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
Aguilar, Jenny I; Dunn, Matthew; Mingote, Susana et al. (2017) Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT. Neuron 95:1074-1088.e7
Covey, Dan P; Mateo, Yolanda; Sulzer, David et al. (2017) Endocannabinoid modulation of dopamine neurotransmission. Neuropharmacology 124:52-61
Borgkvist, Anders; Lieberman, Ori J; Sulzer, David (2017) Synaptic plasticity may underlie l-DOPA induced dyskinesia. Curr Opin Neurobiol 48:71-78
Sulzer, David; Cragg, Stephanie J; Rice, Margaret E (2016) Striatal dopamine neurotransmission: regulation of release and uptake. Basal Ganglia 6:123-148
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
Kempadoo, Kimberly A; Mosharov, Eugene V; Choi, Se Joon et al. (2016) Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory. Proc Natl Acad Sci U S A 113:14835-14840
Kharkwal, Geetika; Brami-Cherrier, Karen; Lizardi-Ortiz, José E et al. (2016) Parkinsonism Driven by Antipsychotics Originates from Dopaminergic Control of Striatal Cholinergic Interneurons. Neuron 91:67-78
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 110:386-395
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
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

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