Optogenetic Activation of Striatal D1/D2 Medium Spiny Neurons Differentially Engages Downstream Connected Areas Beyond the Basal Ganglia

The basal ganglia (BG) are a group of subcortical nuclei responsible for motor control, motor learning and executive function. Central to BG function are striatal medium spiny neurons (MSNs) expressing D1 and D2 dopamine receptors. D1 and D2 MSNs are typically considered functional antagonists that facilitate voluntary movements and inhibit competing motor patterns, respectively. While their opposite role is well documented for certain sensorimotor loops of the BG-thalamocortical network, it is unclear whether MSNs maintain a uniform functional role across the striatum and which influence they exert on brain areas outside the BG. Here, we addressed these questions by combining optogenetic activation of D1 and D2 MSNs in the mouse ventrolateral caudoputamen (vl CPu) with whole-brain functional MRI (fMRI) recordings. Neuronal excitation of either cell population in the vl CPu evoked distinct activity patterns in key regions of the BG-thalamocortical network including the pallidum, thalamus and motor cortex. Importantly, we report that striatal D1 and D2 MSN stimulation differentially engaged cerebellar and prefrontal regions. We characterised these long-range interactions by computational modelling of effective connectivity and confirmed that changes in D1 / D2 output drive functional relationships between regions within and beyond the BG. These results suggest a more complex functional organization of MSNs across the striatum than previously anticipated and provide evidence for the existence of an interconnected fronto - BG - cerebellar network modulated by striatal D1 and D2 MSNs. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=129 HEIGHT=200 SRC="FIGDIR/small/436576v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@a18349org.highwire.dtl.DTLVardef@1b256faorg.highwire.dtl.DTLVardef@16c454aorg.highwire.dtl.DTLVardef@1392b23_HPS_FORMAT_FIGEXP M_FIG C_FIG