Our main research goal is to understand the development of highly-specific neuronal circuits in the mammalian neocortex. Proper formation of neuronal circuit critically depends on the production, positioning, and differentiation of various types of neurons, which largely occur during early developmental stages. We thus hypothesize that neuronal circuit development is tightly linked to the early developmental processes of neurogenesis, neuronal migration and differentiation. To test this, a major focus of our research program is to bridge the gap between early development of the embryonic and neonatal neocortex and the emergence of highly-specific neuronal circuits in the postnatal neocortex. Specifically, we are working on the following two areas using rodents as a model with a combination of approaches including electrophysiology, two-photon/confocal laser scanning microscopy, mouse genetics/in utero manipulation:
Neurogenesis, Neuronal Migration and Differentiation in the Embryonic and Neonatal Neocortex
Recent studies have shown that radial glial cells are the major neuronal progenitor cells that divide to give rise to neurons in the developing neocortex. Radial glial cells divide either symmetrically or asymmetrically at the ventricular surface of the ventricular zone (VZ). While symmetric divisions generate two more radial glial cells to amplify the progenitor pool, asymmetric divisions generate another radial glial cell and a postmitotic neuron or an intermediate progenitor cell (IPC). The IPC, also referred as basal progenitor cell, moves to the subventricular zone (SVZ) and subsequently divides symmetrically to produce two neurons. Hence, asymmetric division of radial glial progenitor cells is the primary means of generating neurons in the developing neocortex. Furthermore, while renewing radial glial progenitor cells remain in the proliferative VZ, differentiating neurons migrate progressively away from the VZ into the cortical plate to constitute the future neocortex. Here are some questions related to this area that we are interested:
- What are the mechanisms that control radial glial cells to divide symmetrically or asymmetrically?
- What are the mechanisms that mediate distinct behaviors of renewing radial glial progenitor and differentiating neurons?
- Once being produced, how do neurons undergo proper morphogenesis and migrate to their destination?
Circuit Development in the Postnatal Neocortex
It is well accepted that the neocortex is functionally organized into “columns”. Furthermore, synaptic connections in the functional columns are sparse yet highly-specific. Even neighboring neurons of the same anatomical type can receive synaptic input from different sources and display distinct physiological properties. This fine-scale synaptic connectivity with single-cell resolution is unlikely generated entirely depending on the spatial overlapping of axons and dendrites. How then do functional columns with this precise synaptic connectivity emerge in the neocortex? Is there an anatomical 'substrate' being laid-out during early developmental stages on which functional columns are built? What are the intrinsic (nature) and extrinsic (nurture) mechanisms responsible for the formation of synapses with single-cell resolution?