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Cell-type-specific asynchronous modulation of PKA by dopamine in learning
Open accessAbstract
Reinforcement learning models postulate that neurons that release dopamine encode information about action and action outcome, and provide a teaching signal to striatal spiny projection neurons in the form of dopamine release 1. Dopamine is thought to guide learning via dynamic and differential modulation of protein kinase A (PKA) in each class of spiny projection neuron 2. However, the real-time relationship between dopamine and PKA in spiny projection neurons remains untested in behaving animals. Here we monitor the activity of dopamine-releasing neurons, extracellular levels of dopamine and net PKA activity in spiny projection neurons in the nucleus accumbens of mice during learning. We find positive and negative modulation of dopamine that evolves across training and is both necessary and sufficient to explain concurrent fluctuations in the PKA activity of spiny projection neurons. Modulations of PKA in spiny projection neurons that express type-1 and type-2 dopamine receptors are dichotomous, such that these neurons are selectively sensitive to increases and decreases, respectively, in dopamine that occur at different phases of learning. Thus, PKA-dependent pathways in each class of spiny projection neuron are asynchronously engaged by positive or negative dopamine signals during learning.
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“Real-time monitoring of the kinase activity in behaving animals indicates that DA release, via regulation of intracellular cAMP production, controls the activity of protein kinase A (PKA) in SPNs over the timescale of tens of seconds, with differential effects on neurons that express type 1 or type 2 dopamine receptors.122”
From Synaptic and circuit functions of multitransmitter neurons in the mammalian brain (2023) · cites this paper as [122]
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“the dopamine, GABA, and glutamate released by DANs may elicit prolonged waves of postsynaptic effects, cascading from the millisecond changes in excitability triggered by ionotropic receptors, to the tens of seconds on biochemical signaling and excitability 109,115,122,123 (Figure 3A).”
From Synaptic and circuit functions of multitransmitter neurons in the mammalian brain (2023) · cites this paper as [122]
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Metadata
- Authors
- Lee, S. J., Lodder, B., Chen, Y., Patriarchi, T., Tian, L., & Sabatini, B. L.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Zurich (CH)
- University of California, Davis (US)
- Corresponding author
- Sabatini, Bernardo L.
- Venue
- Nature
- Published
- 2020-12-23
- Volume
- 590
- Issue
- 7846
- Pages
- 451-456
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7889726
- OpenAlex
- W3116416936
- Cited by
- 160
- References
- 45
- Citations by year
- 2026: 14 · 2025: 35 · 2024: 25 · 2023: 30 · 2022: 33 · 2021: 18 · 2020: 4
- FWCI
- 9.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (U01NS013522, R35NS105107)
- National Institute on Drug Abuse (F32DA035543)
- National Institute of Neurological Disorders and Stroke (P30NS072030, U01NS090604, R37NS046579, U19NS113201)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- dopamine, protein kinase A, medium spiny neurons, nucleus accumbens, reinforcement learning, dopamine receptors, dopamine release, learning, striatum
- MeSH terms
- Animals, Dopamine, Female, Fluorescence, Learning, Male, Neuronal Plasticity, Nucleus Accumbens, Photometry, Receptors, Dopamine, Cyclic AMP-Dependent Protein Kinases, Mice, Dopaminergic Neurons, GABAergic Neurons
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