Abstract:

Extracellular dopamine (DA) dynamics are tightly regulated by a balance between exocytotic release and reuptake via the dopamine transporter (DAT). Disruption of this balance contributes to several diseases including parkinsonism, schizophrenia, ADHD and substance use disorder.

Using the genetically encoded DA sensor dLight1.3b together with multiregion fiber photometry and machine learning in mice, we recently revealed strikingly different DA release dynamics across striatal subregions that shape behavioral organization during self-paced exploration. In subsequent studies, we mapped DA dynamics in the dorsolateral, dorsomedial, and ventral striatum during the rodent continuous performance task (rCPT), a reward-based attentional paradigm. The experiments uncovered distinct release signatures across striatal territories during both learning and in trained animals.

Manipulations of stimulus, action, and reward provided further insight into the unique roles of each subregion.

Computational modeling of striatal DA dynamics identified determinants of the observed regional differences and suggested that they arise primarily from variation in DAT activity rather than release mechanisms. Notably, the application of super-resolution microscopy including single molecule localization microscopy and structured illumination microscopy conceived, together with our simulations, DAT nanoclustering in dopaminergic release sites as a modulator of this activity.

Moreover, the imaging data revealed subregion-specific differences in release site geometry, density, and organization that may represent previously unrecognized contributors to DA function. Our findings advance the understanding of how dopamine operates across distinct anatomical domains and time scales to shape behavior.