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Cell identification and reproducibility Each of the 40 neurons
of the C. elegans posterior nervous system has a reproducible
set of features by which it can be unambiguously identified in
different individuals. These features include cell body position,
number and direction of fiber projections, and size and cytoplasmic appearance of the fibers. For each of the different sorts of features, the degree of reproducibility between isogenic individuals appears to be as good as that bilaterally within a given
individual. Table 2 provides a summary list of some of the most
salient features and a correspondence of naming systems between previous
publications.
There is a remarkable economy of cell number, cell shape,
and synaptic arrangements. The number of neurons serving any
particular function is very small. Neurons with combined functions occur, and there are few layers of interneurons interposed
between sensory cells and motor cells. Each neuron lacks secondary branches within the tail region; the anterior nervous
system is fairly similar in this respect. The absolute number of
synaptic contacts per neuron or per synapse class is certainly
not large, even compared to most invertebrates. This limited
set of reproducible neurons with distinct functional roles offers
unique opportunities for physical manipulation of the nervous system, by laser
ablation or by genetic or pharmacological means.
Cell function: sensory reception and processing. A principal
function of the C. elegans posterior nervous system appears to
be the reception and processing of information from posterior
sensory receptors. Previous behavioral and genetic studies have
shown that C. elegans is able to distinguish chemical stimuli
(Ward, 1973; Dusenbery et al., 1975), mechanical stimuli (Chalfie and Sulston, 1981), optical stimuli (Burr, 1985), osmotic
gradients (Culotti and Russell, 1978), and thermal gradients
(Hedgecock and Russell, 1975). Morphological studies of sensory mutants indicate that many of the above capabilities derive
from the amphidial sense organs (Lewis and Hodgkin, 1977;
Albert et al., 1981; Hedgecock et al., 1985; Perkins et al., 1986).
Response to light touch is localized to 6 neurons whose microtubule-fllled mechanocilia lie along the lateral margins of the
head, body, and tail (Chalfie et al., 1985). No sensory mutant
has yet shown morphological changes restricted to the phasmids,
but several chemosensory and osmotic avoidance mutants show
similar defects in both amphids and phasmids (Perkins et al.,
1986).
The phasmids appear likely on anatomical grounds to be chemosensory. The changes in phasmidial staining or in phasmidial
cilia ultrastructure noted in several chemosensory mutations
support this conclusion (Perkins et al., 1986). Their extreme
posterior placement suggests comparison of phasmid signals
with signals to the anterior amphids. Because the phasmids
could be involved in detecting both attractants and repellents,
and because each contains 2 ciliated neurons (PHA, PHB), we
speculate that the synapses of one neuron class might promote
forward movement; the other, backward movement. Indeed,
the synaptic output of PHA and PHB are strikingly different,
as discussed below.
Bilaterally homologous sensory cells are probably functionally
identical. There are 4 pairs of bilaterally homologous sensory
cells (PLM, PHA, PHB, PHC), which are very nearly mirror
images of one another at all anatomical levels from gross cell
position down to their axon and dendritic projections. There
remains the question whether 2 sensory homologues act in concert with one another or in a lateralized manner, perhaps for
purposes of orientation. Lateralization seems unlikely for many
reasons. The paired sensilla for PHA, PHB, and PHC are arranged so close to one another and in such an orientation as to
effectively preclude differential stimulation of one member of
the pair. Chalfie and Sulston (1981) have reported that laser
ablation of a single member of the PLM pair "does not detectably affect touch sensitivity." Also, the 2 homologous members
of a sensory pair often form gap junctions and/or chemical
synapses onto one another. The gap junctions, in particular, are
difficult to reconcile with the notion of lateralized function.
Finally, the synaptic outputs from the homologous members of
a sensory pair, rather than occurring to separate neurons for
potentially separate parallel processing, are instead largely overlapping. This feature is not evident in Figure 9, where homologues are combined, but can be seen in Tables 3 and 4, where
they are kept separate. As noted above, the excess of ipsilateral
contacts by some sense cells seems to reflect incomplete mixing
of left and right lumbar processes near the posterior limit of the
preanal ganglion.
Sensory information from the tail is primarily converged onto
a few major interneurons. The output of most tail receptors
converges onto AVA, AVD, and PVC interneurons (Fig. 9). A
model of the ventral-cord circuitry based upon laser ablations
of motoneurons or interneurons (Chalfie et al., 1985; Chalfie and White, 1988) suggests that PVC and AVB interneurons can
stimulate class B motoneurons to promote forward locomotion,
while AVA and AVD interneurons can stimulate class A motoneurons to promote backwards locomotion. This model for
forward versus backward motion is reasonably consistent with
neurophysiological and biochemical studies of identified motoneurons in a larger nematode species, Ascaris (Stretton et al.,
1985). We speculate that the very common PHB->AVA, PVC
synapses may underlie an escape response. If the PHB cells were
sensitive to chemical repellents, the net effect of PHB excitation
of PVC would be to promote rapid forward movement and
hence escape. The simultaneous PHB contacts onto AVA might
be inhibitory, shutting down backwards motion, thus sharpening the escape response. Similarly, stimulation of the PHC
mechanoreceptors could also excite PVC and result in forward
movement. The gap junctions found in the posterior ventral
nerve cord between the PLM touch neurons and PVC interneurons (Chalfie et al., 1985; White et al., 1986) are consistent
with this general notion. These speculations may be testable by
selective laser ablations or perhaps by genetic dissection of the
circuits.
The PHA chemoreceptors are well situated to allow comparisons between amphid and phasmid. PHA sense cells synapse
primarily onto other sense cells and onto the AVG interneuron.
The sensory feedback of PHA onto other tail receptors might
serve to inhibit other sensory modalities during PHA activity.
From the wiring diagrams of White et al. (1986), the following
circuit is evident:
The PHA outputs onto AVG can potentially conduct a phasmidial signal to the head, where AVG synapses via large gap junctions onto the RIF interneurons. In the nerve ring, RIF interneurons also receive processed sensory signals from amphidial chemoreceptors via the AIA interneurons. Thus, RIF interneurons may compare processed chemosensory signals from head and tail. In turn, the RIF interneurons have prominent synaptic inputs onto the AVB interneurons, which may reset the animals body motion in response to the compared chemical stimuli. As noted above, the AVB interneurons are prominent components of the ventral cord wiring, contacting class B motoneurons along the length of the body and thus controlling forward motion.
The dyadic synapse provides a basic unit for processing. One of the most striking features of the preanal ganglion circuitry is the preponderance of dyadic synapses. The 2 postsynaptic partners in a given contact are almost never homologous (Table 5); this makes sense if the function of the dyadic synapse is to diverge the information into distinct channels with different opportunities for modification. We presume that the 2 postsynaptic partners are affected simultaneously and proportionately by the presynaptic neuron. In many cases, the 2 postsynaptic cell types make direct contact with one another elsewhere, and most such contacts are in a single direction (Fig. 9). This circumstance can be represented diagrammatically as follows:
where A is the original presynaptic cell, and B and C are the 2
original postsynaptic partners. In this circumstance ("feed-forward"), cell C may receive 2 versions of an initial synaptic
output from cell A; the first is direct, via the original dyadic
synapse, and the second is indirect, and potentially modified,
through cell B. The indirect version, of course, could depend
on the state of cell B; it might arrive with a time delay, with
either an enhancing or an opposing effect, with an altered duration, and so forth. This basic 3-cell configuration could serve
a variety of functions, for example, prolongation of the signal's
effets, gating the signal's effects with respect to a threshold in
cell C or selecting for signals with a pronounced rate of change.
Dyadic and triadic synapses are well known anatomically in
many other sensory ganglia, both in vertebrates and in invertebrates, but have not been widely studied physiologically. While
their function is not yet well understood, current information
seems compatible with the divergence/reconvergence idea presented above. Specific combinations of postsynaptic partners
are also known to be preferred at tetradic photoreceptor terminals in the fly's visual system (Nichol and Meinertzhagen,
1982; Fröhlich, 1987), and feedback relationships of these synapses appear to be functionally plastic (Kral and Meinertzhagen,
1989). Dyads are involved in feedback relationships in the dragonfly ocellar retina (Klingman and Chappell, 1978) and in both
feed-forward and feedback relationships in the visual system of
the desert ant (Meyer, 1979). Physiological studies of vertebrate
dyadic synapses have explored their feedback relationships (cf.
Byzov and Golubtsov, 1978; Raviola and Dacheux, 1987). (In
the vertebrate literature, dyadic synapses are often called "triads," and triadic synapses may be called "tetrads." In other
instances, "triads" may refer to serial synapses.)
Infrequent synapse classes. There are many synapses listed in
Table 3 that do not fall into one of the common synapse classes;
that is to say, they involve a postsynaptic partner that is rarely
contacted at all, or rarely by the particular presynaptic neuron.
Because practically all of the individual synapse categories involve relatively low numbers on an absolute scale, it is difficult
to define an infrequent synapse class on a simple numerical
criterion. Depending upon what criterion is selected, infrequent
synapses may represent 10-25% of all contacts.
Within the synaptically active cell group listed in Table 5,
infrequent synapse classes accounted for only 28 of the 427
contacts observed in B126 and B136, suggesting that they played
a minor role, at best, in the functions of that group. A majority
of the infrequent synapse classes are due to the presynaptic
involvements of only 4 cell types, PHA, PHC, PVN and DVB,
which contact many less active cell types. PHA and PHC each
form several frequent synapse classes, while DVB forms 1 and
PVN forms no frequent synapse class. DVB and PVN also make synapses to hypodermal cells (see Table 3). Thus, the choice of
postsynaptic partners by some neurons may be relatively non-specific and promiscuous, in contrast to the rules governing the
formation of the frequent synapse classes. The PHA data in
Table 3 demonstrate this tendency rather clearly, as their many
postsynaptic targets do not fall into any highly repeated groups.
The behavioral role of the infrequent synapse classes is unclear. Walthall and Chalfie (1988) have suggested that certain
classes of chemical synapse may have no behavioral function
in C. elegans but are formed as a byproduct of an axonal guidance mechanism and, thereafter, retained to preserve the relative
position of the presynaptic processes within a fiber bundle. However, in their example, the synapses from AVM-> BDU are actually rather frequent in the rostral portion of the ventral cord.
Another possibility is that some neurons function in a way that
requires only that they have a rather diffuse output, not a specific
one. As an example, they might function in a relatively non-specific modulatory way, providing general neuronal activation
or deactivation. Such neuromodulation might be effective at a
distance from the presynaptic release sites, influencing many
neurons which are not in direct contact (Barchas et al., 1978).
This would allow infrequent synapse classes to be somewhat
variable while still maintaining a rationale for their existence
and for their concentration within a few presynaptic cell types.
Developmental noise The infrequent synapse classes formed
by cells other than PVN, PHA, PHC, or DVB are quite widely
distributed among a number of pre- and postsynaptic participants. Almost all of them are nonreproducible, and they usually
contain 1, sometimes 2, contacts per class. It seems unlikely
that they are of behavioral importance; instead, they seem to
us to represent developmental "noise" of some sort. One possibility is that they represent the residue of synapse classes that
were more frequent at an earlier developmental stage. One instance of developmental rewiring, involving the loss of some
synapses and the gain of others, has been reported for C. elegans
(White et al., 1978). Another possibility is that infrequent synapse classes represent a secondary consequence of whatever
mechanisms operate to establish the frequent synapse classes.
This would be an example of developmental noise as described
by Waddington (1957). Macagno et al. (1973) noted a similar
background scatter of infrequent connections in the Daphnia
optic lamina, where each receptor cell forms frequent synapses
(20-80 contacts) onto a particular lamina cell and a lesser or
equal number of contacts onto unidentified processes. Besides
these frequent synapses, much smaller numbers of synapses go
to other lamina cells or even to other receptor cell processes.
Some of these infrequent synapses also appear to be obeying
patterns, but some others, perhaps a few percent of the total,
are sufficiently unusual to indicate that they represent developmental noise. The well-studied development of the optic lamina makes it unlikely that this noise represents the residue of
previously frequent synapse classes.
The existence of developmental noise of the Waddington type
seems reasonable in evolutionary terms. If selection during evolution is simply for appropriate function, and if this function is
carried out principally by the frequent synapse classes, then there
seems to be little reason why programs evolved to establish the
frequent classes should undergo further refinement, probably at
additional informational cost, simply to eliminate a minority
of behaviorally unimportant synapses.
Combinatorial specification of synapse development. A reproducible pattern
among the frequent synapse classes has been noted in the preanal ganglion in 3 animals (Tables 4, 5). It is
intriguing to note that (1) these synapses are almost all dyadic,
(2) bilateral homologues are rarely contacted simultaneously,
(3) several different dyadic combinations occur at different frequencies, and (4) many possible combinations of synaptic partners never occur. The combinatorial aspects of this pattern are
particularly striking, suggestive of the requirement for simultaneous recognition of different postsynaptic recognition factors
from 2 separate partners before a synapse can be formed. Mutant
alleles that fail to form many chemical synapses are already
known to be viable in C. elegans (Hall et al., 1989). Mutations
of synaptic recognition factors are likely to produce viable alleles
as well, probably having an uncoordinated phenotype. Currently, more than
100 unc genes have been isolated as viable
mutant alleles and mapped on the genome (see Wood, 1988).
Thus, the preanal ganglion presents a model system in which
to explore the genetics of synapse specification.
Web adaptation, Thomas Boulin, for Wormatlas, 2002