(Project 1) Project 1 will determine the contribution of neonatal and early childhood neuronal migration to human brain development and will develop an animal model to study the effects of hypoxia on these processes. We previously identified and characterized a novel ventral migratory stream of neurons in the early childhood brain. We now present preliminary data for a prominent dorsal migratory stream. This project will answer the following questions: (1) What is the precise location of young migrating interneurons in the developing human dorsal forebrain, and in which regions do these cells arrive? (2) Using the ferret as an experimental model for this uncharacterized postnatal neuronal migration in the human, what are the origins, identities, and destinations of these cells? (3) Do oxygen-regulated pathways impact postnatal interneuron generation, migration and/or differentiation? The Specific Aims and hypotheses to be tested are:
Aim 1 : Generate precise three dimensional maps of the location and extent of dorsal migratory streams in the infant human brain. Hypothesis: extensive postnatal neuronal migration exists in humans and these cells are late-arriving interneurons that complete circuitry in specific brain regions.
Aim 2 : Develop an animal model to study postnatal migratory streams. Hypothesis: postnatally migrating neurons in the ferret brain are also late-arriving interneurons that migrate to specific brain regions during discrete periods of postnatal development.
Aim 3 : Determine the effect of hypoxia on migrating neurons in the ferret. Hypothesis: neonatal hypoxic injury affects postnatal production and/or migration of interneurons and this changes circuit composition. We will characterize the regions of postnatal neuronal migration in the neonatal and infant human brain, determine possible contributions of these migrations to specific neuronal circuits, and develop an animal model to trace their lineage and determine their susceptibility to hypoxia during early postnatal life. Our preliminary findings reveal that there is a significant contribution of late migrating neurons and that this population is susceptible to hypoxic injury.
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|Watanabe, Momoko; Buth, Jessie E; Vishlaghi, Neda et al. (2017) Self-Organized Cerebral Organoids with Human-Specific Features Predict Effective Drugs to Combat Zika Virus Infection. Cell Rep 21:517-532|
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|Tsai, Hui-Hsin; Niu, Jianqin; Munji, Roeben et al. (2016) Oligodendrocyte precursors migrate along vasculature in the developing nervous system. Science 351:379-84|
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|Paredes, Mercedes F; James, David; Gil-Perotin, Sara et al. (2016) Extensive migration of young neurons into the infant human frontal lobe. Science 354:|
|Nobuta, Hiroko; Cilio, Maria Roberta; Danhaive, Olivier et al. (2015) Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome. Acta Neuropathol 130:171-83|
|Lee, Hyun Kyoung; Chaboub, Lesley S; Zhu, Wenyi et al. (2015) Daam2-PIP5K is a regulatory pathway for Wnt signaling and therapeutic target for remyelination in the CNS. Neuron 85:1227-43|
|Tate, Matthew C; Lindquist, Robert A; Nguyen, Thuhien et al. (2015) Postnatal growth of the human pons: a morphometric and immunohistochemical analysis. J Comp Neurol 523:449-62|
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