The role of dopamine in addiction is a well-studied and complex science, and yet not understood, especially at the level of epigenetics. The impact of drug, alcohol, and nicotine addiction in the United States is devastating in both on human health and costs. Thus, it is an important goal to understand the mechanisms and pathways that relate to dopaminergic neuron biology. The RNAi interference (RNAi) pathway has excited biologists and clinicians, since it provides a means to silence nearly any gene, include pathogenic gene expression. This is because the active intermediates, the small interfering RNAs (siRNAs) have great promise as therapeutics, and there is interesting biology in the brain that relates to microRNAs. To explore these areas further, we have created a conditional mouse knockout for Dicer in Dopamine-receptor-1 expressing neurons. In this application, we plan to interrogate the molecular phenotypes of these mice at the behavioral and molecular level. Our findings should improve our understanding of the epigenetic mechanisms of small RNA function in the mammalian brain, particularly to dopamine-centric pathways. Lay language relevance to public heath: The introduction of double-stranded RNA into an organism causes specific interference of gene expression termed RNA interference (RNAi). Unfortunately much remains to be understood regarding the RNAi pathway in cells, particularly how it functions in the human brain. These studies describe our efforts to dissect small RNA function in mouse models and should shed insight into the biology of small RNA function in diseases such as alcoholism and substance abuse. ? ? ?
| Dugas, Jason C; Cuellar, Trinna L; Scholze, Anja et al. (2010) Dicer1 and miR-219 Are required for normal oligodendrocyte differentiation and myelination. Neuron 65:597-611 |
| Cuellar, Trinna L; Davis, Tigwa H; Nelson, Peter T et al. (2008) Dicer loss in striatal neurons produces behavioral and neuroanatomical phenotypes in the absence of neurodegeneration. Proc Natl Acad Sci U S A 105:5614-9 |
| Davis, Tigwa H; Cuellar, Trinna L; Koch, Selina M et al. (2008) Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus. J Neurosci 28:4322-30 |
| Damiani, Devid; Alexander, John J; O'Rourke, Jason R et al. (2008) Dicer inactivation leads to progressive functional and structural degeneration of the mouse retina. J Neurosci 28:4878-87 |
