Timing-dependent modulation of working memory by dopaminergic release in the prefrontal cortex

Working memory (WM) is the brain process for actively maintaining information during a short delay period. Dopamine is known to strongly modulate WM, but its temporal specificity in modulating WM and its related neuronal activity remain elusive. Here we report that dopamine modulates olfactory WM behavior in a bi-directional and timing-dependent manner in head-fixed mice performing a delay-paired association task. In vivo imaging of dopamine levels in the medial prefrontal cortex (mPFC) by a newly developed GPCR-activation-based-dopamine sensor (GRABDA) revealed phasic elevation of mPFC dopamine concentration specifically during the early phase of delay period. Optogenetic excitation of dopaminergic projections from ventral tegmental area (VTA) to mPFC during the early and late phase of delay period improved and impaired WM performance, respectively. Applying similar excitation during other time periods or to nucleus accumbens during the delay period had no effect. Single-unit recordings showed that excitation of dopaminergic terminals during the early delay period increased the behavior-related activity gain of mPFC neurons, whereas excitation during the late delay period induced activity noise irrelevant to WM behavior. Thus, precisely timed dopamine modulation of mPFC neuronal activity is critical for WM. This work underscores the importance of temporal control of neuromodulation in the brain.