chemicals and direct either attraction or aversion, although lower concentrations of certain chemicals may be sensed as attractive, whereas higher concentrations may become repellent. A few neurons may sense both attractive and aversive cues (NeuroTABLE 1) (Bargmann and Horvitz, 1991; Bargmann et al., 1993; Troemel et al., 1997).

The ADF, ASE, ASG, ASI, ASJ, and ASK neurons mediate chemotaxis to water-soluble attractants. Among these, ASE seems to be the main sensor, with others having weaker roles. ASE is also unique because the two ASE neurons have distinct functions; the ASER preferentially detects chloride and potassium ions, whereas the ASEL preferentially senses sodium ions (Pierce-Shimomura et al., 2001). ASH neurons are the main nociceptors and mediate avoidance from water-soluble and volatile cues. ASH is complemented by other amphid neurons in these functions; ADL neurons contribute to osmosensation and avoidance from octanol, copper, and cadmium, whereas ASK and ASE contribute to avoidance of SDS and to cadmium and copper, respectively (Sambongi et al., 1999; Hilliard et al., 2002). ASJ neurons participate in formation and recovery by detecting dauer-inducing (dauer pheromone) and dauer-suppressing (food) signals in different developmental stages. ADF, ASI, and ASG function to inhibit dauer formation under favorable conditions (Bargmann and Horvitz, 1991). The three “wing” cells AWA, AWB, and AWC sense volatile chemicals, and each neuron is preferentially linked to a particular behavioral response (Wes and Bargmann, 2001). Whereas AWC and AWA mediate odortaxis to volatile attractants, AWB detects aversive odorants important for long-range escape behavior.

As described above, C. elegans lies on either of its sides and moves either forward or backward using a sinusoidal-like undulation by alternately contracting its body wall muscles along the ventral and dorsal surface. Most of the time, the animals simply move forward (smooth runs), but this forward locomotion is occasionally interrupted by a number of processes such as omega-turns, pirouettes and gentle turning. During an omega-turn the worm makes a deep bend with the worm’s head often contacting its tail, before the animal returns to forward motion along a new heading. Pirouettes are a series of reversals with one or more omega-turns that allow the worm to make major re-orientations in its direction of movement. Gentle turns (steering) are generated when the worm gradually changes its heading by a biased head swing during forward locomotion. Pirouettes appear to occur randomly, while steering appears to be a more directional process. Chemotaxis is driven by gently steering up the gradient as the worm moves forward and by altering the probability of pirouette initiation by which runs toward lower concentration are interrupted, whereas runs toward the attractant are sustained, eventually biasing the locomotion toward the higher concentration of the chemical (Appelby, 2012; Pierce-Shimomura et al., 1999; Iino and Yoshida, 2009).

2.4.4 Thermosensation

As a cold-blooded soil nematode, C. elegans can tolerate a limited temperature range (~12-27°C) at which it is both fertile and viable (Hedgecock and Russell, 1975). C. elegans can accurately detect temperatures within this range, and this is reflected in its thermotactic behavior. Following cultivation with food at temperatures ranging from 15°C to 25°C, it migrates to the cultivation temperature on a temperature gradient and continues to move isothermally at that temperature. In contrast, the animals disperse away from the temperature at which they were previously starved (Hedgecock and Russell, 1975; Mori, 1999). This thermal preference/avoidance behavior is plastic and can be reset to a new temperature associated with presence/absence of food within 2–4 hours of cultivation at that temperature. Through thermotactic behavior, C. elegans can escape unfavorable environments and regulate its position in the upper levels of soil, which may display large vertical and temporal temperature gradients. Behaviorally, C. elegans migrates towards its preferred temperature by modulating its turning rate and run length as a function of temperature change. Once it reaches within 3°C of its preferred temperature, it can fine-tune its tracking to 0.05°C differences by constantly reorienting its head movement (Ryu and Samuel, 2002; de Bono and Maricq, 2005)

There are three thermosensors in C. elegans; the amphid AFD neurons (also called “finger” cells) are the major thermosensors (NeuroTABLE 1; see Neuronal Supportal Cells), while the amphid AWC and ASI neurons are supportive (Mori and Ohshima, 1995; Kuhara et al, 2008; Ohnishi et al, 2011; Beverly et al, 2011). AFD neurons have complex, brushlike structures at their dendritic ends that are completely embedded in the amphid sheath. Animals in which AFDs are killed are athermotactic. TAX-6 (calcineurin), three receptor-type guanylyl cyclases which function redundantly (GCY-8, GCY-18, and GCY-23), and cGMP-dependent TAX-2/TAX-4 cation channel have been shown to be involved in thermosensation in AFD (Kuhara et al., 2002; Inada et al., 2006). When tax-6 is mutated, animals display a thermophilic phenotype, whereas gcy-23, gcy-8, and gcy-18 triple mutants show a cryophilic or athermotactic phenotype. In AWC, heterotrimeric G-protein signaling and cGMP-dependent TAX-4 cation channel are involved. In the current model for thermosensation, the downstream AIY interneuron is bidirectionally regulated by AFD and AWC. Thermosensory information is transmitted from AFD and AWC to AIY through EAT-4/VGLUT-dependent glutamatergic neurotransmission. Glutamatergic signals from AFD inhibit AIY via activation of GLC3 (glutamate-gated chloride channel) and induce migration towards colder temperature. Glutamatergic signals from AWC, on the other hand, stimulate AIY to induce migration towards warmer temperature (Kuhara et al, 2008; Ohnishi et al, 2011). When AI Y are killed animals become cryophilic and migrate to colder temperatures than the cultivation temperatures, while ablation of AIZ neurons, which are the main postsynaptic target of AIY, makes animals thermophilic and induce them to migrate to warmer temperatures (Mori, 1999).

C. elegans also reacts to noxious (extreme cold or hot) temperatures. A prolonged exposure at 30°C results in an induction of the heat-shock response and the animals cease egg-laying within a few hours (Lithgow et al., 1995), but resume reproduction if returned to lower temperatures (Aprison and Ruvinsky, 2014). Behaviorally, when they encounter a noxious heat source they respond with a reflexive withdrawal reaction (thermal avoidance response) (Liu et al., 2012; Wittenburg and Baumeister, 1999). PVD neurons in the body respond to acute cold shock, while AFD and FLP neurons in the head and PHC neurons in the tail sense noxious high temperatures (~35-38^oC) (Chatzigeorgiou et al., 2010). This nociceptive heat response utilizes a different neural circuit than thermotaxis and the response of C. elegans to noxious high heat is modulated by glutamate and by the neuropeptides encoded in the flp-1 locus. Two channel protein families contribute to thermonociception in C. elegans in distinct neurons: the TAX-2/TAX-4 cyclic nucleotide-gated channels and thermal-gated TRPV channels (TRPA, TRPM and TRPV ion channel families are considered "thermoTRPs"; the gating of these channels by temperature is facilitated by chemical signals)(Hall & Treinin, 2011). Upon encountering noxious heat, TAX-2 and TAX-4 become activated in AFD neurons by cGMP which is mainly generated through the activity of GCY-12, but also to a lesser extent by GCY-8/18/23. In FLP and PHC neurons thermonociceptive signal transduction involves the OCR-2 and OSM-9 TRPV channels which can assemble into a heteromultimeric channel complex. PVD response to cold requires TRPA-1 channel (Chatzigeorgiou et al., 2010).

2.4.5 Light Sensation

Light stimuli induce a photophobic, movement-reversal response in C. elegans. Recently, it has been found that this response peaks in the high-energy ultraviolet (UV) range (blue-violet) and the head sensory neurons are apparently not required for this behavior (Burr, 1985; K. Miller, pers. comm.). It is suggested that the response originates in the VNC, although the exact sensory mechanism is yet to be described.

2.4.6 Oxygen and Carbon dioxide Sensation

C. elegans lacks a specialized respiratory system and uses diffusion for gas exchange. It can sustain a normal rate of metabolism between 2% and 21% ambient oxygen due to diffusion of oxygen to its tissues through the pseudocoelomic fluid, in which all tissues bathe (Van Voorhies and Ward, 2000). When cultivated under standard laboratory conditions, with a linear gradient from anoxia to atmospheric oxygen in the gas phase, C. elegans rapidly moves to an intermediate preferred oxygen concentration of between 7% and 14% oxygen, avoiding both high and low oxygen levels, although this response can be modified by environment and experience (Gray et al., 2004; Cheung et al., 2005; Rogers et al., 2006). In the wild, C. elegans lives close to decaying organic matter where it is exposed to an air/water interface with rapidly shifting oxygen tensions (0–21%) due to consumption of oxygen by microbes. Ambient oxygen levels may, therefore, be perceived as indicating the presence of food by this animal. Oxygen sensation is performed by a distributed network of neurons that includes AQR, PQR, and URX, possibly gcy-35-expressing SDQ, ALN, and BDU, and osm-9-expressing (nociceptive) ADF and ASH neurons (White et al., 1986; Gray et al., 2004; Chang et al., 2006). AQR, PQR, and URX may perform a head-to-tail oxygen comparison achieved through their positions along the body in close contact with the pseudocoelom because they are suggested to function to monitor the pseudocoelomic fluid, including its oxygen content (NeuroFIG 11) (Rogers et al., 2006). AQR is a right-sided neuron, derived post-embryonically from the QR blast cell; PQR is a left-sided neuron, derived post-embryonically from the QL blast cell. Both have ciliated endings. The AQR ending is free within the pseudocoleomic cavity, whereas the PQR ending lies close to the pseudocoelom, but is wrapped by the phasmid socket cell (see Neuronal Supportal Cells). URX cell bodies lie within the pseudocoelomic cavity. Similar to URX, AQR, and PQR neurons, SDQ, BDU, ALN, and PLN express soluble guanylate cyclases (sGC) that bind to molecular oxygen, consistent with a primary oxygen-sensing function for these AQR neurons. SDQs are also similar in lineage, morphology, and neural connectivity to the AQR and PQR neurons. Additionally, nociceptive ADF and ASH neurons may be modulatory or respond to oxygen directly. The output of the aerotaxis neuron network converges on AVA, the command interneuron responsible for generating backward motion and, hence, avoidance. The presence or absence of food modulates the basic aerotactic responses of hypoxia and hyperoxia avoidance. Modulation of hyperoxia avoidance is accomplished through the neuropeptide receptor NPR-1, the transforming growth factor-β (TGF-β)-related protein DAF-7, and serotonin production by the ADF neurons, whereas hypoxia avoidance seems to be mediated through a neuronal network that is independent of these pathways (Chang et al., 2006).

In the wild, C. elegans inhabits rotting material which contains a broad range of CO₂ levels, however as in other animals, high CO₂ levels are toxic causing deterioration of muscle organization, reducing fertility and slowing development above 9% (Bretscher et al., 2008; Hallem and Sternberg, 2008; Sharabi et al, 2009). Thus, the animal typically shows an acute avoidance response to CO₂ (especially well-fed animals) when CO₂ level is above 0.5%. Animals also respond to changes in ambient CO₂ levels. Primary CO₂ sensors are AFD, BAG and ASE neurons (Bretscher et al., 2011). The signal pathway for CO₂ response in AFD and BAG include the TAX-2/TAX-4 cGMP-gated heteromeric channel and the atypical soluble guanylate cyclases that also mediate oxygen responses in BAG. AFD neurons respond to increasing CO₂ by a fall and then rise in Ca²⁺ and show a Ca²⁺ spike when CO₂ decreases. BAG and ASE are both activated by CO₂ and remain tonically active while high CO₂ persists. The CO₂ responses in AFD, BAG and ASE neurons do not habituate upon multiple exposures to CO₂. The modulators of the CO₂ -response include physiological state of the worm, the neuropeptide Y receptor, NPR-1, and calcineurin subunits, TAX-6 and CNB-1.

2.5 Interneurons

As in other organisms, interneurons comprise the largest group of neurons in the nematode. They function as information processors, receiving inputs from one or more classes of neurons and relaying outputs onto other neurons. They are suggested to compare and process sensory inputs in individual neuronal circuits and modulate the decision to execute a given motor program. They also function as circuit couplers where information from two or more circuits converge to establish circuit hierarchies. As an example, AVF, AVJ, and AVB interneurons link the neural networks for egg-laying and locomotion and function in temporal coordination of these two behaviors (Hardaker et al., 2001).

2.6 Polymodal Neurons

Some C. elegans neurons perform more than one type of circuit function, including both motor and sensory functions or interneuron–motor neuron or interneuron–sensory neuron functions (White et al., 1986). Polymodal neurons are much more common in the male tail circuitry than anywhere else (Sulston et al., 1980; S.W. Emmons et al., unpubl.). M3 neurons of the pharynx have both motor and sensory functions. NSM neurons are both neurosecretory and motor neurons, and they may also have proprioceptive function (Albertson and Thomson, 1984). A- and B-type VNC motor neurons are suggested to be proprioceptive. IL1 neurons in the head perform mechanosensory, motor, and interneuron functions, whereas OLQ neurons are both mechanosensory and interneurons. RIM, SMB, SMD, RMD, RMH, and RMF classes of head neurons seem to be both motor and interneurons. AVL is a motor neuron with additional interneuron-type synapses. DVA is an interneuron that also functions as a stretch-sensitive sensory neuron. DVB is a motor neuron for enteric muscles and is also an interneuron. Alternatively, some neurons have multiple functions within one modality. ASH sensory neurons, for example, function as mechanosensory, osmosensory, odorsensory, and nociceptive, and ADLs are chemosensory, odorsensory and nociceptive.

2.7 Ganglia

Most neuron cell bodies in C. elegans are grouped into ganglia that are typical of invertebrates (Chitwood and Chitwood, 1950; White et al., 1986; Hall et al., 2006). C. elegans ganglia contain clusters of cells but few or no synapses. All except the anterior ganglion are bounded by the basal lamina of the hypodermis. The neuron processes extend from each of these ganglia, traveling in longitudinal nerve bundles into various regions of synaptic neuropil, where they form chemical and electrical synapses. The most prominent neuropil regions are the NR, VNC, and preanal ganglion. In addition to the ganglia, many neuron cell bodies lie in tandem along the length of the VNC. A few other neuron cell bodies lie singly or in small groups along the lateral body wall or within the pseudocoelom (URX, CEPD).

2.8 Process Bundles

Most neuron processes fasciculate into organized bundles (nerves or nerve cords) that may comprise as few as two or as many as 50 processes and run in parallel over long distances within the body (NeuroFIG 7 and NeuroFIG 8). Most of these processes run longitudinally along the body wall, except where they enter the NR. Most nerve cords are specialized to include limited functional groupings. For instance, the amphid nerves in the head and the phasmid nerves in the tail include only sensory dendrites and travel directly from sensory endings to related neuron cell bodies in local ganglia. Conversely, many neuron processes of the VNC, DC, and NR have mixed functions. The number and spatial arrangement of processes within the nerve tracts are essentially conserved between animals (White et al., 1976, 1983, 1986; Chalfie and White, 1988). Neighboring processes generally stay closely associated for long distances, and synapses are made en passant between adjacent processes. The neighborhoods, therefore, determine connectivity between neurons. Switching between neighborhoods, which most commonly occurs at the junctions of process bundles, increases the number of potential synaptic partners for a given neuron. The VNC is the major longitudinal nerve and splits posteriorly to the excretory pore into major (right side) and minor (left side) tracts that flank the ventral hypodermal ridge (NeuroFIG 5). In adult animals, the left VNC tract contains six processes and the right approximately 54 processes due to the decussation of the majority of fibers exiting the NR from the left side (Hedgecock et al., 1990). Near the junction of the NR, anterior to the decussation, the ventral ganglion region contains 170 processes. The VNC is continuous with the RVG at the anterior and with the PAG at the posterior end. Many of the tail neuron processes enter the right tract of the VNC, although a few enter the left tract.

In the VNC, motor neuron processes may navigate between different neighborhoods to accommodate input from interneurons within the fascicle as well as their output to muscle arms positioned outside of the cord. This switch in neighborhood generally occurs at the transition between the presynaptic and post-synaptic regions of each motor neuron. The second largest nerve in the nematode, the DC, is a single tract localized on the left side of the dorsal hypodermal ridge and mainly consists of commissural processes from the VNC motor neurons joined by the processes of a small set of neurons in the head (RMED, RID) and tail (PDA, PDB).

The processes within a nematode nerve cord are nonmyelinated, and available physiological evidence suggests that they do not conduct action potentials (Davis and Stretton, 1992; Goodman et al., 1998). All nerve bundles run in direct contact with the hypodermis, with which they share a common basal lamina separating them from the pseudocoelom or neighboring muscle tissue.

2.9 Commissures

Commissures are circumferential tracts that are created by neuron processes passing from one longitudinal nerve to another through dorsoventral routes. Whereas in higher animals a commissure normally consists of dozens or even thousands of processes, in the nematode a commissure can consist of a single process that pioneers its own route along the body wall. The major commissures include amphid and deirid commissures in the head and lumbar, dorsorectal, and dorsolateral commissures in the tail. There are more than 40 individual commissures along the length of the body where VNC motor neuron processes extend to reach the dorsal side (NeuroFIG 7). The NR, which comprises the largest and most complex region of neuropil in the animal, is essentially an enlarged commissural region encircling the pharyngeal isthmus, with some 200 processes involved, most running a half-circle around the ring. Inside the pharynx, two shorter commissures, the pharyngeal nerve ring and the terminal bulb commissure, connect dorsal and sub-ventral pharyngeal nerve cords (see Alimentary System - Pharynx).

Topologically, the commissures follow two types of routes: medial and lateral (NeuroFIG 12) (White et al., 1986; Durbin, 1987). The fibers in the NR follow a medially positioned route between the basal face of the hypodermis and the central muscle arm plate. During development, pioneer axons for the NR are postulated to grow inwardly along extensions of the hypodermis or along the muscle arms of the head muscles, which themselves may be organized by the GLR scaffold cells (See GLR cells). Other commissures following such medial routes include those from the dorsorectal ganglion to the preanal ganglion in the tail (Hall, 1977; Hall and Russell, 1991) and the ventrally directed HSN processes.

Laterally positioned commissural routes are much more common. In these cases, neuron processes travel singly or in groups along a closely confined space underneath the body wall muscles, always in close apposition to the thin sheet of hypodermis that covers the muscle. Again, the nerves remain separated from the muscle by the basal laminae of the muscle and hypodermis. The right-sided VNC neuron commissures reach the DC by crossing over the dorsal hypodermal ridge.

2.9.1 Commissures in the Head

There are four major commissures in the head: right and left amphid commissures and right and left deirid commissures (NeuroFIG 13 and NeuroFIG 14). The amphid commissures on both sides are mainly composed of axons of the amphid neurons that extend from the neuron cell bodies toward the ventral nerve cord, passing between the ventral body wall muscle and a thin sheet of hypodermis (NeuroFIG 15 and NeuroFIG 16). They also contain processes that come from the ventral cord. Processes of two such neurons, SAAV and SABV, join the anterior ventral sublateral cords as they exit the amphid commissures.

Amphid commissures are located laterally to the junction of the pharyngeal isthmus and terminal bulb. The posterior sections of the amphid commissures are also referred to as sublateral commissures because they are composed of fibers of ventral sublateral cords. Of these, anteriorly traveling PLN processes dive through the amphid commissure to join the VC on their way to the NR, whereas posteriorly traveling SIBV, SMBV, SIAV, and SMDV processes use amphid commissures to join the ventral sublateral cords. The compositions of the right and left amphid commissures are nearly mirror images of each other. The RID process (on the left side) and the SABD process (on the right side) are the exceptions.

The deirid commissures run near the posterior part of the terminal bulb of the pharynx (NeuroFIG 16 and NeuroFIG 17). Originating from their neuronal cell somata on the lateral sides of the head, the processes within the deirid commissures first travel posteroventrally and then medially among the cells of the retrovesicular ganglia until they join the VC. They turn anteriorly in the VC and travel to the NR. AQR is present only on the right side.

There are three pairs of commissures in the tail: right and left lumbar commissures (also called ano-lumbar commissures), right and left dorsorectal commissures (also called rectal commissures), and right and left dorsolateral commissures (NeuroFIG 8 and NeuroFIG 18). The lumbar commissures are made of processes of PQR (left side), DA8 (left side), DA9 (right side), PDB (right side), PDA (right side), PVR (right side), PHAL/R, PHBL/R, PHCL/R, PVQL/R, LUAL/R, PVCL/R, PVWL/R, and PVNL/R. The majority of fibers in the lumbar commissures travel ventroanteriorly toward the PAG after originating from the lumbar ganglia neurons. However, the processes of PDA, DA9, DA8, and PDB neurons, which are situated in the PAG, travel posterodorsally through the lumbar commissures. The PDB process then continues traveling toward the tail and makes a dorsal turn within the tail tip to reach the DC, whereas the processes of PDA, DA9, and DA8 motor neurons continue their dorsal trajectory to the DC along the dorsolateral commissures. The dorsorectal commissures contain processes from DVA (right-side), AVFR (right-side), DVB (left-side), DVC (left-side), and AVG (left-side) neurons. The three dorsorectal ganglion neurons (DVA, DVB, DVC) grow their processes ventrally toward the PAG (Hall and Russell, 1991).

Of the 46 VNC motor neurons that extend processes to the dorsal side, 44 (7 DA, 7 DB, 6 DD, 13 VD, and 11 AS) send their processes via body commissures, whereas DA8 and DA9 send processes to the DC via tail commissures (NeuroFIG 7 and NeuroFIG 18). The commissural processes in the body are sandwiched between muscle and hypodermis as they travel along the lateral body wall. Most of these processes travel on the right side of the animal; however, 11 of them (DA1, DA3–7, DB2, DB4, DB5, DD1, VD2) make left-sided commissures (NeuroFIG 19 and NeuroFIG 20). Many travel alone or at times, two processes can join together to travel in a single commissure. The anteriormost right (made by VD1 and SABD processes) commissure is located near the posterior end of the terminal bulb of the pharynx, whereas the left (made by DB1) is around the procorpus of the pharynx (NeuroFIG 8 and NeuroFIG 20). The posteriormost body commissure (made by AS11) is close to the preanal ganglion in the tail. Along the body, other neuron processes travel dorsally or ventrally to reach longitudinal process tracts and make shorter commissures. These include SDQ dorsal processes extending to the dorsal sublateral tract on each side; HSN, PLM, PDE, and PVD ventral processes to the VNC on each side; AVM ventral process to the VNC on the right side; and PVM ventral process to the VNC on the left side.

The most important concentrations of synapses (also referred to as neuropils) are the NR, VNC, and DC. The tail has an additional region of specialized neuropil in the preanal ganglion that is substantially enlarged in the adult male tail. Very sparse chemical synapses are also found along the sublateral nerve cords, but practically none are found in the other longitudinal nerves, including the amphid, phasmid, or the lateral nerves. Synapses involving commissural axons are apparently rare except for those locations in which a commissure crosses in close proximity to a longitudinal nerve. In general, the ganglia consist entirely of cell bodies and have no synapses. However, the lumbar and dorsorectal ganglia of the male tail also include small regions of neuropil. Occasional chemical synapses may also include alternate cell types as apparent post-synaptic partners, including hypodermal fingers in the nerve cords, marginal (epithelial) cells in the pharynx, the excretory gland, and some sex-specific epithelial cells.

2.10.1 Chemical Synapses

In C. elegans, chemical synapses may occur between one presynaptic and one post-synaptic cell (a monad) or more than one post-synaptic partner (a polyad; two recipients make it a dyad and three recipients make it a triad), and one may be muscle (NeuroFIG 21). Chemical synapses are made en passant between neighboring processes where synaptic swellings are formed along the process shafts. These synapses are distinguished by the presence of a small (~50 nm wide and 100–400 nm long), electron-dense presynaptic density on the cytoplasmic side of the membrane. A small cluster of synaptic vesicles lies near this density both docked and in reserve pools that comprise the “active zone” (Weimer and Jorgensen, 2003; Rostaing et al., 2004; Zhen and Jin, 2004; Nakata et al., 2005). Further away from the active zone is a periactive zone, where molecules that coordinate synaptic organization and growth are localized and vesicle membrane may be recovered by endocytosis (Jin, 2002; Rostaing et al., 2004; Nakata et al., 2005). The size of the presynaptic region varies considerably even within the same neuron or among synapses of the same type of neuron (Jin, 2005).

Unlike vertebrates, little or no specialization is evident by standard TEM on post-synaptic membranes in C. elegans, and, therefore, proximity determines synaptic partners. Immunochemical staining has recently confirmed that post-synaptic receptors are clustered on the post-synaptic processes, very close to the presynaptic release zone, and improved fixation methods show the presence of small post-synaptic densities (NeuroFIG 21) (Gally et al., 2004; Jin, 2005; J.-L. Bessereau and R. Weimer, pers. comm.). Recent physiological studies of neuromuscular junctions in C. elegans support the observation that a single neuron can elicit responses in multiple post-synaptic elements (Liu et al., 2006). The synaptic cleft generally appears unspecialized in the nematode.

As in other organisms, rapid neurotransmission in C. elegans uses classical neurotransmitters, including various monoamines, acetylcholine, GABA, and glutamate. The synaptic vesicles (SV) for classical neurotransmitters that are present at the release zone tend to be small and spherical (30–45 nm in diameter) and have clear contents. The absolute number of nearby vesicles ranges from 10 to 100 in the readily releasable pool. Docked vesicles are closely tethered to the presynaptic membrane within 75 nm of the presynaptic density. Cytoplasmic dense material often surrounds some or all of these vesicles, making the release zone darker than the nearby axoplasm. Vesicles are initially formed in the cell body and may lie in small clusters in the soma cytoplasm before being actively transported down the axon (Hall and Hedgecock, 1991). These transport vesicles are larger in diameter (50 nm) and more electron-dense in contents than the vesicles clustered at the release zone. While traveling along the axon as the cargo of MT-based motors, transport vesicles lie in close proximity to the MT bundle of the nerve process (Hall and Hedgecock, 1991; Zhou et al., 2001).

In contrast to SVs, which are clustered near the release sites, large dense-core vesicles (LDCV; 40–50 nm) that contain proneuropeptides and copackaged proprotein-processing enzymes are seen throughout the presynaptic compartment (NeuroFIG 21D) (Jacob and Kaplan, 2003). C. elegans contains more than 150 putative neuropeptides that are thought to modulate synaptic function but can also mediate rapid neurotransmission via gated ion channels (Richmond and Broadie, 2002). A large fraction of C. elegans neurons use peptide neurotransmitters, and a range of behavioral defects are observed in mutants lacking these enzymes. The molecular mechanisms used for transport and membrane fusion of LDCV share some components, such as UNC-104, with those used in rapid synaptic vesicle neurotransmission.

Small clusters of free ribosomes have been seen at both presynaptic swellings and in post-synaptic processes (Rolls et al., 2002). These ribosomes may permit local translation of messages in distal neurites.

2.10.2 Neuromuscular Junctions

Neuronal input to muscles occurs at specialized chemical synapses called NMJs (NeuroFIG 2D and NeuroFIG 21; also see Muscle system - Introduction). The anatomical features of these synapses are essentially the same as those for chemical synapses between neurons; however, one distinction is the basal lamina that separates the presynaptic motor neuron and the postsynaptic muscle. Basal-lamina-associated proteins nidogen/entactin (NID-1) and type XVIII (CLE-1) collagen are enriched near synaptic contacts. Nidogen is concentrated between the nerve cords and muscles, whereas CLE-1 is concentrated above the regions in which NMJs form (Ackley et al., 2003). Mutations in these basal lamina proteins lead to defects in the organization of NMJs. In contrast to most other organisms, muscles extend long, thin processes (arms) to nerve bundles to make synapses with the motor neurons in C. elegans. In many cases, chemical synapses onto muscle arms occur in specialized zones where several muscles extend arms that interdigitate to form a “muscle plate” around a presynaptic specialization so that vesicle release from a single axon can simultaneously stimulate more than one muscle (White et al., 1976, 1986; Liu et al., 2006). In addition, there are often gap junctions between these muscle arms. For example, along the VNC and DC, muscle arms crowd around the presynaptic varicosities of the motor neurons to receive simultaneous input. Besides the VNC and DC, NMJs are also concentrated on the inside surface of the NR where muscle arms from head muscle rows arrange into a circumferential muscle plate. Unlike somatic muscles, pharyngeal muscles do not form arms, and presynaptic processes are often embedded directly in the muscle soma. In the male tail, presynaptic motor axons often terminate at the synapse, and again, contact is sometimes made directly onto the muscle soma for certain sex muscles.

2.10.3 Electrical Synapses (see also chapter on Gap Junctions)

Electrical synapses, or gap junctions (GJs), form by close contact between cells. They are found virtually in all tissues of C. elegans, and essential for embryogenesis (Phelan 2005). In the nervous system, gap junctions are made between neurons and between muscle cells (but not between neurons and muscle cells as they are generally separated by a basal lamina.) The adult C. elegans nervous system has about 600 highly reproducible neuronal gap junctions, in addition to the 5000 predicted chemical synapses (White et al., 1986). The number of gap junctions throughout the life cycle of the animal is likely much higher as some neuronal gap junctions are assembled during embryonic development but are remodeled in early larval stages and dissolved by the adult stage (Chuang et al., 2007). Between neurons, axon-to-axon and axosomatic contacts are common; soma-to-soma contacts are less common. Electrical synapses can occur at any locale within the nervous system; they are not restricted to any neuropil. These synapses may affect behavioral events by synchronizing neuronal activity, by cross-inhibition of neighboring axons, or by relaying signals along neighboring segmental regions from one homolog to another. Alternately, the gap junction may transmit metabolic signals. Some GJs have a developmental role in halting axon outgrowth when two homologous axons establish the limits of their neighboring territories, an event known as contact termination (White et al., 1986). These GJs between homologs are very common; many bilateral neuron pairs in the head encircle only half of the NR (cf. ASH, ASI, ASJ, etc.), because they stop when they encounter the process of their functional homolog to form a GJ. This property is also seen in VD motor neurons along the VNC. Important synaptic connections in the VNC can involve GJs between a command interneuron (AVA or AVB) and the cell body of a motor neuron (White et al., 1976, 1986). Other functions for gap junctions include regulation of asymmetric gene expression in a neuron pair and synchronization of neuron and muscle activities (e.g., synchronization of action potentials and Ca⁺⁺ transients in body-wall muscle, Ca⁺⁺ wave propogation during defecation motor program, facilitation of intermuscular electrical coupling for synchronous pharyngeal muscle contractions, transmission of signals among male-specific muscles during male copulation) (Liu et al, 2011a; Liu et al., 2011b; Chuang et al., 2007; Peters et al., 2007, Li et al, 2003). During embryogenesis transient gap junction networks may regulate formation of nascent circuits (Chuang et al., 2007).

GJs in nematodes are formed by intramembrane proteins called “innexins,” which are completely different in their amino acid sequence from the vertebrate “connexins.” Instead, they are the homologs of vertebrate "pannexins" (Starich et al., 1996; Phelan and Starich, 2001; Altun et al., 2009). They may coassemble to form homotypic, heterotypic and heteromeric gap junctions (NeuroFIG 22). Additionally, these molecules may form hemichannels that connect a cell’s interior to the extracellular space, providing a pathway for release and uptake of molecules and ions in a controlled manner. In addition to eat-5, unc-7, and unc-9, which had been discovered previously through mutant analyses, the completion of genomic sequencing of C. elegans revealed 22 more innexin genes (C. elegans Sequencing Consortium, 1998; Bargmann, 1998). These additional innexins were numbered arbitrarily from inx-1to inx-22. Further sequencing and genomic analysis of two additional Caenorhabditis species (C. briggsae and C. remanei) revealed that each of these species has retained at least one member of each type of these innexins, except inx-8 and inx-9, which share a single ortholog in C. briggsae, but have distinct orthologs in C. remanei (see Wormbase). This strongly suggests that each innexin gene is a true gene rather than a pseudogene. Among C. elegans innexins, there are 3 sets of polycistronic ones: inx-12 and inx-13, inx-16 and inx-17, and inx-21, and inx-22. Individual GJs in neurons can involve heteromeric channels made from several different innexin subunits. Neuronal GJs differ from those in other nematode tissues by showing equal numbers of intramembrane particles in both the “E-face” and “P-face” (Hall, 1987). Through expression analyses all innexins except inx-5, inx-15, inx-16, inx-20, inx-21, inx-22, and eat-5 were found in the C. elegans nervous system (Altun et al., 2009). Among these, the most widely expressed innexins were inx-7, unc-7, and unc-9, while the least widely expressed ones were inx-1, inx-2, and inx-11. Also, TEM analyses revListealed that gap junctions exist between glia (socket and sheath cells) and hypodermis as well as between the socket and sheath cells, but not between glia and neurons (Altun et al., 2009).

3 List of Neurons

Individual neurons

Use drop down menus to go to individual neuron pages.
Select Cell A ADAL ADAR ADEL ADER ADFL ADFR ADLL ADLR AFDL AFDR AIAL AIAR AIBL AIBR AIML AIMR AINL AINR AIYL AIYR AIZL AIZR ALA ALML ALMR ALNL ALNR AQR AS1 AS2 AS3 AS4 AS5 AS6 AS7 AS8 AS9 AS10 AS11 ASEL ASER ASGL ASGR ASHL ASHR ASIL ASIR ASJL ASJR ASKL ASKR AUAL AUAR AVAL AVAR AVBL AVBR AVDL AVDR AVEL AVER AVFL AVFR AVG AVHL AVHR AVJL AVJR AVKL AVKR AVL AVM AWAL AWAR AWBL AWBR AWCL AWCR
Select Cell B-H BAGL BAGR BDUL BDUR CA1 CA2 CA3 CA4 CA5 CA6 CA7 CA8 CA9 CANL CANR CEMDL CEMDR CEMVL CEMVR CEPDL CEPDR CEPVL CEPVR CP0 CP1 CP2 CP3 CP4 CP5 CP6 CP7 CP8 CP9 DA1 DA2 DA3 DA4 DA5 DA6 DA7 DA8 DA9 DB1/3 DB2 DB3/1 DB4 DB5 DB6 DB7 DD1 DD2 DD3 DD4 DD5 DD6 DVA DVB DVC DVE DVF DX1/2 DX3/4 EF1/2 EF3/4 FLPL FLPR HOA HOB HSNL HSNR
Select Cell I-O I1L I1R I2L I2R I3 I4 I5 I6 IL1DL IL1DR IL1L IL1R IL1VL IL1VR IL2DL IL2DR IL2L IL2R IL2VL IL2VR LUAL LUAR M1 M2L M2R M3L M3R M4 M5 MCL MCR MI NSML NSMR OLLL OLLR OLQDL OLQDR OLQVL OLQVR
Select Cell P PCAL PCAR PCBL PCBR PCCL PCCR PDA PDB PDC PDEL PDER PGA PHAL PHAR PHBL PHBR PHCL PHCR PLML PLMR PLNL PLNR PQR PVCL PVCR PVDL PVDR PVM PVNL PVNR PVPL PVPR PVQL PVQR PVR PVS PVT PVU PVV PVWL PVWR PVY PVX PVZ
Select Cell R R1AL R1AR R1BL R1BR R2AL R2AR R2BL R2BR R3AL R3AR R3BL R3BR R4AL R4AR R4BL R4BR R5AL R5AR R5BL R5BR R6AL R6AR R6BL R6BR R7AL R7AR R7BL R7BR R8AL R8AR R8BL R8BR R9AL R9AR R9BL R9BR RIAL RIAR RIBL RIBR RICL RICR RID RIFL RIFR RIGL RIGR RIH RIML RIMR RIPL RIPR RIR RIS RIVL RIVR RMDDL RMDDR RMDL RMDR RMDVL RMDVR RMED RMEL RMER RMEV RMFL RMFR RMGL RMGR RMHL RMHR
Select Cell S-V SAADL SAADR SAAVL SAAVR SABD SABVL SABVR SDQL SDQR SIADL SIADR SIAVL SIAVR SIBDL SIBDR SIBVL SIBVR SMBDL SMBDR SMBVL SMBVR SMDDL SMDDR SMDVL SMDVR SPCL SPCR SPDL SPDR SPVL SPVR URADL URADR URAVL URAVR URBL URBR URXL URXR URYDL URYDR URYVL URYVR VA1 VA2 VA3 VA4 VA5 VA6 VA7 VA8 VA9 VA10 VA11 VA12 VB1 VB2 VB3 VB4 VB5 VB6 VB7 VB8 VB9 VB10 VB11 VC1 VC2 VC3 VC4 VC5 VC6 VD1 VD2 VD3 VD4 VD5 VD6 VD7 VD8 VD9 VD10 VD11 VD12 VD13

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