Background and Training
PhD: University of New Hampshire, Durham
Postdoctoral training: Yale University
The focus of my research is to understand how the neurotransmitter dopamine modulates the activities of neurons. Dopamine signaling is involved in learning and memory and abnormal dopamine signaling has been implicated in a variety of mental disorders including schizophrenia, drug addiction, and Parkinson’s disease. Despite the importance of understanding how dopamine affects brain function, we do not have a clear understanding of the signaling mechanisms through which dopamine acts. This lack of understanding is in large part due to the inability to identify the molecular components involved in dopamine signaling. Biochemical approaches to identify such components are hampered by the cellular heterogeneity of the brain, by the difficulty in preparing large, pure populations of primary neurons and by the lack of cell lines that can be cultured and that accurately reflect the cellular environment present in neurons.
Like mammals, the nematode C. elegans uses dopamine to modulate the activities of neurons. We use genetic screens in C. elegans to isolate mutants defective in dopamine signaling and these mutants identify the molecular components through which dopamine acts. We have recently identified several genes that encode novel dopamine signaling components. We plan to characterize these new signaling components using a combination of genetic, behavioral, imaging, and biochemical approaches. We then plan to test whether these components are conserved and serving similar roles in the brain.
Several features of C. elegans, including the fact that animals are transparent and can stably express trangenes, help us to understand how and where dopamine acts. Shown is a fluorescent image of an animal carrying integrated transgenes that express a green fluorescent protein (GFP) from the D1-like dopamine receptor (dop-1) promoter and a red fluorescent protein (RFP) from the D2-like dopamine receptor (dop-3) promoter. dop-1::GFP is expressed in the support cells of the head (bracket 1) and both dop-1::GFP and dop-3::RFP are expressed in neurons of the head (bracket 2), tail(bracket 3), and ventral cord (bracket 4).
Maher KN, Catanese M, and Chase D. Large-scale gene knockdown in C. elegans using dsRNA feeding libraries to generate robust loss-of-function phenotypes. In Press at Journal of Visualized Experiments (2013).
Maher KN, Swaminithan A, Patel P, and Chase D. A novel strategy for cell-autonomous gene knockdown in C. elegans defines a cell-specific function for the G-protein subunit GOA-1.Genetics 194: 363-373 (2013). [PubMed]
Wani KA, Catanese M, Normantowicz R, Herd M, Maher KN, Chase DL. PLoS One. 2012. 7:e37831. D1 Dopamine Receptor Signaling Is Modulated by the R7 RGS Protein EAT-16 and the R7 Binding Protein RSBP-1 in Caenoerhabditis elegans Motor Neurons. [PubMed]
Allen AT, Maher KN, Wani KA, Betts KE, Chase DL. Coexpressed D1- and D2-like dopamine receptors antagonistically modulate acetylcholine release in Caenorhabditis elegans. Genetics. 2011 Jul;188(3):579-90. [PubMed]
Jose AM, Bany IA, Chase DL, Koelle MR. A specific subset of transient receptor potential vanilloid-type channel subunits in Caenorhabditis elegans endocrine cells function as mixed heteromers to promote neurotransmitter release. Genetics. 2007 Jan;175(1):93-105. [PubMed]
Chase DL, Koelle MR. Biogenic amine neurotransmitters in C. elegans. WormBook. 2007 Feb 20:1-15. Review. [PubMed]
Chase DL, Pepper JS, Koelle MR. Nat Neurosci. 2004. 10:1096-103. Mechanism of extrasynaptic dopamine signaling in Caenorhabditis elegans. [PubMed]
Chase DL, Koelle MR. Methods Enzymol. 2004;389:305-20. Review. Genetic analysis of RGS protein function in Caenorhabditis elegans.
Chase DL, Patikoglou GA, Koelle MR. Curr Biol. 2001. 11(4):222-31. Two RGS proteins that inhibit Galpha(o) and Galpha(q) signaling in C. elegans neurons require a Gbeta(5)-like subunit for function. [PubMed]