Abstract
The striatum plays important motor, associative and cognitive roles in brain functions. However, the rodent dorsolateral (the primate putamen) and dorsomedial (the primate caudate nucleus) striatum are not anatomically separated, making it difficult to distinguish their functions. By contrast, anatomical separation exists between the caudate nucleus and putamen in primates. Here, we successfully decreased dopamine D1 receptor (D1R) or D2R mRNA expression levels selectively in the marmoset caudate using shRNA knockdown techniques, as determined using positron emission tomography imaging with specific D1R and D2R ligands and postmortem in situ hybridization analysis. We then conducted a voxel-based correlation analysis between binding potential values of PET imaging and visual discrimination learning task performance in these genetically modified marmosets to find a critical role for the caudate D2R but no apparent role for the caudate D1R. This latter finding challenges the current understanding of the mechanisms underlying D1R activation in the caudate.
Highlights
Roles in striatal functions through activation and inhibition, respectively, of cortical-striatal-thalamic circuits[6,20]
An exact quantitative evaluation by in situ hybridization (ISH) is difficult without using autoradiograms, which we did not use, it appears that positron emission tomography (PET) results showed somewhat less reduction of D1R and D2 receptors (D2R) bindings than ISH results
Since our ISH analysis did not indicate the reduced expression levels of D1R and D2R mRNAs in the non-injected site (Fig. 1a and Supplementary Fig. 3), there should be some mechanisms that underlie this discrepancy between PET and ISH results
Summary
Roles in striatal functions through activation and inhibition, respectively, of cortical-striatal-thalamic circuits[6,20]. The use of RNA targeting rather than pharmacological methods is advantageous because of the limited specificities of D1R and D2R agonists and antagonists. The RNA targeting method provides regional selectivity, effects that can be evaluated using positron emission tomography (PET) and postmortem in situ hybridization (ISH), and a long duration of action. Because only the striatal neurons taking up the shRNA are affected, the presynaptic D2R on neurons projecting to the striatum are not. These advantageous features can be used to identify the unambiguous roles of striatal D1R and D2R in cognitive functions. We found significant effects on D2R but no apparent phenotype on D1R in the caudate nucleus during visual discrimination learning
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