The cerebral cortex is essential for integration and processing of information that is required for most behaviors. Correct functioning of the cerebral cortex necessitates the concerted assembly of circuits involving glutamatergic projection neurons and GABAergic interneurons. The exquisitely precise laminar arrangement of neurons, axon collaterals and dendritic processes arises during embryonic development when neurons migrate successively from proliferative ventricular zones to coalesce into specific cortical layers. While radial glia was identified as substrates or guide rails for migration of projection neuron precursors to the cortical plate in the early seventies, the substrate for GABAergic interneuron migration was a missing link. Our recent work has shown that pre-formed vascular networks in the embryonic forebrain are strategically positioned to fulfill the formidable task of providing support and guidance cues to GABA neurons as they migrate from the subpallium to the developing cerebral cortex. This application will examine this novel paradigm of endothelial cell-neuron interactions at detailed cellular and molecular levels. It will elucidate the importance of new signaling mechanisms via forebrain endothelial cells that were hitherto believed to be exclusively neuronal. It will examine how alterations in these novel developmental pathways disturb hierarchical vascular patterns; perturb neuronal migration and cortical organization. Results will illustrate a powerful impact on cerebral cortex circuitry, blood flow and postnatal behavior with new significance for psychiatric disorders.
This research is relevant to public health because it will generate new insights into the fundamental cellular and molecular mechanisms that are altered in substrates of neural function leading to diverse mental health conditions.
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