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-paltidal 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043426-05
Application #
7149981
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Riddle, Robert D
Project Start
2002-12-01
Project End
2007-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
5
Fiscal Year
2007
Total Cost
$340,762
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Crandall, James E; Goodman, Timothy; McCarthy, Deirdre M et al. (2011) Retinoic acid influences neuronal migration from the ganglionic eminence to the cerebral cortex. J Neurochem 119:723-35
Balcioglu, Aygul; Ren, Jia-Qian; McCarthy, Deirdre et al. (2009) Plasma and brain concentrations of oral therapeutic doses of methylphenidate and their impact on brain monoamine content in mice. Neuropharmacology 57:687-93
Caviness Jr, Verne S; Nowakowski, Richard S; Bhide, Pradeep G (2009) Neocortical neurogenesis: morphogenetic gradients and beyond. Trends Neurosci 32:443-50
Vasudevan, Anju; Long, Jason E; Crandall, James E et al. (2008) Compartment-specific transcription factors orchestrate angiogenesis gradients in the embryonic brain. Nat Neurosci 11:429-39
Caviness, V S; Bhide, P G; Nowakowski, R S (2008) Histogenetic processes leading to the laminated neocortex: migration is only a part of the story. Dev Neurosci 30:82-95
Metin, Christine; Vallee, Richard B; Rakic, Pasko et al. (2008) Modes and mishaps of neuronal migration in the mammalian brain. J Neurosci 28:11746-52
Whalen, Michael J; Dalkara, Turgay; You, Zerong et al. (2008) Acute plasmalemma permeability and protracted clearance of injured cells after controlled cortical impact in mice. J Cereb Blood Flow Metab 28:490-505
Suter, Bernhard; Nowakowski, Richard S; Bhide, Pradeep G et al. (2007) Navigating neocortical neurogenesis and neuronal specification: a positional information system encoded by neurogenetic gradients. J Neurosci 27:10777-84
McCarthy, Deirdre; Lueras, Paula; Bhide, Pradeep G (2007) Elevated dopamine levels during gestation produce region-specific decreases in neurogenesis and subtle deficits in neuronal numbers. Brain Res 1182:11-25
Araki, Kiyomi Y; Sims, John R; Bhide, Pradeep G (2007) Dopamine receptor mRNA and protein expression in the mouse corpus striatum and cerebral cortex during pre- and postnatal development. Brain Res 1156:31-45

Showing the most recent 10 out of 15 publications