Disease-Associated Changes in the Striosome and Matrix Compartments of the Dorsal Striatum

Observations of disease-associated changes in the basal ganglia are key to our current understanding of cortico-thalamo-basal ganglia circuits. Postmortem findings of imbalances between the direct and indirect striatal output pathways led to mechanistic hypotheses that are now being directly tested in animal models by genetic engineering to enable cell-type-specific expression of opsins, DREADDs (designer receptors exclusively activated by designer drugs), calcium indicators, and disease–gene constructs. Such methods have confirmed but also questioned aspects of the direct–indirect pathway circuit model for how we select distinct movements and inhibit competitive movements. Disease-associated imbalances are also found between the striosome and matrix compartments of the striatum, which overlap but are distinct from the direct–indirect pathways. Here, we review evidence that striosomes are enriched in limbic loops that include direct connections to dopamine-containing neurons in the substantia nigra, and how this pivotal position of striosomes could relate to striosome–matrix imbalances in human disorders affecting mood, motivation, and action–selection.