Volume 27, Issue 19, Pages 3042-3048.e4 (October 2017) Distinct Roles of Ventromedial versus Ventrolateral Striatal Medium Spiny Neurons in Reward-Oriented Behavior  Iku Tsutsui-Kimura, Akiyo Natsubori, Marina Mori, Kenta Kobayashi, Michael R. Drew, Alban de Kerchove d’Exaerde, Masaru Mimura, Kenji F. Tanaka  Current Biology  Volume 27, Issue 19, Pages 3042-3048.e4 (October 2017) DOI: 10.1016/j.cub.2017.08.061 Copyright © 2017 Elsevier Ltd Terms and Conditions

Current Biology 2017 27, 3042-3048.e4DOI: (10.1016/j.cub.2017.08.061) Copyright © 2017 Elsevier Ltd Terms and Conditions

Figure 1 Opposing Changes of Compound Intracellular Ca2+ Signals of D2-MSNs in the VLS versus VMS during a Reward-Oriented Discrimination Task (A) Drd2-tTA-dependent YCnano50 expression (D2-YC). (B) Recording sites of Ca2+ signals of D2-MSNs (green, direct fluorescence) in the VMS (left) and VMS (right). The scale bars represent 1 mm. (C) Schema of ratiometric fiberphotometry system. (D) Schematic illustration of the fixed ratio (FR)-10 discrimination task sequence. (E–G) Temporal changes of compound Ca2+ signals in the VLS at TS (E; n = 15 sessions from 5 mice), LP (F; n = 15 sessions from 5 mice), and RW (G; n = 15 sessions from 5 mice). (H–J) Temporal changes of compound Ca2+ signals in the VMS at TS (H; n = 12 sessions from 4 mice), LP (I; n = 12 sessions from 4 mice), and RW (J; n = 12 sessions from 4 mice). Averaged signals are from all sessions of all mice. Black bar indicates the statistical period; green and red bars indicate p < 0.05 and p < 0.01; paired t test with Bonferroni correction (mean Z score during 5 s just before TS versus that during each 1-s period for 5 s after TS, respective 5 s before and after LP, or 20 s after RW). See also Figure S1 and Table S1. Current Biology 2017 27, 3042-3048.e4DOI: (10.1016/j.cub.2017.08.061) Copyright © 2017 Elsevier Ltd Terms and Conditions

Figure 2 Optogenetic Countering of D2-MSN Activities in the VLS and VMS Impairs Initiation and Direction of Reward-Oriented Behavior, Respectively (A) Virus strategy for expressing ArchT in the VLS D2-MSNs. (B) Virus strategy for expressing ChR2 in the VMS D2-MSNs. (C) Yellow or blue light was applied at the time of every TS for 2 s. (D) VLS D2-MSNs counter-silencing at the timing of TS (n = 12 sessions from 4 animals) decreased the number of rewarded LPs and prolonged first LP latency. (E) VMS D2-MSNs counter-activation at the timing of TS (n = 12 sessions from 4 animals) increased the number of non-rewarded LPs. ∗p < 0.05; paired t test compared to the control light. Error bars represent + SEM. The scale bars represent 1 mm. RC, reward collection. See also Figures S1 and S2. Current Biology 2017 27, 3042-3048.e4DOI: (10.1016/j.cub.2017.08.061) Copyright © 2017 Elsevier Ltd Terms and Conditions

Figure 3 Temporal VMS D2-MSN Activation during Reversal Learning and Optogenetic Gain of Function to Accelerate Strategy Change (A) Recording site of Ca2+ signals in D2-MSNs (green) in the VMS. (B) Behavioral performances during the FR-1 discrimination task and reversal learning. Percent accuracy decreased on day 1 and day 2 of reversal learning, and mice totally adapted the new contingency on day 3. Error bars represent ± SEM. (C) Temporal changes of Ca2+ signals in the VMS D2-MSNs aligned to the TS time at the end of FR-1 (Norm 10-d), at day 1 reversal (Rev 1-d), at day 2 reversal (Rev 2-d), and at day 3 reversal (Rev 3-d; n = 6 sessions from 6 mice). Averaged signals are from all sessions of all mice. ∗p < 0.05; Bonferroni correction compared to the Norm 10-d. Error bars represent + SEM. (D) Bilateral optogenetic activation of VMS D2-MSNs. (E) Gain-of-function manipulation of VMS D2-MSNs at the TS time (ChR2-expressing mice, n = 6; YFP-expressing control mice, n = 6) accelerated the strategy changes. ∗p < 0.05; paired t test compared to the YFP control. Error bars represent ± SEM. The scale bars represent 1 mm. Current Biology 2017 27, 3042-3048.e4DOI: (10.1016/j.cub.2017.08.061) Copyright © 2017 Elsevier Ltd Terms and Conditions