UCSF

Studies in organisms from worms to humans have brought an increasing appreciation for a crucial role of the central nervous system in the regulation of many basic physiological processes including energy homeostasis, immune responses, development and aging. However, the mechanisms underlying such regulation are still incompletely understood. In C. elegans, two physiological processes that are notably modulated by the nervous system are the developmental decision to arrest in the hibernation-like dauer larval stage and the regulation of aging. In this thesis, we studied the interplay between endocrine systems controlling aging and dauer formation, such as insulin/IGF-1 signaling, and neuronal signaling, such as neurotransmitter and sensory signaling. We found that dopamine signaling may be specifically modulated by insulin/IGF-1 signaling to regulate the quiescence behavior of dauer, and it may also be involved in the process of exit from the dauer stage. Because there are physiological and molecular similarities between the dauer stage and seasonal hibernation in mammals, it is possible that dopamine signaling contributes to behavioral quiescence in hibernating mammals. In a separate study, we found that signals from the sensory system feed into the regulation of at least two different transcription factors, the FOXO homolog daf-16 and the steroid nuclear hormone receptor daf-12, both targets of endocrine pathways. In addition, we found that the sensory system is required for normal expression of immune response genes, and that sensory system mutants have increased susceptibility to a bacterial pathogen. These results indicate that sensory inputs can coordinately regulate several processes by affecting a number of important transcriptional responses. The insulin/IGF-1 pathway, the dopamine pathway and sensory inputs are crucial in the mammalian central nervous system for the regulation of many physiological as well as behavioral responses. Therefore these studies in a simpler, genetically tractable organism may offer valuable insights on how these systems may be coordinated in higher organisms.