Year of Publication

2005

Document Type

Dissertation

College

Medicine

Department

Anatomy and Neurobiology

First Advisor

Don Gash

Abstract

Stem/progenitor cells are present in the adult brain; they undergo constantproliferation and differentiate into mature neurons in certain brain areas, a phenomenoncalled neurogenesis. This study investigated the effects of GDNF, a potent trophic factorof dopaminergic neurons, on neurogenesis in the brain. Nestin and 5-Bromo-2'-deoxyuridine (BrdU) were used as stem/progenitor cells markers.First, we observed extensive bilateral increases of stem/progenitor cells in thedentate gyrus and substantia nigra after continuous infusion of GDNF into the normal ratbrain. However, none of the BrdU+ cells showed neuronal features in the substantia nigraas characterized by immunocytochemical procedures. Next, we identified themorphology of BrdU+ cells after infusing the marker into the brain. While the proceduresincreased the BrdU labeling, neurogenesis was not observed in the basal ganglia. Underelectron microscope, the BrdU+ cells either were undifferentiated or showedcharacteristics of astrocytes. This observation is consistent with suggestions thatastrocytes serve as multipotent progenitors. Later, we repeated GDNF intrastriatalinfusion one month after a severe 6-hydroxydopamine (6-OHDA) lesion. The number ofBrdU+ cells was significantly higher in the GDNF recipients in the ipsilateral substantianigra and both sides of the dentate gyrus. However, no neurogenesis was observed. Inaddition, motor functions were not improved by GDNF treatment. Thus, we measured theeffects of GDNF administration directly into the substantia nigra six hours before apartial 6-OHDA lesion. HPLC measurements of dopamine and its metabolites showed asignificant increase of tissue level in the substantia nigra and striatum, respectively.Despite this, no newly generated dopaminergic neurons was detected in the basal ganglia.Taken together, our studies investigated the effects of GDNF on adultstem/progenitor cells in normal and lesioned rat brain. For the first time, we demonstratedthat GDNF promoted their proliferation in the dentate gyrus, suggesting it has a role inneurogenesis and the function of learning and memory. In each scenario, GDNFpromoted stem/progenitor cell proliferation, but failed to induce neurogenesis in thesubstantia nigra. We believed that the local microenvironment in the substantia nigra mayprevent the stem/progenitor cells to mature into functional neurons.

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