The olfactory bulb, as well as the olfactory sensory epithelium, retain the ability to generate new neurons throughout life. The major sources of neurons destined to populate the olfactory bulb, as with other telencephalic structures, are the ventricular and subventricular zones surrounding the lateral ventricles. We have previously identified a region of the anterior part of the subventricular zone, the SVZa, that consists of purely neuronal progenitor cells whose progeny migrate to the olfactory bulb where they differentiate into GABAergic and dopaminergic interneurons. In the proposed studies we will examine the spatial- temporal features that establish the SVZa as a unique germinal zone, and identify signals that control the proliferation and differentiation of its cells.
In Specific Aim 1 we will perform in situ studies using cell- type specific antibodies and the cell proliferation marker BrdU to examine the anterior-posterior axis of the ventricular-subventricular zone complex as a function of age. The results will determine if changes in the underlying ventricular zone presage the appearance of the SVZa as a distinct region, or whether the SVZa arises de novo from the subventricular zone. To further determine the place and timing of SVZa genesis, complementary in vitro studies will examine the mitotic behavior and phenotype of SVZa cells from different developmental stages and regions of the ventricular-subventricular complex.
In Specific Aim 2 we will determine if epigenetic factors resulting from cell-cell interactions regulate the proliferation and differentiation of SVZa cells. SVZa cells will be cultured either alone or in combination with olfactory bulb and/or olfactory epithelial cells. The proliferation of SVZa cells will be assessed by BrdU-incorporation and their neurotransmitter phenotype determined by immunohistochemical labeling for GABAergic and dopaminergic markers.
In Specific Aim 3 we will determine if previously identified growth factors, which are known to influence the development of other neural populations, also influence SVZa cell development. The proliferative behavior of treated SVZa cells will be measured as above, and their neurotransmitter phenotype determined by immunocytochemical labeling. The factors to be tested include: neurotrophins (NGF, BDNF, NT3, NT4/5), ciliary neurotrophic factor, EGF, basic FGF, heregulin, and glial-derived neurotrophic factor. The results of these studies will identify molecular signals that influence the proliferation and differentiation of olfactory bulb interneurons.
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