The dopaminergic (DA) synapse has been studied since the 1950s, when it was implicated in motor function, actions of antipsychotic drugs, and drug abuse. The study of DA synapses has however lagged behind that of other synapses, due to a lack of means to record dopamine release. To address this, chemical techniques have been developed, in particular electrochemical recording techniques and fluorescent false neurotransmitters (FFNs), that provide the first optical measure of neurotransmitter release from individual presynaptic sites. From these techniques, in some ways, we now know more about DA synapses than any other in the CNS. Here, we extend the contemporary understanding of DA synapses to reveal their roles in the interaction of higher organisms with the environment. This is now possible due to technical and conceptual advances, including the use of techniques novel to this proposal, including FFNs and DA-specific voltage sensors. This project tests if a) an interaction between sensory-related and reward-related excitation ?gates? local DA release, and whether this is required for normal learning and behavior; b) DA filters excitation by specific interactions with cannabinoid receptors to mediate decision-making and learning, c) learned behaviors that become established ?refine? synaptic circuits by selectively decreasing local DA activity, and that this enables future learning. The results of these experiments promise to indicate how addictive drugs such as amphetamine and opiates act to disrupt the normal operation of these steps.
Drug abuse, psychosis in schizophrenia, attention deficit disorders, and Parkinson's disease are each caused by or treated by alterations in dopamine synaptic function: these synapses are further involved in normal learning and decision making. The precise steps by which dopamine synapses enable these functions remain unclear, but new technological advances in optical recordings have recently enabled our laboratory and others to identify specific interactions that control decisions and learning. This project will define how an animal's experience modulates dopamine synaptic activity and learning, and will help explain how addiction develops and how dopaminergic drugs treat schizophrenia, attention deficit, and Parkinson's.
|Lieberman, Ori J; McGuirt, Avery F; Tang, Guomei et al. (2018) Roles for neuronal and glial autophagy in synaptic pruning during development. Neurobiol Dis :|
|Borgkvist, Anders; Lieberman, Ori J; Sulzer, David (2018) Synaptic plasticity may underlie l-DOPA induced dyskinesia. Curr Opin Neurobiol 48:71-78|
|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|
|Zucca, Fabio A; Segura-Aguilar, Juan; Ferrari, Emanuele et al. (2017) Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease. Prog Neurobiol 155:96-119|
|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|
|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|
|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|
|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|
Showing the most recent 10 out of 40 publications