Neurons in zebrafish brains are releasing neurotransmitters along the length of their axons, not just at the specialised junctions called synapses, and this happens as often as synaptic release does. This matters because neuroscience has long assumed that most meaningful neural communication happens at synapses. The discovery that axons release neurotransmitters broadly, where they can diffuse to reach many nearby neurons and glial cells, suggests a fundamentally different mode of brain signalling. Until now, no one has been able to watch this process in a living, behaving animal and test what it actually does. This project is fundamental science. It will use live imaging and genetic tools in zebrafish to map how axonic release occurs, what responses it triggers in target cells, and how it shapes neural circuit activity and behaviour. If successful, it will rewrite the basic textbook understanding of how neurons talk to one another. That deeper knowledge could eventually inform treatments for neurological conditions where communication between brain cells goes wrong, but the immediate payoff is a clearer picture of the brain’s core operating principles.
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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.
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