(A) Schematic diagram depicting core components of the proposed cellular mechanisms underlying the DA-induced conversion of t-LTD into t-LTP (de-depression and potentiation). (Ai) Model based on postsynaptic NMDAR-dependent potentiation (Bi and Poo, 1998; Caporale and Dan, 2008; Zhang et al., 2009; Edelmann and Lessmann, 2011; Yang and Dani, 2014) and metabotropic glutamate receptor-dependent (mGluRs) depression (Otani and Connor, 1998; Kemp and Bashir, 1999; Huber et al., 2000). De-depression (red, left): Activation of G protein-coupled D1/D5 receptors stimulates AC, increasing cAMP and activating PKA (Greengard et al., 1999; Neve et al., 2004), which, via phosphorylation of I-1 (Ingebritsen and Cohen, 1983), reverses the PP1-induced dephosphorylation of synaptic AMPARs (Lee et al., 2000; Mockett et al., 2007). Potentiation (red, right): PKA activation enhances NMDAR function (Westphal et al., 1999; Chen and Roche, 2007). (Aii) Model based on presynaptic depression (Bolshakov and Siegelbaum, 1994; Siegel et al., 1994; Oliet et al., 1997; Charton et al., 1999; Watabe et al., 2002; Jourdain et al., 2007). De-depression (red, left): Activation of presynaptic DA receptors stimulates AC, increasing cAMP and activating PKA (Greengard et al., 1999; Neve et al., 2004), which reverses the calcineurin-dependent presynaptic depression. Potentiation (red, right): as in Ai. Arrow indicates activation/phosphorylation, blunt-ended line indicates inhibition/dephosphorylation. Abbreviations: AMPAR, AMPA-type glutamate receptor; NMDAR, NMDA-type glutamate receptor; mGluR1/5, group I metabotropic glutamate receptor; DAR, dopamine receptor; AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; I-1, inhibitor 1; PP1, protein phosphatase 1; PLC, phospholipase C; IP3, inositol 1,4,5-trisphosphate; ER, endoplasmic reticulum; DAG, diacylglycerol; eCB, endocannabinoid; CB1R, cannabinoid receptor type 1; CN, calcineurin; CaMKII, calcium-calmodulin-dependent protein kinase II. (B) Schematic diagram of synaptic and behavioral timescales in reward learning. During Exploration, the activity-dependent modification of synaptic strength due to spike timing-dependent plasticity (STDP) depends on the coordinated spiking between presynaptic and postsynaptic neurons on a millisecond time scale. Post-before-pre pairing leads to synaptic depression that develops gradually on a scale of minutes. When Reward, signaled via dopamine, follows Exploration with a Delay of seconds to minutes, synaptic depression is converted into potentiation.