The Role of Prefrontal Dopamine D1 Receptors in the Neural Mechanisms of Associative Learning

Dopamine is thought to play a major role in learning. However, while dopamine D1 receptors (D1Rs) in the prefrontal cortex (PFC) have been shown to modulate working memory-related neural activity, their role in the cellular basis of learning is unknown. We recorded activity from multiple electrodes while injecting the D1R antagonist SCH23390 in the lateral PFC as monkeys learned visuomotor associations. Blocking D1Rs impaired learning of novel associations and decreased cognitive flexibility but spared performance of already familiar associations. This suggests a greater role for prefrontal D1Rs in learning new, rather than performing familiar, associations. There was a corresponding greater decrease in neural selectivity and increase in alpha and beta oscillations in local field potentials for novel than for familiar associations. Our results suggest that weak stimulation of D1Rs observed in aging and psychiatric disorders may impair learning and PFC function by reducing neural selectivity and exacerbating neural oscillations associated with inattention and cognitive deficits. ► Prefrontal D1 receptors are probably involved in learning but not memory ► Prefrontal D1 receptors sculpt neural selectivity during learning ► Neural selectivity for familiar associations is less dependent on D1 receptors ► Alpha/beta oscillations are exacerbated during low prefrontal D1 receptor stimulation Dopamine D1 receptors are thought to be involved in working memory, though their role in the neural basis of learning remains unknown. Here, Puig and Miller show that blocking prefrontal D1 receptors impairs associative learning, but not long-term memory, by altering neural selectivity and alpha/beta oscillations.