Extended Data Fig. 8: Dopamine depletion reduces the movement-type specificity of iSPN activity patterns.

a, Following dopamine depletion, we classified mouse movement bouts into different types, as in Extended Data Fig. 3. After 6-OHDA lesion, there were insufficient bouts of upward rearing to allow statistical analyses. b, Percentages of SPNs (mean ± s.e.m.) that exhibited Ca²⁺ activity, relative to the baseline periods (dashed line) immediately before each movement type, >14 days after 6-OHDA lesion. Compared to baseline periods, there was a significant increase in dSPN and iSPN activity for all movement types, except during grooming. *P < 0.05 and **P < 5 × 10⁻³ for dSPNs; #P < 0.05 and ##P < 5 × 10⁻³ for iSPNs; Wilcoxon signed-rank test. Data in b and c are based on 206 forward movements, 200 right turns, 290 left turns and 314 grooming bouts in 13 Drd1a^cre mice and 331 forward movements, 295 right turns, 194 left turns and 339 grooming bouts in 21 Adora2a^cre mice. c, Rates of Ca²⁺ events (mean ± s.e.m.) in dSPNs and iSPNs as a function of time relative to the onsets of different types of movements, >14 days after 6-OHDA lesion. Event rates are shown normalized to the values from −2 to −1 s before motion onset. As found when all movements were grouped together (Fig. 3g), the rates of iSPNs hardly increase at motion onset in parkinsonian mice. d, Mean values of the neural ensemble similarity computed for the sets of dSPNs and iSPNs that were active during pairs of bouts of either the same (on-diagonal) or different (off-diagonal) types of movements, in freely behaving mice >14 days after 6-OHDA lesion (Methods). For each pair of movement types, values are shown normalized to the corresponding value found in healthy mice before 6-OHDA lesion. Asterisks indicate a significant difference between the pre- and post-lesion values. *P < 0.05; Wilcoxon rank-sum test, corrected for multiple comparisons using a Benjamini–Hochberg procedure with a false-discovery rate of 0.05. e, Cumulative distribution functions showing the range of ensemble similarity values for the sets of dSPNs and iSPNs that activated on two bouts of different movement types. The similarity of the dSPN ensembles activated on different movement types decreased significantly after 6-OHDA, indicating that the representations of different movements became more distinct. P < 0.05; Kolmogorov–Smirnov test. By comparison, the iSPN ensembles activated on different types of movements became more similar after 6-OHDA lesion, consistent with a reduction in the selectivity of iSPN movement encoding. P < 0.05; Kolmogorov–Smirnov test. f, Mean pairwise distances between the individual dSPNs or iSPNs activated on bouts of two different movement types, in freely behaving mice >14 days after 6-OHDA lesion. We expressed the values as z scores, as described in Extended Data Fig. 3f. For each pair of movement types, we then normalized each z score by the corresponding value found in healthy mice before 6-OHDA lesion. g, Cumulative distribution functions showing the normalized distances between dSPNs (left) and iSPNs (right) (computed as in f) before and after 6-OHDA lesion, for bouts of different movement types. The mean pairwise distances between iSPNs, but not dSPNs, that activated on bouts of different movement types decreased significantly after 6-OHDA lesion, indicating that the iSPN cell ensembles active on the different movement types were less spatially distinguishable after 6-OHDA lesion. P = 0.02; Kolmogorov–Smirnov test. Plots in d–g are based on n = 102 and n = 126 comparisons between bouts of the same movement type, and 255 and 315 comparisons of bouts of different movement types, in 17 Drd1a^cre and 21 Adora2a^cre mice, respectively, before 6-OHDA lesion, and on n = 72 and n = 78 comparisons between bouts of the same movement type, and 180 and 195 comparisons of bouts of different movement types in 12 Drd1a^cre and 13 Adora2a^cre mice, respectively, >14 days after 6-OHDA lesion. The pre-lesion data are the same as in Extended Data Fig. 3. The data >14 days after the lesion are aggregated from the 1-h recordings on day 14 plus the 30-min recordings on day 20 that occurred after saline vehicle injection but before administration of 6 mg kg⁻¹ l-DOPA (see Fig. 1a).