Cell-type-specific Modulation by Dopamine in Learning

 

Nature 590 , 451–456  18 February 2021

Cell-type-specific asynchronous modulation of PKA by dopamine in learning

Suk Joon Lee, et.al.

Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA

Department of Neuroscience, Washington University School of Medicine, St Louis, MO, USA

Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA

Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland

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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.    Dopamine is thought to guide learning via dynamic and differential modulation of protein kinase A (PKA) in each class of spiny projection neuron. 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.

Across phylogeny, dopamine (DA) release in the brain induces cellular plasticity that promotes behavioural adaptation. In mammals, DA action in the nucleus accumbens (NAc)—a striatal region that is heavily innervated by DA-releasing neurons (DANs) of the ventral tegmental area (VTA)—mediates the association of motor actions with action outcomes, as necessary for individuals to learn to repeat behaviours that lead to good outcomes. Previous manipulations of VTA DANs and DA levels in the NAc have established the sufficiency of DA release in the NAc for action reinforcement. Furthermore, the activity of VTA DANs and DA levels in the NAc encode reward prediction error (the difference between the actual and expected values of the outcome of an action)

The anatomical and molecular organization of spiny projection neurons (SPNs), the principal cells of the NAc, suggest an antagonistic model of DA action on SPNs. SPNs of the NAc (analogous to the direct- and indirect-pathway SPNs of the dorsal striatum) consist of striatomesencephalic SPNs (which innervate midbrain regions) and striatopallidal SPNs (which innervate the ventral pallidum). This anatomic division correlates with molecular differences: striatomesencephalic SPNs express G_αs-coupled type-1 DA receptors (D1Rs) through which DA enhances cAMP production and PKA activity, whereas striatopallidal SPNs express G_αi/o-coupled type-2 DA receptors (D2Rs), which inhibit cAMP production and suppress PKA. Models of reinforcement learning incorporate these differences and link DA transients that encode reward prediction error to the PKA-dependent modulation of excitability, synaptic plasticity and transcription in SPNs.

Here we investigate the relationship between DA and net PKA activity in SPNs (that is, the balance between PKA and phosphatase activities) in freely behaving mice undergoing reward-based learning, using multichannel fibre photometry and fluorescence lifetime photometry (FLiP). Our results support a model of learning, dependent on DA and basal ganglia, in which PKA in SPNs that express D1R and D2R (hereafter, D1R-SPNs and D2R-SPNs, respectively) is asynchronously engaged to mediate the action of positive and negative DA signals during learning.

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