- To examine the early laminar and areal commitment of cortical progenitor cells in the rodent and in the primate as well as the origin of the instructions to the precursors.
- To investigate the role of thalamic afferents in the specification of the identity of cortical areas in the primate.`
- To determine the potentiel of neurotrophins to influence the specification of cortical areas and the formation of functional connections.
The aim of the present proposal is to advance our understanding of the role of environmental factors in the three major stages of corticogenesis. First, the six layers of the cortex are generated by processes of cell proliferation, migration and differentiation. Here the early laminar and areal commitment of progenitors will be examined. Second, the newly formed cortex establishes connections both between areas and with subcortical structures. Here the role of thalamic afferents in the specification of the cortex will be studied. Third there is a period of refinement of connections during which the electrophysiological properties of the cortex emerge. Here the potential of neurotrophins to influence the formation of functional connections will be assessed.
A particular effort will be made to progress in the understanding of the theoretical basis for future therapeutic procedures. This will be achieved by (i) focusing on those aspects of environmental control which are heavily implicated in the developmental neuropathology of the cortex and (ii) by pooling our resources, it will be possible to establish a primate model of cortical development.
Two complementary experimental approaches will be undertaken: (i) A reductionist approach where the origins and effects of extracellular signals that determine the areal and laminar fate of cortical precursor cells as well as the role of afferent connections in the differentiation of the cortex will be investigated. The primary goal will be to elucidate the interactions between cells. Of secondary concern will be to determine the molecules involved in these interactions. (ii) An integrated approach where the influence of a group of intercellular signalling molecules, the neurotrophins, on complex developmental processes will be investigated. This will generate important data on the plasticity of the cortex and contribute to the understanding of the formation of functional pathways.
Specification of cortical areas and layers. Early events in corticogenesis which influence cell proliferation and differentiation will be studied. Using cell and tissue methods as well as transplantation techniques the commitment of newborn progenitors to their areal and laminar fate will be examined. In the long term this work will offer new perspectives for the understanding of human diseases resulting from areal and laminar malformations.
Primate model of early cortical damage and repair. The neuronal circuitry of the cortex following massive areal reorganisation will be examined. This will provide a data base for interpreting the anatomical consequences of intermodal sensory competition and compensation as well as guidelines for the education of the handicapped.
Influence of neurotrophins. Cell division, cell death and remodelling of connections are mediated by neurotrophins. The involvement of neurotrophins in certain of these events will be assessed in vivo and in vitro as well as their influence on the developmental plasticity of cortical structure and function. The issue of how best to deliver neurotrophins to the brain will be directly assessed. Initially carried out in rodents, these studies will be subsequently taken to primates and will have direct implications for future treatment of degenerative disorders of the cortex.
Funding SchemeCSC - Cost-sharing contracts
EH8 9AG Edinburgh