Molecular mechanisms of neural circuit function (360G-Wellcome-209504_Z_17_Z)

I aim to (i) discover molecular and cellular mechanisms that underpin neuronal properties; (ii) elucidate how these properties shape neural circuit activity to generate behaviour. C. elegans offers special opportunities to address these questions. C. elegans kept at 21% O2 adopt a different state from animals kept at 2. We are deconstructing the tonically signalling circuit that coordinates this state change via fast and slow-acting mechanisms. To achieve this, we isolated 583 mutants defective in escape from 21% O2. I propose to elucidate the function of several conserved protein complexes highlighted by these mutants. These include: 1) An interleukin-17 signalling pathway that changes circuit gain; 2) Membrane proteins of unknown function that I speculate promote biogenesis of many ion channels; 3) An ER complex promoting biogenesis of GPCRs; 4) A pan-neuronally expressed calmodulin-binding transcription factor controlling neural excitability. These studies combine genetics, biochemistry and cell biology, and integrate in vivo C. elegans work with studies in mammalian cells. To complement the genetics, we will use RNA-seq of FACS-sorted C. elegans neurons to study circuit plasticity, and adapt a platform developed for pan-neuronal imaging of freely-moving zebrafish larvae to freely-moving C. elegans, to provide a more comprehensive phenotypic readout.