Dopamine (DA) neurotransmission in the striatum is implicated in a broad range of behaviors and disorders. Understanding presynaptic mechanisms that regulate DA transmission and their consequences on corticostriatal transmission is important for understanding the synaptic basis of drug abuse and addiction, and habit and motor learning. This application is a competing continuation intended to elucidate presynaptic mechanisms underlying plasticity of DAergic neurotransmission and its effects on synaptic computation in the striatum. Efforts to date by our laboratory and others on characterizing striatal DA transmission have monitored combined release from hundreds to thousands of synapses. Here we describe a novel optical approach that will extend previous investigations by introducing """"""""false fluorescent neurotransmitters"""""""" that provide the first means to directly visualize neurotransmitter release, doing so by monitoring the presynaptic activity of individual striatal DA terminals, allowing subpopulations to be identified. We outline direct means to answer long-asked questions on synaptic modulation of DA release, a highly controversial area, and how psychostimulant drugs interfere with these processes. These properties must be characterized to understand how DA regulates habit learning and its role in addiction.
The aims and underlying hypotheses of this application are: 1) Identify regional and activity-dependent mechanisms in DA presynaptic regulation. Hypothesis: DA terminals experience ongoing feedback regulation by presynaptic receptors, including D2 DA autoreceptors and nACh and mGlu heteroreceptors that act as high-pass filters to provide focal DA input. 2) Determine how individual presynaptic DA terminals regulate the kinetics of vesicle fusion to modulate terminal state. Hypothesis: """"""""Flickering"""""""" fusion associated with ongoing tonic activity converts to """"""""full"""""""" fusion during burst firing to provide focal DA input. 3) Define how focal DA input selects particular corticostriatal terminals. Hypothesis: Enhanced signal/background of DA input regulated by the mechanisms above selects nearby sets of corticostriatal inputs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA007418-18S1
Application #
8418518
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Pilotte, Nancy S
Project Start
1991-07-01
Project End
2013-06-30
Budget Start
2012-02-15
Budget End
2013-06-30
Support Year
18
Fiscal Year
2012
Total Cost
$18,666
Indirect Cost
$7,000
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Freyberg, Zachary; Sonders, Mark S; Aguilar, Jenny I et al. (2016) Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain. Nat Commun 7:10652
Pereira, Daniela B; Schmitz, Yvonne; Mészáros, József et al. (2016) Fluorescent false neurotransmitter reveals functionally silent dopamine vesicle clusters in the striatum. Nat Neurosci 19:578-86
Sulzer, David; Cragg, Stephanie J; Rice, Margaret E (2016) Striatal dopamine neurotransmission: regulation of release and uptake. Basal Ganglia 6:123-148
Avegno, Elizabeth M; Salling, Michael C; Borgkvist, Anders et al. (2016) Voluntary adolescent drinking enhances excitation by low levels of alcohol in a subset of dopaminergic neurons in the ventral tegmental area. Neuropharmacology 110:386-95
Mrejeru, A; Martí-Prats, L; Avegno, E M et al. (2015) A subset of ventral tegmental area dopamine neurons responds to acute ethanol. Neuroscience 290:649-58
Wong, M Y; Borgkvist, A; Choi, S J et al. (2015) Dopamine-dependent corticostriatal synaptic filtering regulates sensorimotor behavior. Neuroscience 290:594-607
Borgkvist, Anders; Avegno, Elizabeth M; Wong, Minerva Y et al. (2015) Loss of Striatonigral GABAergic Presynaptic Inhibition Enables Motor Sensitization in Parkinsonian Mice. Neuron 87:976-88
Mosharov, Eugene V; Borgkvist, Anders; Sulzer, David (2015) Presynaptic effects of levodopa and their possible role in dyskinesia. Mov Disord 30:45-53
Steinbeck, Julius A; Choi, Se Joon; Mrejeru, Ana et al. (2015) Optogenetics enables functional analysis of human embryonic stem cell-derived grafts in a Parkinson's disease model. Nat Biotechnol 33:204-9
Zucca, Fabio A; Segura-Aguilar, Juan; Ferrari, Emanuele et al. (2015) Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease. Prog Neurobiol :

Showing the most recent 10 out of 32 publications