Sunday, May 19, 2024
5/19/2024
Project Summary/Abstract The superior colliculus (SC) is a sensorimotor mammalian midbrain structure that integrates multimodal sensory input and guides our everyday responses to environmental cues and determines what events are most relevant and deserve our attention. Accumulating evidence has implicated the SC in neurodevelopmental disorders, such as autism spectrum disorder (ASD), and in neurodegenerative disorders, such as Lewy body dementia, Parkinson disease, progressive supranuclear palsy etc. Establishing a functional neurocircuitry that leads to proper behavioral responses requires correct neuronal differentiation and specification during development. One mechanism thought to regulate neuronal differentiation is the reduction-oxidation (redox) state of the cell. Regulation of the redox state of a cell can be crucial in inducing protein modifications, therefore regulating their function in cells and tissues. In a recent paper, our labs showed that treatment of the developing zebrafish embryos/larvae with the drug valproic acid (VPA) led to 1) delay in the specification of neurons in the homologous, non-mammalian structure of the SC, named the optic tectum (OT) and 2) lack of formation of at least one subtype of neurons in the OT. Since VPA has been shown to perturb the redox state in other neurons (and has been associated with a higher incidence of ASD in children with fetal exposure to VPA), this study suggests that redox state might in fact be important during neuronal development in the OT. Our proposal is designed to follow up on these initial studies and fill the gap in understanding how OT neurocircuitry and associated behaviors are regulated by changes in redox state during OT development. In the first aim, we plan to follow in vivo how the redox state of different cell-compartments in OT neurons changes during normal development and after the redox state is perturbed by VPA-treatment. In the second aim, we would like to determine when are the different neuronal cell-subtypes generated in the OT, and if their formation is affected upon redox state changes by VPA-treatment. Finally, in the third aim, we would like to explore how the changes of redox state, specifically in the OT, affect behavior. Very few studies have investigated the effects of redox state in OT circuitry, therefore, our study would fill an important gap in the current understanding. Additionally, since the SC is associated with ASD, and VPA exposure is also correlated with higher ASD incidence, this study might shed light into the molecular and cellular underpinnings of ASD.
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