Neurogenesis has been demonstrated in several juvenile and adult vertebrates, and the applicant proposes not only that this process is likely to underlie aspects of neural plasticity but that it may well serve as a tool in """"""""brain repair"""""""". The persistent anterior subventricular zone of the rodent, for example, gives rise to a continuous stream of postmitotic cells whose fate can include death, migration and/or further division. The author has been in the forefront of the characterization of this stream, one of whose products is the granule cell population of the olfactory bulb. During the previous granting period the PI has analyzed the rostral migratory pathway to show that the newly formed cells migrate in clusters that he calls chains. Further, these same studies have suggested that the cells migrate within a glial scaffolding that he calls a tube. The current proposal grows out of a prolific set of findings achieved during a five year FIRST award. It uses both mammalian and avian brains as model systems in which to investigate the exact location and identity of the neuronal precursors, how their progeny reach distant targets and how the survival of these cells is regulated. Toward this end, the applicant has outlined an approach composed of eight specific aims: five in mice and three in song birds. The PI proposes to further study chain migration in vitro using explant cultures and brain slices. In the first system, preliminary evidence shows that explants of the subventricular zone, grown in a collagen matrix, produce emigrating cells that seem to leave either in clusters or alone. In an intriguing system, developed by the PI, Neurospheres plated on collagen grow out large fascicles that the PI proposes are the in vitro equivalent of chains. Further, left for longer times, satellite spheres develop all of which seem to interconnect with broad fascicles. The PI proposes to analyze the movement of cells in these cultures as well as in DiI labeled sagittal brain slices with time-lapse video microscopy. Using PSA-NCAM as a marker of chains, the PI stains the walls of the lateral ventricles to reveal a pattern of chains that is not restricted to the rostral migratory stream. Based on the pattern he proposes a series of novel migratory paths for VZ neurons, but presents no evidence to substantiate either that the additional stained structures are actually migratory neurons or that they are populating such structures as the Islands of Calleja. He proposes to study the PSA-NCAM structures first by reconstruction and subsequently by transplantation of transgene- marked cells. The source of the precursors of the migratory neuroblasts will be identified using AraC to kill all dividing precursors followed by BrdU pulses at various times after drug treatment to ask where the newly dividing cells arise. The existence of chain migration in the subventricular zone of the lateral ventricle will be inferred based on reconstructions. The applicant proposes to determine the inter-cellular relationships in this region, particularly those among neurons, ependymal cells and glia. Preliminary evidence (n=1) from animals infused with neurotrophins into the olfactory bulb (methods unspecified) indicate that BDNF increases the percentage of olfactory granule cells that retain 3H-thymidine pulse label. The applicant proposes to extend these studies as a means to investigate why so many of the newly generated neurons die rather than become incorporated into the olfactory circuitry. The study of the songbird HVC nucleus is a more mature experimental system and the applicant proposes to follow up on earlier observations in several ways. First, the """"""""hotspots"""""""" in the ventral and dorsal ventricular zone have been shown to contain cells with a radial morphology. Using DiI and locally injected 3H-thymidine double labeling, the applicant hopes to prove that the radial cells are dividing and, possibly to follow their fate in vivo. The ventral and dorsal """"""""hotspots"""""""" of the ventricle give rise to different populations of neurons in adult birds. Homotopic and heterotopic transplantations will be used to determine if the different ventricular zones are predetermined to produce a specific type of neuron. Ultrastructural observations of neuronal precursors at additional times after 3H-thymidine injection will be used to determine the ventricular site of origin of newly formed HVC neurons. Finally, a list of alternative experiments are proposed to indicate the richness of the model system and to serve as a backup if any of the proposed do not work out.
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