Regulation of Behavioral Arousal and Quiescence in C. elegans

Abstract

Animals switch between periods of behavioral quiescence and arousal in response to environmental, circadian, or developmental cues. C. elegans exhibit periods of behavioral quiescence during larval molts (termed lethargus) and as adults. Little is known about the circuit mechanisms that establish these quiescent states. Mutants lacking the neuropeptide receptor NPR-1 are a model for heightened arousal and have dramatically reduced locomotion quiescence during lethargus as a result of increased sensory acuity and secretion of the arousal peptide PDF-1. In Chapter 2 of this thesis, we show that the aroused locomotion of npr-1 mutants results from the exaggerated activity in multiple classes of sensory neurons, including nociceptive (ASH), touch sensitive (ALM and PLM), stretch sensing (DVA) neurons, and chemosensory neurons (ASI). These sensory neurons accelerate locomotion via both neuropeptide and glutamate release and their relative contribution to arousal differs between larval molts and adults. These results demonstrate that a broad network of sensory neurons and transmitters dictates transitions between aroused and quiescent behavioral states. We propose that locomotion quiescence during molts is mediated by diminished sensory inputs (termed sensory gating) and that NPR-1 plays a central role in this process. In Chapter 3, we identify a second arousing neuropeptide, FLP-2, which promotes locomotion through an orexin-like receptor (FRPR-18). FLP-2 secretion is inhibited by NPR-1 and enhanced secretion is associated with aroused locomotion during molts. This locomotion arousal is stabilized by reciprocal positive feedback between two arousing neuropeptides (FLP-2 and PDF-1). FLP-2 and FRPR-18 are co-expressed in ASI neurons, suggesting that ASI activity is regulated by autocrine positive feedback. Our results suggest that FLP-2 and FRPR-18 are the C. elegans homologs of mammalian hypocretin/orexin peptide and receptor, respectively. We propose that aroused locomotion is stabilized by two circuit motifs: reciprocal positive feedback between different classes of arousing neurons and autocrine positive feedback of FLP-2 expressing neurons. These motifs may be conserved in the arousal circuits of other model systems.