The human brain has a limited ability for repair, and thus, diseases or injuries to the nervous system are usually irreversible. The addition of new neurons into the olfactory bulb and hippocampus of the adult mammalian brain suggests that cell replacement may be a promising strategy for brain repair. However, developing successful strategies for cell-replacement based brain repair requires an understanding of how newly generated neurons integrate into pre-existing, functioning neural circuits in the adult brain. Previous observations suggest that the incorporation of new neurons into the olfactory bulb of newborn animals is more efficient than in adult animals. The goal of this proposal is to understand the mechanisms that may regulate the increased ability of new neurons generated in the newborn brain to integrate into the olfactory bulb, compared to adult-born neurons, with the long-term objective of applying this understanding towards improving strategies for brain repair. An important clue comes from our recent discovery that new neurons added to the olfactory bulb in newborn rodents integrate into the bulb circuit with a pattern of connectivity distinct from that of the adult animal. This difference offers an ideal experimental opportunity with which to uncover the mechanisms that regulate how new neurons integrate into functioning brain circuits. In this proposal we will concentrate our efforts on three aims. First, we will investigate the differences in the connectivity of interneurons generated in the adult versus the newborn olfactory bulb by labeling neuronal progenitors with retroviruses to analyze their morphology, and will use a genetic marker to reveal their synaptic input. Second, we will assay the contribution of cell-autonomous or target-dependent mechanisms in the establishment of the different patterns of connectivity of new neurons born in postnatal olfactory bulb by analyzing the morphology of granule neurons derived from neuronal progenitors after transplantation into isochronic or heterochronic hosts. Third, we will characterize how genetic manipulations of activity affect the integration of new neurons born in the bulb of newborns or adults by delivering into neural progenitors three different constructs to alter the intrinsic excitability and the synaptic properties of newly generated bulb neurons. This proposal will investigate how different classes of neurons survive and connect to other neurons in the brain of adult and newborn animals. The insights gained from the experiments that we describe will guide future efforts towards harnessing replacement of neurons as a strategy for brain repair in humans.
