Axonic Neurotransmission In Neural Circuit Formation And Function

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This project will be the first in-depth in vivo examination of the hypothesis that axonic neurotransmission is a fundamental mode of cellular communication and neuronal circuit regulation using zebrafish as a model organism.A key goal in neuroscience is to understand how behaviour emerges from neurotransmission between brain cells. That neurons communicate at synapses using neurotransmitters is well known. But neurons also secrete neurotransmitters away from synapses, and how this occurs and impacts associated cells is, by contrast, poorly understood. My live-imaging studies of neurotransmitter release in individual zebrafish neurons revealed extensive axonic neurotransmission, whereby neurons release neurotransmitters along their axons, away from synapses. This was as frequent as synaptic release, which begs the questions of how axonic neurotransmission occurs and what purposes it serves. Unlike transmission at discrete synaptic sites, axon-released neurotransmitters can potentially diffuse broadly and reach many neurons and glia - now appreciated as active participants in circuit function. The impact of axon-released neurotransmitters in vivo is poorly understood because it has not been examined in a model in which it can be easily visualized and manipulated. Therefore, it remains unclear whether axonic transmission is a specialized mechanism that neurons employ to regulate circuit function in certain conditions.I will now undertake the ambitious task of examining the full impact of axon-released neurotransmitters in vivo. To do this, I will exploit the amenability of zebrafish for live imaging and the genetic toolkit I developed to elucidate mechanisms of axonic transmission, the elicited responses in target cells, and its effects on circuit function and behaviour. AxonicTransmission will provide key insights into the fundamental principles of cellular communication in the nervous system.