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

Reinforcement learning models postulate that dopamine (DA) releasing neurons (DANs) encode information about action and action outcome and provide a teaching signal to striatal spiny projection neurons (SPNs) in the form of DA release(1). DA is thought to guide learning via dynamic and differential modulation of protein kinase A (PKA) in each class of SPN(2). However, the real-time relationship between DA and SPN PKA remains untested in behaving animals. Here, we monitor the activity of DANs, extracellular DA levels, and net PKA activity in SPNs in the nucleus accumbens in mice during learning. We find positive and negative modulation of DA that evolves across training and is both necessary and sufficient to explain concurrent fluctuations in SPN PKA activity. The modulations of PKA in SPNs that express type-1 and type-2 DA receptors are dichotomous such that they are selectively sensitive to increases and decreases in DA, respectively, which occur at different phases of learning. Thus, PKA-dependent pathways in each class of SPNs are asynchronously engaged by positive or negative DA signals during learning.