Molecular genetics of sensory modulation of motor programs

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PROJECT SUMMARY Neuromodulators such as serotonin and neuropeptides can exert widespread and lasting effects on neural circuits and behavior. This mode of signaling is critical for brain function. Dysfunctional neuromodulator signaling causes a host neurological and psychiatric disorders, and neuromodulator signaling pathways are targets of clinically important therapeutics and drugs of abuse. The goal of this project is to advance understanding of molecular mechanisms that regulate the development and function of neuromodulatory systems that control behavior. For this, we study the roundworm C. elegans, whose small and accessible nervous system is endowed with most of the neuromodulators found in the human brain. Many behaviors of C. elegans require specific neuromodulators and are amenable to genetic analysis, which permits unbiased discovery of factors required for neuromodulator signaling or the development of neuromodulatory systems. We have found a circuit that combines two types of neuromodulation to control a simple and stereotyped C. elegans behavior. Chemosensory BAG neurons release neuropeptides that potently inhibit a pair of serotonergic neurons in the reproductive neuromusculature of the C. elegans hermaphrodite - the HSNs. Through genetic studies of behaviors generated by this circuit we have discovered genes required for the development and function of peptidergic BAGs and factors required for neuropeptides to modulate HSN function and reproductive behavior. In addition to serving as a model for neuromodulation, this circuit allows us to investigate the neurobiology of animal-microbe interactions. BAG neurons detect the carbon dioxide generated by microbial respiration, and they function in a circuit that evaluates the quality of environmental microbes and that allows C. elegans to discriminate between nutritive microbes and pathogens. We have linked our interest in host-microbe interactions to our interest in neuromodulation through a study of microbial metabolites that function as agonists of serotonin signaling to affect animal behavior. To date our studies have revealed functions in the development and function of neuromodulatory systems for a Toll-like receptor and its associated signaling pathway, insulin signaling, evolutionarily conserved transcription factors, and regulators of neuronal excitability. Biochemical and genetic screens based on these discoveries continue to yield new factors, and we expect that this circuit will continue to serve as a powerful platform for understanding molecular mechanisms of neuromodulation.