Social cues provide essential feedback for behavior, and defective processing of social cues is a central symptom of autistic spectrum disorder. Understanding how the brain uses social cues to influence behavior may therefore yield insight into the neural underpinnings of this and other neuropsychiatric disorders. The connection between social cues and their behavioral outputs is complex, and for this reason simple model systems may allow for the easiest and most accurate analysis of how social cues influence behavior. One such simple model system, Caenorhabditis elegans, demonstrates several social behaviors, but has only 302 neurons. C. elegans offers several advantages as a model system for the study of social behavior. These including the availability of a complete neural circuit diagram, the capacity to manipulate the activity of individual neurons in behaving animals, and the ability to easily make transgenic strains. Together these properties of C. elegans will enable us to elucidate the circuitry by which social cues influence behavior. C. elegans transitions between two behavioral states when on food - a "roaming" state characterized by high speed and low turning rate and a "dwelling" state characterized by low speed and high turning rate. Roaming and dwelling may reflect the decision to explore versus exploit local resources. In accordance with this possibility, the fraction of time worms roam is affected by food quality, experience, and sensory inputs. We found roaming and dwelling is also influenced by C. elegans density pheromones called ascarosides. Crude pheromone extract as well as the individual synthetic ascarosides C3, C5, C6, C7paba and C9 increased the fraction of time worms spent dwelling. To study the mechanism of this "ascaroside-induced dwelling," I tested the sensitivity to ascarosides of a panel of strains lacking specific neurotransmitters or neurotransmitter receptors. This screen revealed that the neurotransmitter GABA is necessary for ascarosides to induce dwelling and that the putative GABA receptor ggr-2 accounts for part of this effect. To understand the precise role of GABA in the circuitry mediating ascaroside-induced dwelling, I propose this research plan with the following specific aims: 1) to identify the GABAergic cells mediating response to ascarosides both through laser ablation studies and through cell-specific rescue of GABA;2) to identify the postsynaptic effectors neurons to GABA by performing cell-specific rescue of ggr-2;and 3) to identify the sensory neurons involved in ascaroside-induced dwelling through ablation studies and to determine their role in regulating GABAergic activity as quantified by immunohistochemistry and calcium imaging. The successful completion of these aims will provide a foundation to understand how social cues produce and maintain an altered behavioral state.
Social cues inform most human behaviors, and dysfunction in processing social cues is a central element of autism spectrum disorders. Our research seeks to understand how pheromones, a form of social cue, modify behavior in Caenorhabditis elegans by defining the role of GABAergic signaling in this process. Our work will reveal the neural circuitry by which social cues alter the behavioral state of an organism and may thereby yield insight into autism spectrum disorders and other disorders associated with social dysfunction.
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