Activation of Direct and Indirect Pathway Medium Spiny Neurons Drives Distinct Brain-wide Responses

A central theory of basal ganglia function is that striatal neurons expressing the D1 and D2 dopamine receptors exert opposing brain-wide influences. However, the causal influence of each population has never been measured at the whole-brain scale. Here, we selectively stimulated D1 or D2 receptor-expressing neurons while visualizing whole-brain activity with fMRI. Excitation of either inhibitory population evoked robust positive BOLD signals within striatum, while downstream regions exhibited significantly different and generally opposing responses consistent with—though not easily predicted from—contemporary models of basal ganglia function. Importantly, positive and negative signals within the striatum, thalamus, GPi, and STN were all associated with increases and decreases in single-unit activity, respectively. These findings provide direct evidence for the opposing influence of D1 and D2 receptor-expressing striatal neurons on brain-wide circuitry and extend the interpretability of fMRI studies by defining cell-type-specific contributions to the BOLD signal.