M Reigl et al. West Coast Worm Meeting "Search for computational modules in the C. elegans brain."

U Alon, M Reigl, D B Chklovskii

[West Coast Worm Meeting]

Are there multi-neuron computational modules in the C. elegans nervous system? We attempt to answer this question by applying a systematic statistical approach to the C. elegans wiring diagram (White et al. 1976). Our approach is to identify multi-neuron inter-connectivity patterns that are significantly over-represented in the actual wiring diagram compared to the randomized wiring diagram, which preserves the number of synapses per neuron but not the identity of connections. To do this we compute the numbers of occurrences of all n-neuron (n=2...5) inter-connectivity patterns in the actual and randomized wiring diagrams. This statistical approach confirms previous reports of the over-abundance of reciprocal connections and triangular connectivity patterns (White et al. 1976). Moreover, we discover several new four-neuron and five-neuron inter-connectivity patterns that appear significantly more often in C. elegans than in randomized wiring diagrams. We suggest that these inter-connectivity patterns may serve as computational modules that perform stereotypical functions.

Reigl M et al. (2002) West Coast Worm Meeting "Search for computational modules in the C. elegans brain"

Reigl M, Chklovskii DB, Alon U

[West Coast Worm Meeting, 2002]

Are there multi-neuron computational modules in the C. elegans nervous system? We attempt to answer this question by applying a systematic statistical approach to the C. elegans wiring diagram (White et al. 1976). Our approach is to identify multi-neuron inter-connectivity patterns that are significantly over-represented in the actual wiring diagram compared to the randomized wiring diagram, which preserves the number of synapses per neuron but not the identity of connections. To do this we compute the numbers of occurrences of all n-neuron (n=2...5) inter-connectivity patterns in the actual and randomized wiring diagrams. This statistical approach confirms previous reports of the over-abundance of reciprocal connections and triangular connectivity patterns (White et al. 1976). Moreover, we discover several new four-neuron and five-neuron inter-connectivity patterns that appear significantly more often in C. elegans than in randomized wiring diagrams. We suggest that these inter-connectivity patterns may serve as computational modules that perform stereotypical functions.

Brittin, Christopher et al. (2015) International Worm Meeting "A 3D Analysis of the Mind of the Worm Connectome."

Brittin, Christopher, Emmons, Scott, Cook, Steven, Cohen, Netta, Hall, David

[International Worm Meeting, 2015]

A connectome is a comprehensive map of all neural connections in an organism's nervous system. The first connectome was published almost 30 years ago by White et al. (1986) and described the structure of the nervous system of the nematode C. elegans adult hermaphrodite. Subsequent network analyses of this data have focused only on the synaptic connectivity of the nervous system, while neglecting much of the spatial information in the data. Initial spatial analyses of the C. elegans connectome reported in (White et al., 1983; Durbin, 1987) used only a sparse sampling of physical neuron contacts. Using the original electron micrographs from (White et al., 1986), we have extended this analysis by performing a 3D reconstruction of every neuron in the C. elegans nerve ring in both the L4 and adult. This represents the first complete volumetric reconstruction of the main neuropil of any animal from multiple developmental stages. With this enriched data set, we have been able to do a comparative analysis of synaptic connectivity, characterize the spatial distribution of synapses for each neuron and analyse the relationship between neuron contact and synapse formation in the C. elegans nerve ring. Similar to (White et al., 1983), we found that ~40% of all possible physical contacts result in a synapse or gap junction. We also found a positive correlation between the frequency of synapse formation and the amount of physical contact between neurons. Specifically, the frequency of synapse formation between two neurons approaches ~0.7 as the amount of physical contact approaches 10% of a neuron's total measured surface area. However, like (Durbin, 1987), we find that synapse probability and synapse number between any pair neurons does not depend strongly on the amount of shared physical contact. Furthermore, synapse volumes appear to be conserved between the L4 and adult, while the number of synapses between any two neurons appear to be, on average, greater in the adult. This could suggest that during late nervous system development, synaptic partnerships are reinforced by creating additional small synapses between neurons rather than enlarging the volume of current synapses. .

Ken-ichi Oshio et al. (2002) Japanese Worm Meeting "Revision of synaptic connectivity database"

Eizo Akiyama, Yuishi Iwasaki, Yuko Osana, Ken-ichi Oshio, Sohei Gomi, Satoru Morita, Kotaro Oka, Kazumi Omata

[Japanese Worm Meeting, 2002]

The synaptic connectivity of C. elegans is well known from observations of the somatic system by White et al. and those of the pharyngeal system by Albertson et al. So far, three databases were constructed for computational usage by Achacoso et al. and Durbin, and recently in WormBase. However, they lack some data such as those in tables of White's paper and those in figures of Albertson's book. Our database (K. Oshio, S. Morita, Y. Osana and K. Oka: Technical Report of CCEP, Keio Future No.1, 1998) includes all data described in White's paper and Albertson's book. Unfortunately, some mistakes were found in the database through private communications with John White who is the author of White's paper and with the users of the database. Thus we have been proceeding with the revision to make it perfect one. We are planning to complete the revision in September 2002. The database should be worthwhile not only for neurophysiological studies, but also for post-genomic interests mediating genomes and behavior.

Gerami B et al. (1997) International C. elegans Meeting "MAPPING QUANTITATIVE TRAIT LOCI FOR CHEMOTAXIS: CORRESPONDENCE BETWEEN QTL AND odr CANDIDATE LOCI"

Phillips PC, Gerami B, Morphew JJ

[International C. elegans Meeting, 1997]

Understanding the genetics of complex traits is challenging because it can be difficult to separate out the effects of the numerous genes affecting the trait. C. elegans can serve as a useful model system for studying complex traits because of the wealth of genetic and functional information available. Chemotaxis provides an ideal trait for this type of study because it ecologically important to the nematodes, as well as likely to be influenced by many genes (a number of which are known). In collaboration with Thomas Johnson and David Shook [1] and Robert Shmookler Reis and Robert Ebert [2], who provided genotyped lines generated in a cross between N2 and BO, we have assayed the chemotaxic response of 180 recombinant inbred lines to benzaldehyde at two concentrations. These concentrations, 50 nl and 500 nl, respectively lead to an attraction or repulsion response. Separate analysis of the lines from the two labs yield different results. The SR lines show a QTL mapping to the fourth chromosome, whereas the TJ lines show several QTL, primarily on the X chromosome. The QTL on X map to the same locations as two mutants known to block the response to benzaldehyde, odr-1 and odr-5 [3]. We are in the process of evaluating these candidate loci as the actual QTL using backcrossing and complementation testing approaches. Our hope is to create a model system for studying a variety of quantitative genetic questions. [1] Genetics 142:801 (1996), [2] Genetics 135:1003 (1993), [3] Bargmann et al., Cell 74:515 (1993)

Zeyu Zheng et al. (2007) International Worm Meeting "Quantitative 4D analysis of centrosome movement in early embryos."

Asako Sugimoto, Yumi Iida, Takafumi Konishi, Zeyu Zheng

[International Worm Meeting, 2007]

Caenorhabditis elegans embryos undergo stereotypic cell division patterns. Because the cleavage plane for each cell division is defined by the orientation of the mitotic spindle, positioning of spindle poles, or centrosomes, is crucial to regulate cell division patterns. Previous reports revealed that centrosomes are positioned by interactions between microtubules and the particular region of the cell cortex (1-3). However, a detailed mechanistic understanding of centrosome movement is still limited. As a step to better understand the regulation of centrosome movement in early cell divisions, we are developing a quantitative approach to analyze dynamic movement of centrosomes at high spatial and temporal resolution. 4D images of embryos expressing GFP markers visualizing centrosomes and cell membrane are acquired using a spinning-disc confocal microscope, and positions of individual centrosomes are extracted from each image. Using these positional data, direction and speed of each centrosome movement, and rotation angle and distance of each centrosome pair are quantitatively and statistically analyzed in a 3-dimensional space. We will present our progress on the analysis of wild-type and mutant embryos having spindle orientation defects. 1.Hyman and White (1987) J. Cell Biol. 105:2123-2135. 2.Hyman (1989) J. Cell Biol. 109:1185-1193. 3.Keating and White (1998) J. Cell Sci. 111:3027-3033. .

German EA et al. (1998) East Coast Worm Meeting "CROSSED WIRES IN UNC-37 VENTRAL CORD"

Hall DH, Miller DM, German EA

[East Coast Worm Meeting, 1998]

Uncoordinated movement in unc-37 adults is superficially similar to the impairment observed in unc-4 animals (1). In unc-4, loss of coordination results from a specific wiring deficit between interneurons and motorneurons in the ventral nerve cord (3,4). We are currently analyzing the detailed synaptic pattern in an adult unc-37 nerve cord from serial thin sections. Preliminary data were discussed previously (2). We have now identified the major interneurons and 20 motorneurons in the anterior ventral nerve cord, and have determined their synaptic interactions. The morphological phenotype of unc-37 is not as limited as the specific wiring defect in unc-4. Many neurons show minor changes in branching or axon caliber, and there is a wider variety of wiring changes. However, in both mutations the AVB interneurons form inappropriate gap junctions onto class A targets, while AVAs fail to make normal junctions onto these targets. This specific change may explain the similarity in their gross behavioral phenotypes. 1. Pflugrad et al. (1997) Development 124:1699-1709. 2. Hall, German and Miller (1997) 11th Annual C. elegans meeting. 3. J.G. White et al. (1986) Phil. Trans. R. Soc. Lond 314:1-340. 4. J.G. White et al. (1992) Nature 355:838-41.

K Oshio et al. (1999) International C. elegans Meeting "Analysis of neuronal connectivity of C. elegans using random walker"

Y Osana, K Kawamura, S Morita, Y Funabashi, K Oshio, K Oka

[International C. elegans Meeting, 1999]

From the detailed report of White et al. and Albertson et al. , we have almost complete knowledge about the synaptic connectivity of C. elegans with the type of synapse (electric junction or chemical synapse). However, the type of each chemical synapse (excitatory or inhibitory one) is not described. Conventional electrophysiological methods for C. elegans is difficult because the size of the neurons is too small to penetrate the intracellular electrode. On the other hand, computational studies of neuronal circuit are now possible by virtue of the above mentioned elaborate experimental studies of neuroanatomists. We have built a new data base of the whole neuronal circuit including pharyngeal neurons only from the article of White et al. and Albertson et al. There exist two other data bases to the knowledge of the present authors. The first data base was constructed by Achacoso and Yamamoto who also analyzed the properties of the network. Another data base was constructed from the article of White et al. by Durbin, which is available on the internet homepage. To begin understanding signal processing on the nervous system, we have investigated the neuronal connectivity by putting random walkers on certain neurons of the network. Here we ignore internal structure of neurons. Random walker is a particle which moves among neurons randomly, and can be considered to be transmitted signal. In our simulation, random walkers are put on certain sensory neurons at each time step, this corresponds to stimulation which sensory neurons accept. We removed random walkers at certain motor neurons, this means, for instance, signals are transmitted to muscles which cause normal action. As a result, we have found that the degree of relation of each neuron for input neurons can be known from the probability to find random walker, although the difference between excitatory and inhibitory of chemical synapses is not taken into account. The simulational results will be shown comparing with real function such as the touch sensitivity. E-mail: oshio@future.st.keio.ac.jp

Zahreddine Fahs, Hala et al. (2021) International Worm Meeting "Multi-species nematode screening uncovers a new broad-spectrum class of anthelmintic compounds targeting mitochondrial lipid metabolism"

Gopinadhan, Suma, Refai, Fathima, White, Robert, Pearson, Yanthe, Kremb, Stephan, Butterfoss, Glenn, Gunsalus, Kristin C., Zahreddine Fahs, Hala, Xie, Xin, Cipriani, Patricia, Page, Anthony, Piano, Fabio

[International Worm Meeting, 2021]

Parasitic worms infect more than 1.5 billion people and cause significant losses in livestock and crops. New anthelmintic drugs are urgently needed, as resistance to the existing drugs is emerging. We built a high-throughput (HTP) and high-content robotic screening platform to identify bioactive small molecules and their molecular targets, focusing on novel disease therapeutics and broad spectrum anthelmintics. The platform is capable of screening compound collections and genetic libraries in model organisms and mammalian cells in a fully integrated manner. To find novel anthelmintics we screened a ~2300 compound library containing most of the FDA-approved approved drugs, plus natural products and bioactive compounds for broad spectrum toxic effects on two distantly related free living nematodes C. elegans and P. pacificus as model animals while having low toxicity on human cell lines. The screen confirmed the effects of most known anthelmintics on these nematode models. Additionally, among a set of new compounds, we found six natural lipid molecules that exhibit broad-spectrum anthelmintic activity. These novel compounds kill C. elegans and P. pacificus when applied at various developmental stages, including the dauer and embryonic stages, in a dose-dependent manner. Importantly, these compounds cause mortality in all three veterinary parasite species we tested: the hookworm Haemonchus contortus (ruminants), Teladorsagia circumcincta (sheep and goat) and Heligmosomoides polygyrus (rodents). Further characterization of their mode of action using C. elegans revealed defects associated with mitochondrial function and lipid metabolism. The lethality phenotype in C. elegans is partially rescued by knocking down the enzymes acs-2, cpt-4, dif-1 and cpt-2, which facilitates mitochondrial lipid transfer, while drug inhibitors of CPT1 and CPT2 enhance the phenotype, suggesting that these compounds perturb specifically fatty acid oxidation in nematodes. These compounds constitute a new class of broad-spectrum anthelmintics targeting lipid metabolism.

Sarah Bauer Huang et al. (2003) International Worm Meeting "Identification and characterization of genes involved in neuronal connectivity in C. elegans"

Gage Crump, Cori Bargmann, Susan Kirch, Sarah Bauer Huang

[International Worm Meeting, 2003]

Neurons form specific connections that result in a fixed circuitry (Sanes and Yamagata, 1999). The precision of these connections arises from a series of events in development: the initial projection of an axon to a target area, followed by a recognition event between specific cells, ultimately forming a synapse. Significant progress has been made in understanding the molecular basis of axon guidance. However, little is known about how the cells recognize their synaptic targets. C. elegans provide an excellent in vivo system in which to study this question. We are studying selective recognition in the nerve ring, which contains axons from >170 neurons that are interconnected by specific and reproducible synapses (White et al, 1986). We are studying the interaction between the amphid neuron ASJ and its synaptic partner PVQ, whose cell bodies are located in the lumbar ganglia. Each ASJ neuron forms about ten synapses onto the axon of the PVQ neuron, ignoring many other neurons that it contacts in the nerve ring (White et al, 1986). The ASJ cell bodies and axons were brightly labeled with RO9F10.6::GFP, with additional light pharynx expression. The PVQ interneurons and their axons were labeled with C25G6.5::dsRED2. Additional amphid neurons expressed this transgene faintly. Using these markers, we can visualize the fasciculation of ASJ and PVQ axons. To identify genes involved in the targeting and fasciculation of ASJ and PVQ, we performed a screen for mutants in which the fasciculation event was disrupted between ASJ and PVQ, and for mutants that exhibited axon guidance defects in either ASJ or PVQ. We will present the results from this screen. We will also present further characterization of sax mutants (sensory axon guidance), which were identified in a screen for altered ASI axons (Crump and Bargmann, 1997 I.W.M.). The mutant sax-10 has axon guidance defects in AWB, ASH, ASI and PVQ, yet maintains overall normal nerve ring structure (Kirch et al, 2001 I.W.M). We are using additional markers to study its nerve ring in more detail. Sanes, J. R. and Yamagata M. (1999). Formation of lamina-specific synaptic connections. Curr Opin Neurobiol 9(1): 79-87. White, J. G., E. Southgate, et al. (1986). "The structure of the nervous system of Caenorhabditis elegans." Philos Trans R Soc Lond B Biolo Sci 314(1165): 1-340.