Grant: CIHR Fellowship

In our nervous system, billions of cells called neurons are connected with one another in an elaborate network that transmits information essential for our everyday function. Each neuron within this network sends signals via its axon, a long branch that extends from the cell body and connects with target cells. The speed signals travel along the axon is critical for fast information processing. Much like electrical wires, speed can be increased by enlarging the axon's cross-sectional area (caliber) and/or by insulating the axon by wrapping it with a membrane sheath called myelin. Regulation and variation of these two parameters is what controls the precise timing of signals throughout the nervous system. If this precise signalling becomes disrupted, it leads to neurological disease. Thus, there is a need to identify the regulators of axon caliber and myelin formation in the brain, which are currently largely unknown. Since individual axons have different speed requirements within the network, it is logical that the network itself might act as one such regulator. I am proposing to examine whether axon caliber and myelin are regulated by the formation and function of connections between neurons in the network. To test this, I will perform time-lapse 3D live-imaging in zebrafish, whose transparency allows for following growth of individual axons. Using a variety of genetic manipulations, I will determine how changing network structure or function affects axon caliber and myelin. Linking network circuitry to caliber growth and myelination will provide new insight into how alterations in connectivity not only influence the path a message takes, but also the speed at which it travels. This work will address a fundamental gap in our knowledge of nervous system assembly, as well as allow us to better understand what goes wrong in neuronal networks during disease. This will have important implications for the development of therapeutics in the future.