Harriet Baker, Ph.D

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The olfactory system is one of the brain regions in which significant neurogenesis occurs even in adults including humans. Among the neurons generated is a population of dopaminergic interneurons that serve to modulate sensory activation in the olfactory bulb. Significantly, these neurons appear to survive in Parkinson’s Disease in the same individuals who have lost their midbrain dopamine neurons. The dopaminergic neurons are a subset of the periglomerular cells that are derived from the subventricular zone and migrate into the olfactory bulb by way of the rostral migratory stream. Little is known about the mechanisms responsible for the derivation and migration of the dopaminergic progenitors. My laboratory uses several model systems to study these mechanisms including in vivo and in vitro analysis of two transgenic mouse lines that express either enhanced Green Fluorescent Protein (GFP) or LacZ reporters using 9kb of rat tyrosine hydroxylase (TH) promoter (the rate limiting enzyme in dopamine synthesis) to direct transgene expression. We also use mice null for expression of the transcription factor ER81 that we have shown is involved in OB TH expression. The spatiotemporal expression of a number of molecules thought to be important in the derivation of dopamine neurons has been characterized in these mice (see publications). During development and in adults, full expression of the dopamine phenotype was shown to be dependent on odor-mediated activity in the olfactory receptor cells that project to the olfactory bulb and make axodendritic synapses with the dopaminergic periglomerular cells. Using a Zeiss confocal microscope procured with a combination of private, NIH and Burke Institute funds, molecular mechanisms underlying migration of the dopaminergic progenitors are being addressed in short and long term slice culture. An olfactory bulb cell line developed at Burke is being used to investigate mechanisms regulating expression of the dopamine phenotype. We are currently characterizing the cells as olfactory dopaminergic progenitors. In addition, primary cultures of neonatal olfactory bulb have been used to demonstrate a role for L-type calcium channels in the induction of tyrosine hydroxylase expression. Currently, slice cultures of neonatal olfactory bulb from the GFP-expressing mice are being used to characterize the role of depolarization and GABA on the generation and differentiation of the dopamine neurons in the olfactory bulb. The long term goal of this research is to assess the molecular mechanisms that specify phenotypic choice during development and by the adult generated neurons. Understanding dopaminergic differentiation is essential if these interneurons are to be considered in autologous transplants for the treatment of Parkinson’s Disease or as a model for inducing the dopamine phenotype in stem cells isolated from other systems.