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

Suk Joon Lee, Bart Lodder, Yao Chen, Tommaso Patriarchi, Lin Tian and Bernardo L. Sabatini ()
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Suk Joon Lee: Harvard Medical School
Bart Lodder: Harvard Medical School
Yao Chen: Harvard Medical School
Tommaso Patriarchi: University of California
Lin Tian: University of California
Bernardo L. Sabatini: Harvard Medical School

Nature, 2021, vol. 590, issue 7846, 451-456

Abstract: Abstract 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 release1. Dopamine is thought to guide learning via dynamic and differential modulation of protein kinase A (PKA) in each class of spiny projection neuron2. 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.

Date: 2021
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DOI: 10.1038/s41586-020-03050-5

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