Chute, Christopher et al. (2015) International Worm Meeting "Neural circuits involved in octopamine succinylated ascaroside #9 mediated avoidance responses."

Srinivasan, Jagan, Chute, Christopher

[International Worm Meeting, 2015]

Innate behaviors are mediated by the integration of external stimuli and internal signals. These cues often take the form of small biogenic molecules, and range from exogenous compounds to endogenous neuromodulators. These molecules are known to govern behavior across all domains of life. Although the basic components have been characterized in complex systems, the underlying physiological and neural mechanisms are largely unknown. C. elegans is an ideal organism for studying the relationship between small molecules and behavior due to its ability to survive in an unpredictable habitat. In order to successfully navigate their environment, these nematodes must sense and respond to multiple external cues, including physiological state-dependent signals produced and secreted by conspecifics that communicate important ecological contexts. A novel compound of interest, produced exclusively by starved first larval stage worms, is the neurotransmitter-derived metabolite octopamine-succinylated ascaroside #9 (osas#9) [1]. This molecule elicits an acute avoidance response in conspecifics [1], suggesting the communication of unfavorable environmental conditions from starved L1 worms. The avoidance response can be quantified by observing reversal in the worm's locomotion upon application of a drop of osas#9. A reverse genetic approach revealed the involvement of the bioamine neurotransmitters glutamate, octopamine, and tyramine in the avoidance response. Furthermore, through neuronal ablations, the glutamanergic neuron ASH has been identified as the primary sensory neuron necessary for mediating response to this metabolite. Notably, assaying biosynthetic enzymes tdc-1 and tbh-1, known to be required for tyramine and octopamine biosynthesis [2], indicates that the absence of both neurotransmitters does not display a behavioral defect, but the absence of only the downstream neurotransmitter, octopamine, does. This implies the existence of either an uncharacterized antagonistic relationship between octopamine and tyramine, or of an uncharacterized biosynthetic salvage pathway. Since tyramine and octopamine are structurally similar to human catecholamines, understanding their role in governing fear-like states in C. elegans will provide insights on the role of bioamines in mediating human behavior.1. Artyukhin, A.B., et al. J Biol Chem, 2013. 288(26): p. 18778-83.2. Alkema, M.J., et al. Neuron, 2005. 46(2): p. 247-60.

Liu, Zheng et al. (2015) International Worm Meeting "A redundant neural circuit drives C. elegans responses to social cues."

Tong, Ada, Leinwand, Sarah, Curran, Kevin, Chalasani, Sreekanth, Chute, Christopher, Liu, Zheng, Srinivasan, Jagan

[International Worm Meeting, 2015]

Animals communicate with each other using social cues. Typically, the sender sends a signal that modifies the current and/or future behaviors of the receiver. One particular form of communication that has been well studied is the interactions between a predator (sender) and prey (receiver). Despite these efforts, the neural circuits in the receiver that detect signals and driving behaviors remain poorly understood. We have developed a novel model of social behaviors analyzing the interactions between two nematodes P. pacificus (sender) and C. elegans (receiver).We find that C. elegans avoids secretions from a starving P. pacificus. We used cell ablations and calcium imaging to map the underlying sensory circuit. We find that either ASH and ASI or ASH and ASJ neurons detect P. pacificus derived signals. Moreover, we show that tax-4 (cyclic nucleotide gated ion channel) is required in both ASI and ASJ neurons while ocr-2 (TRP channel) is required in ASH for the avoidance response. We performed a pilot screen using small molecule drugs and identified Sertraline, (Zoloft, a selective serotonin reuptake inhibitor) as a candidate hit. Animals treated with Zoloft show greatly attenuated responses to P. pacificus. Surprisingly, its action requires GABA but not serotonin signaling to attenuate C. elegans avoidance. Apart from this rapid avoidance, we also show that prolonged exposure to Pristionchus secretions also modifies future C. elegans behaviors. These studies show how a receiver neural circuit detects social signals and modifies its current and future behaviors. .

Christopher J Cronin et al. (2005) International Worm Meeting "The Combined UC San Diego/Caltech Quantitative Behavior Analysis System"

William R Schafer, Zhaoyang Feng, Kuang-man Huang, Paul W Sternberg, Christopher J Cronin

[International Worm Meeting, 2005]

California Institute of Technology and University of California, San Diego have each developed practical, automated movement analysis systems to quantify aspects of worm behavior and morphology (see An imaging system for standardized quantitative analysis of C. elegans behavior, Zhaoyang Feng, et al, BMC Bioinformatics 2004, 5:115, An automated system for measuring parameters of nematode sinusoidal movement, Christopher J Cronin, et al, BMC Genetics 2005, 6:5, and previous meeting abstracts). We have consolidated our development efforts and merged our independent system designs to create a single, unified behavior analysis system. The combined system provides researchers with all of the quantification tools and database functionality of the individual UCSD and Caltech systems, but also establishes a common, open software and hardware foundation for continued development by Caltech, UCSD and the community. Current efforts include expanding system capabilities for the automated analysis of mating behavior with the challenge of tracking multiple moving individuals, both in contact with and separated from each other.

Muirhead, Caroline et al. (2021) International Worm Meeting "Decision-making in C. elegans: Neuronal mechanisms underlying behavioral choice"

Srinivasan, Jagan, Muirhead, Caroline

[International Worm Meeting, 2021]

Animals constantly weigh opposing sensory cues to decide and execute appropriate behavioral responses as they navigate their environment. These decisions and their subsequent behaviors demonstrate the nervous system's ability to integrate and process heterogenous sensory information (i.e. risk or reward) into proper decision making neural correlates. We test a value-based decision-making model using responses to pheromones. We discovered that the pheromone, osas#9, which incorporates the neurotransmitter octopamine is released exclusively by starved first larval stage (L1) animals to elicit a strong avoidance response in conspecifics (Chute et al., 2019). This avoidance response is strongly dependent on the physiological state of the animal and is attenuated by the concurrent detection of food odor(s). This suggests that the possibility of nearby food sources can override an innate avoidance to the starvation cue, osas#9. The interplay between opposing olfactory sensory signals provides a strong paradigm for studying decision-making in the context of multisensory integration. Additionally, we have observed disrupted decision-making in a neurodegenerative model of worms that expresses the Abeta42 peptide. We will present data that elucidate the signaling networks necessary for mediating attenuation to osas#9 allowing us to deconstruct the neural circuits controlling decisions in both healthy and disease states of the worm.

Pena-Gonzalez, I. et al. (2013) International Worm Meeting "Suppressors of TDP-1 toxicity in Caenorhadbitis elegans."

Link, CD., Pena-Gonzalez, I.

[International Worm Meeting, 2013]

Suppressors of TDP-1 toxicity in Caenorhadbitis elegans Ilana Pena-Gonzalez1 and Christopher D Link1, 2 1 Integrative Physiology, University of Colorado, Boulder, CO 80309, USA 2 Institute for Behavioral Genetics, University of Colorado, Boulder, CO 80309, USA RNA binding protein TDP-43 forms damaging aggregates in multiple neurodegenerative diseases. We have found that the deletion of tdp-1, the C. elegans ortholog of TDP-43, leads to increased accumulation of double stranded RNA. TDP-1 is not believed to bind to dsRNA itself; however the marked increase in dsRNA accumulation in worms deleted for tdp-1 implies TDP-1 normally participates in limiting the stability and structure of dsRNA. Although worms deleted for TDP-1 do not have a severe phenotype, overexpressed nuclear TDP-1 is toxic in worms. One possible explanation for this is that too much TDP-1 leads to excessive disruption of structured RNAs needed for normal RNA metabolism. Making use of this overexpression model we have established a heat shock induction system to help identify components associated with TDP-1's prevention of dsRNA accumulation. Identifying mutations that suppress the neurotoxic effects of overexpressed TDP-1 could help identify others factors contributing to the complex mechanism of disassembling dsRNA. A mutagenesis screen has identified four mutant strains that partially suppress the toxicity of overexpressed TDP-1. We have also tested suppressors of other toxic proteins. Further identifying the pieces of the mechanism regulating dsRNA breakdown could help better explain the pathogenic pathway of TDP-1 and consequently TDP-43 in disease.

Bauer CC et al. (1998) West Coast Worm Meeting "a, b AND g-FILAGENIN - NEW PROTEINS IN THE CORE'S OF THICK FILAMENTS"

Schmid MF, Ortiz I, Epstein HF, Liu FZ, Bauer CC

[West Coast Worm Meeting, 1998]

The cores of muscle thick filaments are composed of an outer layer of paramyosin surrounding an inner tubular region containing additional core proteins. In order to study the structure of the thick filament core and the mechanisms and molecules involved in the formation of this length-regulated, multi-protein structural assemblage, we have isolated and characterized three novel proteins: a, b and g-filagenin. We obtained partial peptide sequences from each of the filagenin proteins and determined their predicted protein sequences from the C. elegans Genome Project's database and correlated this information with cDNA sequence obtained from RT-PCR or phage libraries. All three filagenins are novel proteins with no significant homologies to any known proteins (although homologues in parasitic nematodes have been found in the databases). All filagenins also possess the distinction of having calculated isoelectric points of over pH 10 and having a higher than average number of aromatic amino acids. Both b and g-filagenin are predicted to have secondary structures containing only beta strands and loops, whereas a-filagenin is composed of both alpha helices and beta strands. Structural studies of the core indicate that there are seven paramyosin subfilaments crosslinked by additional internal proteins. We tested our structural model with Western blotting using an affinity-purified antibody and have showed that a, b and g-filagenins are associated with the cores. All three filagenins were localized by immunofluorescence microscopy to the A bands of body wall muscles, but there was no detectable reaction with the pharynx, with the exception of a slight reaction with anti-a-filagenin antibody. b-Filagenin has been shown by immunoelectron microscopy to be assembled with paramyosin into the tubular cores of wild-type nematodes at the same periodicity of 72-nm as observed with paramyosin. In CB1214 paramyosin null mutants, b-filagenin assembles with myosin to form abnormal tubular filaments with a periodicity identical to that of wild type. These results verify that the filagenins are core proteins that co-assemble with either myosin or paramyosin in C. elegans to form tubular filaments. Further studies on nematode muscle thick filaments are intended to elucidate the mechanisms behind the formation and regulation of these stable assemblies of myosin and associated proteins. *Supported by grants from the Muscular Dystrophy Association, the National Science Foundation and a NRSA postdoctoral fellowship for Christopher Bauer.