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Vaikakkara Chithran, Aarya

University of British Columbia

One of the most extraordinary characteristics of the nervous system is the complexity of its neural circuits. Understanding the molecular programs that maintain the neural circuits in adulthood is important for understanding brain function, and ultimately this may provide insights into how these processes are dysregulated in neurodegenerative disorders. In adults, neurodegeneration and neuronal loss may be caused due to the lack of an essential protein resulting in the loss of its physiological function, or neurotoxicity of misfolded and aggregated proteins resulting in the gain of pathogenic function. The overall objectives of my thesis were to firstly, explore the roles of axon guidance cues in the maintenance of adult neural circuits and secondly, to develop a novel model for studying the consequences of tau pathogenicity on neural circuits. During the development of the nervous system, neurons extend axons in response to various guidance cues to reach their targets and form functional circuits. More recently it has become clear that after functional circuits have been established, many neurons continue to express developmental guidance cues implying additional roles for them in adults. A major part of this thesis focuses on the role of specific axon guidance cues in the active maintenance of adult neural circuits. After knocking down axon guidance cues in the adult Drosophila nervous system, I examined well-established circuits such as the olfactory system and motor neuron circuits. Knocking down Semaphorins and Plexins, members of the canonical repulsive guidance signalling pathway, resulted in the loss of motor neurons. Knocking down Fasciclin-3, an Ig-containing homophilic cell adhesion molecule, led to neuronal death in the adult olfactory system. This phenotype was rescued by overexpressing p35, an anti-apoptotic protein. This study begins to unravel the importance of stable expression of axon guidance cues in the maintenance of the mature nervous system. The last part of my thesis discusses a novel Drosophila tauopathy model that allows for high-volume testing of tau variants in the adult olfactory circuit in an unbiased and systematic approach. This model overcomes several limitations of commonly used tauopathy models.

Text; Still Image

2024-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/83462

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/