WHOLE-BRAIN FUNCTIONAL MAPPING OF DOPAMINERGIC PATHWAYS USING PHARMACOLOGICAL MRI

Dopaminergic neurotransmission is essential for normal physiological function and development, and its dysfunction underlies various neurological disorders, including schizophrenia, addiction, and Parkinson’s disease. Here, we have established a novel pharmacological MRI (phMRI) protocol that enables brain-wide mapping of direct (D₁) and indirect (D₂) dopaminergic pathway-associated responses. T2*-BOLD-based phMRI data were acquired from anaesthetised male mice (3-8 months, N=13) on a 9.4T MRI system (Bruker BioSpin, TE/TR=15ms/5000ms, 67min). After the initial baseline acquisition (15min), mice received an intraperitoneal injection selectively activating either (one per scanning session) the direct (D₁-receptor agonist + D₂-receptor antagonist) or indirect pathway (D₂-receptor agonist + D₁-receptor antagonist). Drug-induced brain activity changes were assessed using voxel-wise statistical parametric mapping (voxel-level p<0.001; cluster-level FWE-corrected p<0.05; k>10 voxels) and region-based time-course analyses (one-way ANOVA and Dunnett’s post-hoc test) to compare post-injection BOLD signals against the baseline. Following direct pathway stimulation, our results revealed a clear increased BOLD signal within the striatum and the motor cortex, which returned to baseline before the end of the scanning session. In contrast, activation of the indirect pathway resulted in a time-dependent decrease in striatal and thalamic activity, which both returned to baseline. These findings not only align with the canonical direct and indirect pathway model but also introduce a novel technique to, for the first time, selectively probe direct and indirect pathway circuit dynamics in the mice brain. Future work will apply this method in various animal models (of neurodegenerative disorders) to characterise dopaminergic signalling and guide therapeutic development.