The manner in which the cerebral cortex develops is extremely important to the fate of most mammals.The neocortex is a laminated structure containing 6 layers, each of which possesses a distinct function and structure. Improper neocortical development, or irregularities in the migration of neurons to their eventual positions within the cortical layers are implicated in many neurologic disorders. Understanding the factors that contribute to normal formation of layers is an important key toward understanding mechanisms that contribute to several forms of dementia and other disorders, such as dyslexia. The studies proposed here will use in vitro and in vivo methods to study development of the somatosensory cortex of ferrets. We will use organotypic cultures of somatosensory cortex to determine their ability to survive and develop in vitro. The first set of experiments will (i) evaluate the ability of static interface organotypic cultures to retain a normal laminar pattern and (il) assess the capacity of neurons to continue their migration to normal laminar positions and (iii) establish normal patterns of connectivity. The second set of experiments will evaluate how deletion of a specific cortical layer, using a toxin known to prevent cells from dividing during a specific period of time, will effect the future development and formation of prior and subsequent layers. Two specific layers will be deleted in different sets of animals: layer 4, a primary recipient layer, and layer 3, a layer concerned with intracortical connections. The effect of layer deletion will be assessed in vitro, using organotypic cultures, and in vivo, in animals that mature normally. In cultures, we will study the pattern of connections in animals with layer deletions, as well as the ability of neurons to migrate to appropriate sites within the neocortex. In mature animals, we will use electrophysiological recordings and current source density analysis to assess the impact of layer deletions on both the vertical and horizontal dimensions of cortical responsivity in somatosensory cortex. Finally, we will study the possibility that abnormalities induced by layer deletion can be reversed by transplanting cell suspensions comprised of the missing neuronal population taken from appropriately-timed normal embryos. The cell suspension transplants will be inserted in organotypic cultures and in young animals that have been subject to layer deletion. The experiments will assess the capacity of transplants to survive in vitro and in vivo, to migrate to their normal site in the cerebral cortex, and to restore normal patterns of connections to layer-deleted animals.
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