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Summary: The dorsal striatum plays a central role in the selection, execution, and evaluation of actions. An emerging model attributes action selection to the matrix and evaluation to the striosome compartment. Here, we use large-scale cell-type-specific calcium imaging to determine the activity of striatal projection neurons (SPNs) during motor and decision behaviors in the three major outputs of the dorsomedial striatum: Oprm1+ striosome versus D1+ direct and A2A+ indirect pathway SPNs. We find that Oprm1+ SPNs show complex tunings to simple movements and value-guided actions, which are conserved across many sessions in a single task but remap between contexts. During decision making, the SPN tuning profiles form a complete representation in which sequential SPN activity jointly encodes task progress and value. We propose that the three major output pathways in the dorsomedial striatum share a similarly complete representation of the entire action space, including task- and phase-specific signals of action value and choice.

Preliminary evidence from postmortem studies of X-linked dystonia-parkinsonism (XDP) suggests tissue loss may occur first and/or most severely in the striatal striosome compartment, followed later by cell loss in the matrix compartment. However, little is known about how this relates to pathogenesis and pathophysiology. While MRI cannot visualize these striatal compartments directly in humans, differences in relative gradients of afferent cortical connectivity across compartments (weighted toward paralimbic versus sensorimotor cortex, respectively) can be used to infer potential selective loss in vivo. In the current study we evaluated relative connectivity of paralimbic versus sensorimotor cortex with the caudate and putamen in 17 individuals with XDP and 17 matched controls. Although caudate and putamen volumes were reduced in XDP, there were no significant reductions in either “matrix-weighted”, or “striosome-weighted” connectivity. In fact, paralimbic connectivity with the putamen was elevated, rather than reduced, in XDP. This was driven most strongly by elevated putamen connectivity with the anterior insula. There was no relationship of these findings to disease duration or striatal volume, suggesting insula and/or paralimbic connectivity in XDP may develop abnormally and/or increase in the years before symptom onset., Highlights • Previous work suggested striosomes might degenerate preferentially in early XDP. • We developed a DTI tractography method to assess striosome and matrix integrity. • Striosomal afferents to putamen were elevated in XDP, despite reduced putamen volume. • Connectivity was particularly elevated from the insula (two to three-fold). • Striosome connectivity strength was not associated with disease duration.

Huntington's disease is characterized by striatal degeneration and progressive motor deficits. To examine striatal compartment-specific pathology and its relation to motor symptoms, we used immunohistochemistry to identify and measure the striosomes and matrix of 7-13-month-old YAC128 and wild type (WT) mice that were previously tested on motor tasks. Compared to WTs, 13-month-old YAC128s showed volume shrinkage in striosomes, and cell loss in both compartments. The percent cell loss was greater in striosomes than matrix. Striosome volume and cell loss was greatest in the dorsolateral striatum. YAC128 rotarod and balance beam deficits preceded volume and cell loss. At 13 months, YAC128 balance beam slips and striosome cell number were inversely correlated. The results show that pathology in older YAC128s manifests as an abnormal striosome to matrix ratio and suggest that this imbalance can contribute to some motor symptoms.

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.

A striking neurochemical form of compartmentalization has been found in the striatum of humans and other species, dividing it into striosomes and matrix. The function of this organization has been unclear, but the anatomical connections of striosomes indicate their relation to emotion-related brain regions, including the medial prefrontal cortex. We capitalized on this fact by combining pathway-specific optogenetics and electrophysiology in behaving rats to search for selective functions of striosomes. We demonstrate that a medial prefronto-striosomal circuit is selectively active in and causally necessary for cost-benefit decision-making under approach-avoidance conflict conditions known to evoke anxiety in humans. We show that this circuit has unique dynamic properties likely reflecting striatal interneuron function. These findings demonstrate that cognitive and emotion-related functions are, like sensory-motor processing, subject to encoding within compartmentally organized representations in the forebrain and suggest that striosome-targeting corticostriatal circuits can underlie neural processing of decisions fundamental for survival., National Institutes of Health (U.S.) (R01 MH060379), National Institute of Mental Health (U.S.) (R01 MH060379), United States. Defense Advanced Research Projects Agency (W911NF-10-1-0059), United States. Army Research Office (W911NF-10-1-0059)

Background Studies have shown that neuroleptics regulate expression of the transcription factor FosB/ΔFosB in the striatum, including the accumbens and caudate-putamen; however, the striatum is also divided into another structural dimension, the striosome and matrix compartments. The precise distribution of FosB/ΔFosB induced by chronic neuroleptics in these striatal compartments is poorly understood. Methods Rats received either single acute injections or chronic injections of clozapine (0 or 20 mg/kg, intraperitoneally [IP]), olanzapine (0 or 5 mg/kg, IP), or haloperidol (0 or 1. 5 mg/kg, IP) for 25 days. The levels and compartmental distribution of FosB/ΔFosB were examined. Results Chronic clozapine induced clustered FosB/ΔFosB expression within striosomes of the caudate-putamen. This pattern was due to increased levels of FosB/ΔFosB in striosomes within the ventrolateral caudate-putamen and reduced levels of basal FosB/ΔFosB in the matrix in the entire caudate-putamen. In contrast, chronic haloperidol increased FosB/ΔFosB equally within the matrix and striosomes throughout the entire caudate-putamen. Chronic olanzapine induced an intermediate pattern. Conclusions The relative absence of FosB/ΔFosB expression in the matrix correlates with the lack of parkinsonism of atypical neuroleptics. Expression of FosB/ΔFosB in the matrix may contribute to parkinsonism of typical neuroleptics.

Presynaptic regulation of 3H-DA release through NMDA receptors was examined in vitro, and found distinct between striosome- and matrix-enriched areas of the rat striatum.