Dopamine release-associated striatal blood oxygenation and whole-brain dynamics during associative learning

Dopaminergic signaling in the nucleus accumbens (NAc) is central to reward-based learning, but its relationship to brain-wide hemodynamics remains unclear. Using concurrent fMRI and dopamine photometry in awake, behaving mice, we reveal that associative learning induces a gradual temporal shift in NAc blood oxygenation responses that mirrors dopamine release dynamics. This shift emerges with cue-reward learning and extends across a distributed network encompassing the lateral septal complex, as well as prefrontal, insular, and hypothalamic regions. Further, dopamine transients tightly correspond with local blood oxygenation level dependent (BOLD) signals, and variations in reward value modulate delayed BOLD responses in both the NAc and additional subcortical structures. Regressing out the measured dopaminergic signal abolishes this reward-related modulation, suggesting that BOLD signals track dopaminergic reward prediction. These findings reveal a close relationship between dopamine signaling and widespread changes in brain activity during learning.