Despite recent interest in reconstructing neuronal networks, complete wiring diagrams on the level of individual synapses remain scarce and the insights into function they can provide remain unclear. Even for Caenorhabditis elegans, whose neuronal network is relatively small and stereotypical from animal to animal, published wiring diagrams are neither accurate nor complete and self-consistent. Using materials from White et al. and new electron micrographs we assemble whole, self-consistent gap junction and chemical synapse networks of hermaphrodite C. elegans. We propose a method to visualize the wiring diagram, which reflects network signal flow. We calculate statistical and topological properties of the network, such as degree distributions, synaptic multiplicities, and small-world properties, that help in understanding network signal propagation. We identify neurons that may play central roles in information processing, and network motifs that could serve as functional modules of the network. We explore propagation of neuronal activity in response to sensory or artificial stimulation using linear systems theory and find several activity patterns that could serve as substrates of previously described behaviors. Finally, we analyze the interaction between the gap junction and the chemical synapse networks. Since several statistical properties of the C. elegans network, such as multiplicity and motif distributions are similar to those found in mammalian neocortex, they likely point to general principles of neuronal networks. The wiring diagram reported here can help in understanding the mechanistic basis of behavior by generating predictions about future experiments involving genetic perturbations, laser ablations, or monitoring propagation of neuronal activity in response to stimulation.
We pursue the hypothesis that neuronal placement in animals minimizes wiring costs for given functional constraints, as specified by synaptic connectivity. Using a newly compiled version of the Caenorhabditis elegans wiring diagram, we solve for the optimal layout of 279 nonpharyngeal neurons. In the optimal layout, most neurons are located close to their actual positions, suggesting that wiring minimization is an important factor. Yet some neurons exhibit strong deviations from ''optimal'' position. We propose that biological factors relating to axonal guidance and command neuron functions contribute to these deviations. We capture these factors by proposing a modified wiring cost function.Caenorhabditis elegans ͉ optimal placement B ecause brain structure is intimately related to its function, understanding structure should provide important clues to brain function. Traditionally, structural features of the brain are explained from the perspective of development, a complex process including such events as cell migration (1, 2), axonal guidance (3-5), cellular signaling (6), and synaptogenesis (7-10). Although much progress has been made in understanding the mechanisms of neural development, many unanswered questions remain. In particular, it is not known what determines the placement of neurons and synapses in the body, a question to be addressed in this paper.Our approach for understanding neuronal structures complements neural development and relies on the existence of general principles governing the architecture of a mature brain. Specifically, we exploit the wiring economy principle proposed by Ramón y Cajal more than 100 years ago (11). This principle postulates that, for a given wiring diagram, neurons are arranged in an animal to minimize the wiring cost. The evolutionary ''cost'' can be attributed to factors such as wire volume (12-14) and signal delay and attenuation (15-17), as well as metabolic expenditures associated with signal propagation and maintenance (18,19). Although the exact origin of the wiring cost is not known, the farther apart two neurons are, the more costly is the connection between them. The wiring cost can therefore be expressed as a function of distance between neurons and consequently minimized (12,(20)(21)(22)(23)(24)(25).Despite many successful applications of the wiring minimization principle (refs. 12-14 and 20-27, but see ref. 28), it has never been tested on the level of individual neurons for an entire nervous system. Such testing was precluded by the lack of wiring diagrams and by the computational complexity of the optimization problem. Previous works have shown that wire length minimization can explain the layout of small systems by tabulating the amount of wire required for every possible permutation of components in the network. The actual ordering of ganglia in Caenorhabditis elegans (20) and the arrangement of areas in the prefrontal cortex in the macaque (27) were found in this manner to have the shortest total wiring. Unfortunately, this brute force method is im...
Alternative patterns of neural activity drive different rhythmic locomotory patterns in both invertebrates and mammals. The neuro-molecular mechanisms responsible for the expression of rhythmic behavioral patterns are poorly understood. Here we show that Caenorhabditis elegans switches between distinct forms of locomotion, or crawling versus swimming, when transitioning between solid and liquid environments. These forms of locomotion are distinguished by distinct kinematics and different underlying patterns of neuromuscular activity, as determined by in vivo calcium imaging. The expression of swimming versus crawling rhythms is regulated by sensory input. In a screen for mutants that are defective in transitioning between crawl and swim behavior, we identified unc-79 and unc-80, two mutants known to be defective in NCA ion channel stabilization. Genetic and behavioral analyses suggest that the NCA channels enable the transition to rapid rhythmic behaviors in C. elegans. unc-79, unc-80, and the NCA channels represent a conserved set of genes critical for behavioral pattern generation.neural rhythms ͉ neurogenetics ͉ sodium leak channel D ifferent forms of rhythmic neural output are ubiquitously observed in motor behaviors such as locomotion, respiration, and feeding (1-4). Extensive research has revealed that a neural network can switch among alternate rhythms by altering the properties of specific intrinsic membrane currents and synapses (5). Consistent with this framework, some proteins appear to contribute more to the generation of one rhythm than other rhythms. For instance, channels that carry the persistent sodium current appear to be important for gasping but not the normal respiratory rhythm when studied in vitro (6). Physiological approaches are sometimes limited when trying to identify specific proteins involved in certain rhythms, however, because of the availability and selectivity of compounds that act on the relevant molecules. With the advent of reverse genetics, these limitations are beginning to be overcome by knocking out or modifying specific genes (7, 8), but both pharmacological and gene manipulation approaches are still limited by the a priori hypotheses on which molecules to target. In contrast, because forward genetic studies are unbiased, they can lead to the identification of novel or uncharacterized proteins that contribute to rhythmic neural output. We have therefore pursued a forward genetic approach to identify neural proteins that contribute more to the generation of one form of rhythmic locomotion (i.e., swimming) than another (i.e., crawling) in the nematode Caenorhabditis elegans.C. elegans moves by generating waves of dorsal-ventral (DV) bends along its body. Prior genetic studies have focused on the molecular mechanisms responsible for crawling over a solid agar substrate (9, 10), whereas the motion C. elegans displays in liquid has only begun to be characterized (11). Although C. elegans encounters water in its natural environment (12), it has been unclear whether its motion i...
Given that brains and computers are similar in many respects, can vast experience in computer engineering help us understand brain design? Here we apply tools developed for physical design of computer chips to understand the layout of the nervous system. Starting with the known wiring diagram of the C. elegans nervous system, we predict the locations of synapses and extent of neurons that minimize the total wiring length. Comparing predicted locations of C. elegans neuronal cell bodies with the actual locations, we find reasonable agreement. Therefore, minimization of wiring length is an important consideration both in chip design and brain architecture. Furthermore, wire length minimization can be used to infer functional roles of neuronal components. General TermsAlgorithms, Design, Theory.
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