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Title: Molecular tuning of a neural circuit that drives aggregation behaviour in C. elegans
Author: Flynn, Sean
ISNI:       0000 0004 7227 2259
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2018
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Modulation of network state is a ubiquitous feature of nervous systems. A major challenge in understanding the physiological flexibility of neural circuits is linking molecules that regulate behaviour to changes in the properties of individual neurons. Here, we use a defined neural circuit in C. elegans to frame this universal problem. By genetic dissection of the behavioural state that sustains escape of 21% O2, we identify novel neuronal functions for several highly conserved genes, including a caspase-like molecule, a calcium-sensitive transcription factor, and two translation initiation factors. These molecules have been implicated in diverse forms of human disease, but their role in the nervous system is either unexplored or poorly understood. Using in vivo Ca2+ imaging techniques to investigate neuron physiology in immobilized and behaving animals, we demonstrate their effect on the properties of individual neurons. The activity of RMG hub neurons is associated with the switch in behavioural state induced by 21% O2. Recently it has been shown that the input-output relationship of RMG is controlled by cytokine signaling, an increasingly appreciated form of neuromodulation. Here I present biochemical and genetic evidence that characterize a novel signaling component downstream of IL-17 receptors in RMG. Our data suggest that, reminiscent of its role in the immune system, it performs both scaffolding and enzymatic functions in neurons. Additionally, we show that RMG responsiveness is controlled by widely expressed, putative regulators of gene expression. Our analyses of these proteins elucidate their function within the URX-RMG circuit, but also raise hypotheses that can be tested more generally in the nervous system. We propose that a calmodulin-binding protein regulates adaptation to ambient O2 conditions, which may reflect a widespread requirement for controlling homeostatic plasticity. Two translation factors that have been shown to be dispensable for general translation are important for regulation of the response to stress. Our study raises the possibility that their role in promoting the activity of all, or some subset of, neurons might underlie this contextual requirement. Together, our findings provide mechanistic insight into the regulation of a behavioural state associated with a specific environmental context.
Supervisor: de Bono, Mario Sponsor: MRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: neuromodulation ; signaling ; genetics