The studies proposed in this application are designed to test the hypothesis that dopamine influences neurogenesis and the development of cellular architecture of the CNS. Dopamine is a neuromodulator whose actions in the regulation of complex behaviors such as mood, motivation and attention are well known. Recent reports indicate that dopamine receptor activation influences neuronal and glial cell differentiation. Fetal exposure to cocaine, a drug that targets dopaminergic systems of the brain, alters neurogenesis and causes permanent deficits in brain structure and function. Schizophrenia and autism spectrum disorder, diseases considered to have developmental origins, also are associated with dopamine imbalance. Thus, imbalances in the dopaminergic system of the developing brain are gaining recognition as potential causes of altered CNS structure and function. The proposed studies are designed to examine the effects of dopamine on cell cycle, the molecular engine that drives neurogenesis. The focus will be on the ganglionic eminence and the neocortical neuroepithelium, two embryonic precursor populations that receive rich dopaminergic inputs and that account for the majority of forebrain cells. The ganglionic eminence is the precursor of the striato-pallidal system and also a source of GABAergic neurons of multiple forebrain regions. Understanding dopamine's role in neurogenesis in the ganglionic eminence acquires added significance as forebrain-wide dopaminergic and/or GABAergic dysfunction occurs in schizophrenia and some forms of epilepsy. The proposed studies will examine the effects of dopamine receptor activation on cell cycle kinetics of neuroepithelial progenitor cells and on the molecular machinery that regulates neurogenesis. A transgenic mouse model will be used in which dopamine receptor transgenes will be induced selectively in neuroepithelial progenitor cells and electively at specified developmental periods, using a tetracycline regulatable gene expression system. The effects of dopamine receptor activation will be examined in this model on cell cycle regulatory molecules, cell cycle kinetics, cell death and cell output during the embryonic period and the cellular architecture of the brain at maturity. The inducible expression of dopamine receptor transgenes in specific cell types offers unprecedented advantages to experimentally model and analyze the pathophysiology of drug abuse, attention/activity disorders and schizophrenia, all of which are associated with imbalances in the dopaminergic system of the developing brain. It is also an excellent model to mimic dopamine imbalance in the CNS that can be produced by therapeutic drugs that intentionally or unintentionally target the dopaminergic system of the developing brain.
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