Lau, Hiu et al. (2013) International Worm Meeting "Food signals modulate sensory integration behavior."

Chalasani, Sreekanth, Lau, Hiu

[International Worm Meeting, 2013]

Neural circuits integrate information to generate behavior outputs. One challenge in neuroscience is to understand how neural circuits generate flexible behaviors. We use a sensory integration assay1 to ask how exposure to various food signals influences behavior. Here, C. elegans crosses a repellent barrier (copper) and chemotax towards a spot of an attractant (diacetyl)1. After C. elegans are exposed to the bacteria P. aeruginosa for 3 hours, we observe a two-fold increase in the number of animals that reach the attractant compared to those fed E. coli. We find that exposure to multiple strains of bacteria (including non-pathogenic ones) causes a similar behavioral change. To test the persistence of this behavior modulation, we transferred animals back to a diet of E. coli after P. aeruginosa exposure. We find that behavioral modulation by P. aeruginosa persists for two hours. Together these results present a form of neural circuit flexibility, where food signals modify behavioral outputs. From a pilot screen of signaling molecules, we found that knocking down neuropeptides impairs integration behavior. Neuropeptides are cleaved by specific proprotein convertase enzymes to form mature neuropeptides. To evaluate the role of individual subsets of neuropeptides, we tested proprotein convertase mutants bli-4, kpc-1, aex-5 and egl-3 2. We found that aex-5 mutants do not change behavioral response even after exposure to P. aeruginosa. This result suggests that neuropeptide(s) processed by AEX-5 is required for behavior modulation in response to food changes. We are in the process of identifying peptides involved in modulation of sensory integration behavior. Using this model, we aim to reveal the mechanisms regulating the dynamics of neural circuit functions in response to changes in prior food experience. 1. Ishihara T et al. Cell, 109: 639-649 (2002). 2. Li, C. and Kim, K. Neuropeptides (September 25, 2008), WormBook, ed. The C. elegans Research Community, WormBook, doi/10.1895/wormbook.1.142.1, http://www.wormbook.org.

Lau, Hiu et al. (2015) International Worm Meeting "Acute food deprivation activates neuropeptide signaling in diverse tissues to modify avoidance behavior."

Chalasani, Sreekanth, Lau, Hiu

[International Worm Meeting, 2015]

Animals detect relevant cues in the environment and modify their behaviors to maximize survival and fitness. Underlying neural circuits integrate information about external stimuli with those from internal states to generate appropriate behaviors. In particular, food status signals are crucial internal state signals with profound effects on an animal's behavior. The underlying neural and molecular machinery for communicating internal state remain incompletely understood.We used acute food deprivation to probe the effects of internal states on behavior. In a sensory integration assay, C. elegans cross a copper barrier and chemotax toward a spot of attractive diacetyl odor. We find that two hours of food deprivation experience is sufficient to elicit robust behavior modification. Animals deprived of food cross the copper barrier more readily compared to animals fed E. coli. Food deprivation acts on different tissues including neurons, intestine and body wall muscle, which process and release peptides. All of these tissues use the AEX-5 peptide processing enzyme and UNC-31 calcium-dependent activator protein for secretion, respectively. Downstream, the insulin receptor, DAF-2, receives these tissue-released peptide signals and modifies neural circuits generating behavioral plasticity. Our analyses of signaling machinery reveal that conserved components and pathways relay the internal status of the animal to neurons to elicit robust modification in behavioral responses. Together, this research provides important insight into the complex signaling required for animals to respond to changes in food availability.

Sulston JE et al. (1992) Nature "The C. elegans genome sequencing project: a beginning."

Staden R, Metzstein MM, Durbin RM, Wilson RK, Du Z, Berks M, Halloran N, Waterston RH, Qiu L, Sulston JE, Hawkins TL, Thomas K, Coulson AR, Ainscough R, Dear S, Thierry-Mieg J, Hillier L, Green P, Craxton M

[Nature, 1992]

The long-term goal of this project is the elucidation of the complete sequence of the Caenorhabditis elegans genome. During the first year methods have been developed and a strategy implemented that is amenable to large-scale sequencing. The three cosmids sequenced in this initial phase are surprisingly rich in genes, many of which have mammalian homologues.AD - MRC Laboratory of Molecular Biology, Cambridge, UK.FAU - Sulston, JAU - Sulston JFAU - Du, ZAU - Du ZFAU - Thomas, KAU - Thomas KFAU - Wilson, RAU - Wilson RFAU - Hillier, LAU - Hillier LFAU - Staden, RAU - Staden RFAU - Halloran, NAU - Halloran NFAU - Green, PAU - Green PFAU - Thierry-Mieg, JAU - Thierry-Mieg JFAU - Qiu, LAU - Qiu LAU - et al.LA - engPT - Journal ArticleCY - ENGLANDTA - NatureJID - 0410462RN - 0 (Cosmids)SB - IM

Matty, Molly et al. (2021) International Worm Meeting "Food Deprivation Induces Behavioral Changes that Require Metabolic Reprogramming and Non-Canonical Insulin Signaling"

Singh, Anupama, Matty, Molly, Chalasani, Sreekanth, Lau , Hiu, Kono, Karina

[International Worm Meeting, 2021]

Behavioral changes are easily attributable to external influences such as temperature, light exposure, and chemical stimuli. However, the effects of internal states such as infection status, stress, and hunger on animal behavior are often less obvious. We sought to determine how an internal state modifies animal behavior and define the pathways necessary to encode the behavioral change. Sensory integration is a conserved behavior in which an animal, or population of animals, must integrate attractive and repulsive signals simultaneously to decide whether to approach or avoid a cue. We conducted sensory integration assays in which populations of C. elegans are presented with an attractant, diacetyl, just beyond a repellant copper barrier. We show that acute food deprivation reversibly reduces copper sensitivity, allowing animals to engage in a "risky behavior": starved animals cross the toxic copper barrier to reach the attractant ~4 times more often than well-fed animals. Our results suggest that decreased copper sensitivity in food-deprived animals requires the transcription factors MondoA and HLH-30 within intestinal cells, which likely detect and respond to the lack of food. Others have shown HLH-30 translocation to intestinal nuclei is correlated with the expression of a few insulin-like peptides, many of which we show are required for the hunger-induced behavioral change. The insulin receptor DAF-2 is required to sense and respond to these insulin-like peptides. We demonstrate that expression of daf-2 and downstream non-canonical insulin signaling molecules in the ASI chemosensory neurons sufficiently rescues this food deprivation-induced risk-taking behavior. Our work suggests that the internal state of hunger or food sensation links animal behavior to intestinal metabolism and neuronal function.

Kono, Karina et al. (2019) International Worm Meeting "Inter-tissue signals drives inter-animal communication driving collective food-seeking behavior in C. elegans."

Sharpee, Tatyana, Dubova, Ilir, Lau, Hiu, Yang, Claire, Chalasani, Sreekanth, Rodrigues, Pedro, Kono, Karina, Tames, Maria, Liu, Zheng, Cecere, Zachary, Schroeder, Frank

[International Worm Meeting, 2019]

Neural circuits extract relevant sensory information from their environment and integrate internal state information and prior experience to generate robust behaviors. However, less is known how internal state information, including hunger affects neural circuit function and behavioral readouts. We combined food-deprivation with sensory integration assay where animals cross a repellent barrier to reach an attractant source. We found that food-deprived animals are more likely to cross the repellent barrier compared to controls. Specifically, we find that food-deprivation affects repellent sensitivity and is reversible. Next, we mapped the molecular pathway sensing and integrating this internal state. We show that MML-1 (a glucose-responsive bHLH/leucine zipper Mondo A homolog) detects the lack of glucose in the intestine and releases an AEX-5 convertase processed peptides using dense core vesicles. These peptides are sensed by DAF-2 insulin receptors on ASI neurons using a non-canonical mTOR complex. Downstream of this intestine-ASI signal, food-deprived animals alter the ascarosides that they secrete affecting the rest of the population. These studies show how intestinal signals modify neuronal signaling and alter inter-animal communication modifying collective behavior.

Vassilieva LL et al. (1999) Genetics "The rate of spontaneous mutation for life-history traits in Caenorhabditis elegans."

Lynch M, Vassilieva LL

[Genetics, 1999]

Spontaneous mutations were accumulated in 100 replicate lines of Caenorhabditis elegans over a period of approximately 50 generations. Periodic assays of these lines and comparison to a frozen control suggest that the deleterious mutation rate for typical life-history characters in this species is at least 0.05 per diploid genome per generation, with the average mutational effect on the order of 14% or less in the homozygous state and the average mutational heritability approximately 0.0034. While the average mutation rate per character and the average mutational heritability for this species are somewhat lower than previous estimates for Drosophila, these differences can be reconciled to a large extent when the biological differences between these species are taken into consideration.AD - Department of Biology, University of Oregon, Eugene, Oregon 97403, USA.larissa@darkwing.uoregon.eduFAU - Vassilieva, L LAU - Vassilieva LLFAU - Lynch, MAU - Lynch MLA - engID - RO1-GM36827/GM/NIGMSPT - Journal ArticleCY - UNITED STATESTA - GeneticsJID - 0374636SB - IM

Mondol V et al. (2012) Curr Top Dev Biol "Let's make it happen: the role of let-7 microRNA in development."

Mondol V, Pasquinelli AE

[Curr Top Dev Biol, 2012]

Noncoding RNAs have emerged as an integral part of posttranscriptional gene regulation. Among that class of RNAs are the microRNAs (miRNAs), which posttranscriptionally regulate target mRNAs containing complementary sequences. The broad presence of miRNAs in lower eukaryotes, plants, and mammals highlights their importance throughout evolution. MiRNAs have been shown to regulate many pathways, including development, and disruption of miRNA function can lead to disease (Ivey and Srivastava, 2010; Jiang et al., 2009). Although the first miRNA genes were discovered in the nematode, Caenorhabditis elegans, almost 20 years ago, the field of miRNA research began when they were found in multiple organisms a little over a decade ago (Lagos-Quintana et al., 2001; Lau et al., 2001; Lee and Ambros, 2001; Lee et al., 1993; Pasquinelli et al., 2000; Wightman et al., 1993). Here, we review one of the first characterized miRNAs, let-7, and describe its role in development and the intricacies of its biogenesis and function.

McIntire SL et al. (1993) Nature "The GABAergic nervous system of Caenorhabditis elegans."

Kaplan JM, Horvitz HR, Jorgensen EM, McIntire SL

[Nature, 1993]

gamma-Aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in vertebrates and invertebrates. GABA receptors are the target of anxiolytic, antiepileptic and antispasmodic drugs, as well as of commonly used insecticides. How does a specific neurotransmitter such as GABA control animal behaviour? To answer this question, we identified all neurons that react with antisera raised against the neurotransmitter GABA in the nervous system of the nematode Caenorhabditis elegans. We determined the in vivo functions of 25 of the 26 GABAergic neurons by killing these cells with a laser microbeam in living animals and by characterizing a mutant defective in GABA expression. On the basis of the ultrastructurally defined connectivity of the C. elegans nervous system, we deduced how these GABAergic neurons act to control the body and enteric muscles necessary for different behaviours. Our findings provide evidence that GABA functions as an excitatory as well as an inhibitory neurotransmitter.AD - Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139.FAU - McIntire, S LAU - McIntire SLFAU - Jorgensen, EAU - Jorgensen EFAU - Kaplan, JAU - Kaplan JFAU - Horvitz, H RAU - Horvitz HRLA - engPT - Journal ArticleCY - ENGLANDTA - NatureJID - 0410462RN - 56-12-2 (gamma-Aminobutyric Acid)SB - IM

Reboul J et al. (2001) Nat Genet "Open-reading-frame sequence tags (OSTs) support the existence of at least 17,300 genes in C. elegans."

Reboul J, Vandenhaute J, Tzellas N, Jackson C, Hartley JL, Lamesch PE, Vidal M, Brasch MA, Hill DE, Thierry-Mieg J, Thierry-Mieg N, Hitti J, Vaglio P, Thierry-Mieg D, Moore T, Shin-i T, Doucette-Stamm L, Temple GF, Lee H, Kohara Y

[Nat Genet, 2001]

The genome sequences of Caenorhabditis elegans, Drosophila melanogaster and Arabidopsis thaliana have been predicted to contain 19,000, 13,600 and 25,500 genes, respectively. Before this information can be fully used for evolutionary and functional studies, several issues need to be addressed. First, the gene number estimates obtained in silico and not yet supported by any experimental data need to be verified. For example, it seems biologically paradoxical that C. elegans would have 50% more genes than Drosophilia. Second, intron/exon predictions need to be tested experimentally. Third, complete sets of open reading frames (ORFs), or "ORFeomes," need to be cloned into various expression vectors. To address these issues simultaneously, we have designed and applied to C. elegans the following strategy. Predicted ORFs are amplified by PCR from a highly representative cDNA library using ORF-specific primers, cloned by Gateway recombination cloning and then sequenced to generate ORF sequence tags (OSTs) as a way to verify identity and splicing. In a sample (n=1,222) of the nearly 10,000 genes predicted ab initio (that is, for which no expressed sequence tag (EST) is available so far), at least 70% were verified by OSTs. We also observed that 27% of these experimentally confirmed genes have a structure different from that predicted by GeneFinder. We now have experimental evidence that supports the existence of at least 17,300 genes in C. elegans. Hence we suggest that gene counts based primarily on ESTs may underestimate the number of genes in human and in other organisms.AD - Dana-Farber Cancer Institute and Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.FAU - Reboul, JAU - Reboul JFAU - Vaglio, PAU - Vaglio PFAU - Tzellas, NAU - Tzellas NFAU - Thierry-Mieg, NAU - Thierry-Mieg NFAU - Moore, TAU - Moore TFAU - Jackson, CAU - Jackson CFAU - Shin-i, TAU - Shin-i TFAU - Kohara, YAU - Kohara YFAU - Thierry-Mieg, DAU - Thierry-Mieg DFAU - Thierry-Mieg, JAU - Thierry-Mieg JFAU - Lee, HAU - Lee HFAU - Hitti, JAU - Hitti JFAU - Doucette-Stamm, LAU - Doucette-Stamm LFAU - Hartley, J LAU - Hartley JLFAU - Temple, G FAU - Temple GFFAU - Brasch, M AAU - Brasch MAFAU - Vandenhaute, JAU - Vandenhaute JFAU - Lamesch, P EAU - Lamesch PEFAU - Hill, D EAU - Hill DEFAU - Vidal, MAU - Vidal MLA - engID - R21 CA81658 A 01/CA/NCIID - RO1 HG01715-01/HG/NHGRIPT - Journal ArticleCY - United StatesTA - Nat GenetJID - 9216904SB - IM

Walhout AJM et al. (2000) Science "Protein interaction mapping in C. elegans using proteins involved in vulval development."

Lu WX, Vidal MI, Hartley JL, Thierry-Mieg N, Walhout AJM, Sordella R, Brasch MA, Temple GF

[Science, 2000]

Protein interaction mapping using large-scale two-hybrid analysis has been proposed as a way to functionally annotate large numbers of uncharacterized proteins predicted by complete genome sequences. This approach was examined in Caenorhabditis elegans, starting with 27 proteins involved in vulval development. The resulting map reveals both known and new potential interactions and provides a functional annotation for approximately 100 uncharacterized gene products. A protein interaction mapping project is now feasible for C. elegans on a genome-wide scale and should contribute to the understanding of molecular mechanisms in this organism and in human diseases.AD - Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.FAU - Walhout, A JAU - Walhout AJFAU - Sordella, RAU - Sordella RFAU - Lu, XAU - Lu XFAU - Hartley, J LAU - Hartley JLFAU - Temple, G FAU - Temple GFFAU - Brasch, M AAU - Brasch MAFAU - Thierry-Mieg, NAU - Thierry-Mieg NFAU - Vidal, MAU - Vidal MLA - engID - 1 R21 CA81658 A 01/CA/NCIID - 1 RO1 HG01715-01/HG/NHGRIPT - Journal ArticleCY - UNITED STATESTA - ScienceJID - 0404511RN - 0 (Genetic Vectors)RN - 0 (Helminth Proteins)RN - 0 (LIN-35 protein)RN - 0 (LIN-53 protein)RN - 0 (Repressor Proteins)RN - 0 (Retinoblastoma Protein)SB - IM