Dopamine (DA) is an important neurotransmitter/ neuromodulator throughout the animal kingdom. In humans, dysfunction of the DA system leads to motor, cognitive, and affective disorders. Detailed studies feasible in the genetic model system Drosophila melanogaster permit circuit level definition of pathways responsible for specific behaviors, allow for detailed temporal/spatial control of DA synthesis, and have the potential to uncover novel neural mechanisms relevant to human diseases of DA dysfunction. In this proposal, we study a novel and spontaneous suppression of a subset of dopamine-loss phenotypes. We will use genetic and molecular techniques to identify and characterize the genetic elements responsible for this suppression. Our model is particularly relevant to early stage Parkinson's disease, where a poorly described pathway can partially compensate for decreased DA levels, delaying appearance of symptoms. This proposal focuses on the mechanisms of this compensation.

Public Health Relevance

Dopamine (DA) is an important neurotransmitter/neuromodulator throughout the animal kingdom, and in humans, dysfunction of the DA system leads to motor, cognitive, and affective disorders. Detailed studies feasible in the genetic model system Drosophila melanogaster permit circuit level definition of pathways responsible for specific behaviors, allow for detailed temporal/spatial control of DA synthesis, and have the potential to uncover novel neural mechanisms relevant to human diseases of DA dysfunction. Our studies are particularly relevant to early stage Parkinson's disease, where a poorly described pathway can partially compensate for decreased DA levels.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084128-06
Application #
9115674
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Sesma, Michael A
Project Start
2009-09-01
Project End
2019-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Virginia
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Cichewicz, Karol; Hirsh, Jay (2018) ShinyR-DAM: a program analyzing Drosophila activity, sleep and circadian rhythms. Commun Biol 1:
Mead, Brian P; Kim, Namho; Miller, G Wilson et al. (2017) Novel Focused Ultrasound Gene Therapy Approach Noninvasively Restores Dopaminergic Neuron Function in a Rat Parkinson's Disease Model. Nano Lett 17:3533-3542
Cichewicz, K; Garren, E J; Adiele, C et al. (2017) A new brain dopamine-deficient Drosophila and its pharmacological and genetic rescue. Genes Brain Behav 16:394-403
Niens, Janna; Reh, Fabienne; Çoban, Bü?ra et al. (2017) Dopamine Modulates Serotonin Innervation in the Drosophila Brain. Front Syst Neurosci 11:76
Nall, Aleksandra H; Shakhmantsir, Iryna; Cichewicz, Karol et al. (2016) Caffeine promotes wakefulness via dopamine signaling in Drosophila. Sci Rep 6:20938
Vinayak, Pooja; Coupar, Jamie; Hughes, S Emile et al. (2013) Exquisite light sensitivity of Drosophila melanogaster cryptochrome. PLoS Genet 9:e1003615
Kaun, Karla R; Azanchi, Reza; Maung, Zaw et al. (2011) A Drosophila model for alcohol reward. Nat Neurosci 14:612-9
Lee, Pei-Tseng; Lin, Hsuan-Wen; Chang, Yu-Hsuan et al. (2011) Serotonin-mushroom body circuit modulating the formation of anesthesia-resistant memory in Drosophila. Proc Natl Acad Sci U S A 108:13794-9
Riemensperger, Thomas; Isabel, Guillaume; Coulom, Hélène et al. (2011) Behavioral consequences of dopamine deficiency in the Drosophila central nervous system. Proc Natl Acad Sci U S A 108:834-9
Hirsh, Jay; Riemensperger, Thomas; Coulom, Helene et al. (2010) Roles of dopamine in circadian rhythmicity and extreme light sensitivity of circadian entrainment. Curr Biol 20:209-14