Optogenetic activation of dSPNs or iSPNs evokes preference or avoidance respectively in the real-time place preference test.

A. An open field was virtually divided into four quadrants, the quadrant where an animal received self-stimulation is highlighted in blue. Middle panels show representative photomicrographs of coronal brain slices from animals with bilateral DMS or DLS implants. Bottom panels, schematic representation of the position of the fiber’s tips. B. Representative examples of the trajectories of two different animals, color coding the time spent per pixel during the test. Activation of dSPNs or iSPN are shown in the upper and lower panels respectively. C. Preference index of the time that animals spent in the quadrant with self-stimulation compared to an average of the other three quadrants for dSPN activation. D. Same as C, but for self-activation of iSPNs. In C and D, * above the horizontal lines is the Dunńs multiple comparison test p<0.001, post Kruskal Wallis. * above a group is p<0.001 Wilcoxon test.

Optogenetic inhibition of dSPNs or iSPNs evokes avoidance or preference in the realtime place preference test.

A. An open field was virtually divided into four quadrants, the quadrant where the animal received self-inhibition is highlighted in green. Middle panels show representative photomicrographs of coronal brain slices of animals with bilateral DMS or DLS implants. Bottom panels, schematic representation of the position of the fibers tips. B. Example of the trajectories of two different animals, color coding the time spent per pixel during the test. Inhibition of dSPNs or the iSPNs is shown in the upper and lower panels respectively. C. Quantification of the time spent in the quadrant with inhibition compared to the average of the other three quadrants. D. Same data as in C but plotted in bins of 5 min and the last 10 minutes in the test. E. and F. Same as C and D for animals with manipulation of iSPNs in the DMS, DLS and Controls. In E, * above the horizontal lines is the Dunńs multiple comparison test p<0.001, post Kruskal Wallis. * above a group is p<0.05 Wilcoxon test. In D and F, * above are p<0.05 Mann Whitney U test vs. the control group.

Self-activation of striatal dSPNs or iSPNs in an action selection test.

A. Schematic of the task: operant chamber with two levers extended, at the moment of executing the action, pressing any of the levers delivered a pellet but only one of them was paired to self-activation. Bottom panels: details of the pellet and light activation. B. Preference index of lever presses across acquisition sessions, comparing the self-activation of dSPNs in the DMS (n=8) vs. DLS (n=9) and Controls (n=20). C. Same as B, comparing self-activation of iSPNs in the DMS (n=7) vs. DLS (n=10) and Controls (n=20). Right panel in B and C: preference index of the corresponding animals in an extinction test (here the actions yield no pellet and no light). D and E. Quantification of the behavioral execution of the actions on the lever that delivered self-activation on the last day of acquisition for animals that received self-activation of dSPNs or iSPNs, respectively. * in B and C left panels: p<0.05 RM-ANOVA. In B, C, right panels and D and E, * above the horizontal lines is the Dunńs multiple comparison test p<0.05, post Kruskal Wallis. * above a group is p<0.05 Wilcoxon test.

Self-inhibition of striatal dSPNs or iSPNs in an action selection test.

A. Schematic of the task: operant chamber with two levers extended, at the moment of executing the action, pressing any of the levers delivered a pellet but only one of them was paired to self-inhibition. Bottom panels: details of the pellet and light inhibition. B. Preference index of lever presses across acquisition sessions, comparing the self-inhibition of dSPNs in the DMS (n=8) vs. DLS (n=6) and Controls (n=17). C. Same as B, comparing self-inhibition of iSPNs in the DMS (n=8) vs. DLS (n=8) and Controls (n=17). Right panel in B and C: preference index of the corresponding animals in an extinction test (here the actions yield no pellet and no light). D and E. Quantification of the behavioral execution of the actions on the lever that delivered self-inhibition on the last day of acquisition for animals that received self-inhibition of dSPNs or iSPNs, respectively. * in B and C left panels: p<0.05 RM-ANOVA. In B, C, right panels and D and E, * above the horizontal lines is the Dunńs multiple comparison test p<0.05, post Kruskal Wallis. * above a group is p<0.05 Wilcoxon test.

Activation of striatal dSPNs or iSPNs during reward seeking and spontaneous displacements in the open field.

A. Schematic of the displacement of animals from the lever that delivered self-activation in the same setup as Figures 3 and 4. In this case, since this is the last day of acquisition of the action (lever press) that delivered an outcome (pellet) animals developed stereotyped displacements from the lever to the food port. Light modulation was switched on at the initiation of the action. B and C. Time from executing the action to visiting the food port for animals that received activation of dSPN or iSPNs, respectively. D. Schematic of the activation in the open field, in which light was delivered every 20-30 sec, with the same protocol as during the operant task (20 Hz, 10 ms pulses), right panel: schematic of the tracking of an animal. E. Normalized distance of animals with activation of dSPNs in the DMS or DLS and Controls. Trials (All trials) were categorized as fast or slow trials depending on the mean displacement of the animal (one second) before the activation (see methods). F. Same as E, for animals that received iSPNs activation in the DMS DLS and Controls. In B, C and the right panels of E and F, * above the horizontal brackets is the Dunńs multiple comparison test p<0.05, post Kruskal Wallis, except in E right panel slow trials, where the grey * is p<0.05 Mann Whitney U test. * beside the vertical brackets in the left panels of E and F is p<0.05, RM-ANOVA, and above are p<0.05, Sidak’s multiple comparison, blue asterisks depict the DMS vs. DLS comparison.

Inhibition of striatal dSPNs or iSPNs on reward seeking and spontaneous displacements in the open field.

A. Schematic of the displacement of animals from the lever that delivered self-inhibition in the same setup as figures 3 and 4. In this case, since this is the last day of acquisition of the action (lever press) that delivered an outcome (pellet) animals developed stereotyped displacements from the lever to the food port. Light modulation was switched on at the initiation of the action. B and C. Time from executing the action to visiting the food port for animals that received inhibition of dSPN or iSPNs, respectively. D. Schematic of the inhibition in the open-field, in which light was delivered every 20-30 sec, with the same protocol as during the operant task (2-second continuous pulse), right panel: schematic of the tracking of an animal. E. Normalized distance of animals with inhibition of dSPNs in the DMS (n=7) or DLS (n=5) and Controls (n=17). Trials (All trials) were categorized as fast or slow trials depending on the mean displacement of the animal (one second) before the activation (see methods). F. Same as E, for animals that received inhibition of the iSPNs [DMS (n=7); DLS (n=7); Controls (n=17)]. In B and F, * above the horizontal brackets is the Dunńs multiple comparison test p<0.05, post Kruskal Wallis. * in E right panel fast trials is p<0.05 Mann Whitney U test. * beside the vertical brackets in E and F left panels is p<0.05, RM-ANOVA, and above are p<0.05, Sidak’s multiple comparison, green asterisks depict the comparison DMS vs. DLS.

Context-dependent contributions of the striatal pathways in the associative and sensorimotor striatum.

A. Summary of the findings of activation and inhibition experiments according to striatal compartment. B. Model supported by the presented findings in each striatal compartment. Opposite: modulation of the striatal pathways has opposite effects on behavior. Complementary: modulation of the striatal pathways has similar effects. Undescribed: neither of the models was observed.