The importance of ventral midbrain dopamine (DA) synaptic activity is clear from its roles in motor and behavioral disorders, including drug dependence. These synapses contribute to the normal execution of motor sequences, learning, and habit formation by mediating short- and long-term plasticity in the basal ganglia. DA neuronal activity has been difficult to characterize by conventional technologies since the axons are extremely long and complex and do not make conventional ionotropic synapses that can be recorded by electrophysiology. We have thus developed new optical techniques, including fluorescent false neurotransmitters (FFNs) that provide the first means to examine neurotransmission at the level of individual synapses: the first two publications were part of the current grant cycle, and the requested continuation will introduce second generation FFNs that have important advantages over the first. In this work, we will first determine the signal by which DA axons grow and make synapses at the correct positions in the striatum: this appears to be triggered by glutamate inputs, apparently either from cortical inputs or from DA neurons themselves. These experiments will use one of the new FFNs, the first to work in neuronal cultures. Then we will identify the signals that make these DA synapses active: our Preliminary Results indicate that most DA terminals are """"""""silent"""""""" and do not normally release neurotransmitter, but that this is modulated by a newly identified form of synaptic plasticity. Thi will use another new FFN that is well adapted for measuring DA transmission simultaneously with the synaptic vesicle fusion probe FM1-43. Finally, we will examine how DA and its loss in a unilateral Parkinson's disease model leads to selection of the correct corticostriatal synapses that underlie simple motor behaviors in the mouse, i.e., paw use to explore a novel environment, and a feeding behavior. To our knowledge, this will be the first time that particular synapses within a neuronal projection would be identified to underlie a behavior in the vertebrate CNS.
This work is to determine how dopamine neurons grow to form the appropriate synaptic connections in the brain, how those synapses become active and inactive, and how they work to select the right synaptic connections to control voluntary motor behavior using a Parkinson's disease model. The importance of dopamine (DA) synaptic activity is clear from its roles in motor, learning and behavioral disorders, including drug addiction. DA neuronal activity has been difficult to characterize by conventional technologies and in this work we have thus developed new optical techniques, including fluorescent false neurotransmitters (FFNs) that provide the first means to examine neurotransmission at the level of individual synapses.
|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|
Showing the most recent 10 out of 38 publications