Nurr1 is a transcription factor essential for the establishment, development, terminal differentiation and maintenance of mesencephalic dopamine neurons. Nurr1 is thought to coordinate the expression of dopamine neurotransmission genes. Nurr1-null heterozygous (+/-) mice have reduced Nurr1 function, which impacts dopamine neuron function in a region specific manner. Since aging can affect Nurr1 expression, we hypothesize that aging and +/- genotype will have significant effects on dopamine regulation and dopamine related behaviors. To test this hypothesis, regional neurochemistry and behavioral tests of wild type (+/+) and +/- mice at 3 months of age (young) and 12-16 months of age (aged)was performed. We also hypothesize that aging will reduce Nurr1 expression in substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) and also reduce expression of the genes associated with dopamine (DA) neurotransmission that are regulated by Nurr1. To test this we isolated dopamine neurons in SNpc and VTA using laser capture microdissection, and measured the expression of Nurr1 and other associated DA neurotransmission genes using quantitative PCR. Nurr1 protein levels in DA neurons in SNpc and VTA and tyrosine hydroxylase (TH) protein levels in dopamine target regions were measured using quantitative immunohistochemistry. A significant increase in openield activity after stress in young +/- mice was observed. Significant reductions in tissue dopamine levels in the ventral striatum, including the core and shell of the nucleus accumbens were seen. In the SNpc, there was a significant increase in D2 receptor expression and a trend toward reduced TH expression, while in the VTA there was a significant decrease in D2 receptor expression and TH expression due to +/- genotype. The +/- genotype caused a significantly lower Nurr1 protein expression in the VTA which was not observed in the SNpc. Thus, it can be concluded that Nurr1 +/- genotype has a greater impact on the mesoaccumbens system as compared to the nigrostriatal system. The amount of Nurr1 protein expressed due to +/- genotype was not a 50% reduction as expected due to knockout of one gene of Nurr1 suggesting compensatory mechanisms that can maintain Nurr1 protein expression closer to the +/+ level.
| Identifer | oai:union.ndltd.org:MSSTATE/oai:scholarsjunction.msstate.edu:td-2771 |
| Date | 14 December 2013 |
| Creators | Kummari, Evangel |
| Publisher | Scholars Junction |
| Source Sets | Mississippi State University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
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