The cerebral cortex is perhaps the most complex structure in the brain, consisting of billions of neurons with trillions of connections. This high level of complexity underlies the massive computational power of the cortex and allows us to perceive the world around us and organize appropriate actions. In an effort to understand how the cortex as a whole functions neuroscientists have attempted to study smaller functional units within the cortex. It has been proposed that the smallest computational unit of the cortex may be the ontogenetic column - vertical columns of pyramidal neurons derived from a single neural progenitor cell. Recent studies suggest that cell lineage is an important predictor for development of functional properties in the neocortex. However, large differences in effect size between studies have led to controversy surround how important cell lineage is in determining function. This project will use in vivo two-photon calcium imaging to characterize visual response properties of clonally- related neurons in mouse primary visual cortex (V1). A tamoxifen-inducible Cre-loxP system will be used to sparsely label neural progenitor cells with a fluorescent marker at the beginning of neurogenesis. The dose and timing of tamoxifen administration will be optimized for spatial isolation of single microcolumns. Calcium responses of related and nearby unrelated neurons in V1 will be used to calculate orientation tuning for individual cells. We will systematically vary age at imaging and clonal size (two variables that have not been controlled for in previous studies) to determine whether these parameters contribute to the variability between studies. In addition, these experiments will lead important insights into the developmental time course of tuning properties of clonally related neurons. While the proposed studies will directly address the significance of ontogenetic microcolumns for encoding visual stimuli, the results will carry implications for the role of microcolumnar unit as a general principle of cortical processing. The proposed experiments may provide a circuit level foundation to study neurodevelopmental disorders such as autism and schizophrenia.
Many cognitive and neurodevelopmental disorders including schizophrenia, autism, and Down syndrome are thought to the development of abnormal functional circuits during development. This project aims to understand how the factors that influence development of functional subnetworks in the neocortex, with the hope that this knowledge will lead to a more principled treatment approach in these patients.
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