PROJECT 3: THALAMIC PATTERNINGAND INFLUENCE ON CORTICAL AREALIZATION Thalamocortical axon (TCA) input from the principal sensory nuclei of dorsal thalamus (dTh) to the primary areas of neocortex define the modality-specific functions of areas in the adult, and we hypothesize that during development TCA input plays a critical role in patterning the neocortex into areas. This patterning process, referred to as arealization, is controlled by intrinsic mechanisms, i.e. regulatory genes that specify positional or area identities of cortical neurons, and extrinsic influences, e.g.area-specific TCA input, or information relayed by it. Recent studies have begun to define genetic mechanisms intrinsic to the developing neocortex that regulate arealization. Relatively little, though, is known about mechanisms that pattern dTh into nuclei, and the degree to which dTh patterning, presented through TCA input, influences arealization.
Our aims fall into two related sets: the first set addresses genetic mechanisms that specify nuclei-specific properties of dTh neurons and pattern the dTh into the principal sensory nuclei; the second set addresses the influence of dTh patterning and TCA input on the patterning of the neocortex into primary sensory areas. To accomplish our aims, we will first examine roles for regulatory genes in specifying nuclei- specific identities of dTh neurons and the differentiation of dTh nuclei, by conditional gain- and loss-of- function analyses using selective gene activation / inactivation in mice designed to survive to adulthood. We will then select mice in which dTh nuclei and their TCA input are disproportionately expanded and reduced by these genetic manipulations selective for dTh, and analyze the effects of changes in TCA input on key features of cortical area patterning, including area-specific input and output projections and gene expression. We will complement these studies by analyzing mice in which TCA input is deleted or substantially diminished using different genetic strategies. As an alternative to change relative sizes of dTh nuclei and TCA input, we will selectively expand progenitors that generate different subsets of dTh nuclei by expressing in them a modified beta-catenin. These studies will define the mechanisms and plasticity of neuronal specification and forebrain patterning, as well as help to provide insights into genetic and environmental causes of neurological disorders, particularly those of a developmental and cognitive nature such as autism.
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