Dissertation Defense: Modeling Neural Stem Cell Dynamics in Congenital Heart Disease

About this Dissertation

Congenital heart disease (CHD) remains a significant cause of abnormal fetal brain development, affecting 1-2% of live births per year. Although many surgical strategies have shown promise in increasing quality of life, the current challenges remain the long-term cognitive deficits and diverse neurodevelopmental disabilities due to CHD. Recent studies suggest that dysregulated neurogenesis, which is associated with impaired neocortical development in human fetuses of CHD, may be influenced by altered brain circulation and oxygen deliverance during critical periods of prenatal cortical growth. The brain's subventricular zone (SVZ) niche is essential for producing new neurons following birth to restore, repair, and replace existing neurons in the developing brain. In addition, these newborn neurons undergo long-distance migration from the SVZ to reach their final cortical destinations and ultimately contribute to brain development/plasticity. This study seeks to characterize the migration pattern of newborn neurons and the substrates (e.g., blood vessels or astrocytes), enabling the movement along the unique migratory routes under normal and pathological (i.e., hypoxia) conditions. In short, we found that the vast majority of the SVZ-derived newborn neurons are cortical inhibitory neurons (i.e., interneurons) that originate in the deep region of the brain called the telencephalon and migrate tangentially utilizing blood vessels as scaffolds to the brain cortex, which is likely to contribute to cortical plasticity. These postnatal piglet findings demonstrate that the piglet species represents a powerful translational model system to study large-brained mammalian cortical development and neuronal migration as it correlates to humans in normal and diseased states.

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