Direct-pathway striatal neurons regulate the retention of decision-making strategies

Abstract

The dorsal striatum has been implicated in reward-based decision making, but the role played by specific striatal circuits in these processes is essentially unknown. Using cell phenotype-specific viral vectors to express engineered G-protein-coupled DREADD (designer receptors exclusively activated by designer drugs) receptors, we enhanced Gi/o- or Gs-protein-mediated signaling selectively in direct-pathway (striatonigral) neurons of the dorsomedial striatum in Long-Evans rats during discrete periods of training of a high versus low reward-discrimination task. Surprisingly, these perturbations had no impact on reward preference, task performance, or improvement of performance during training. However, we found that transiently increasing Gi/o signaling during training significantly impaired the retention of task strategies used to maximize reward obtainment during subsequent preference testing, whereas increasing Gs signaling produced the opposite effect and significantly enhanced the encoding of a high-reward preference in this decision-making task. Thus, the fact that the endurance of this improved performance was significantly altered over time-long after these neurons were manipulated-indicates that it is under bidirectional control of canonical G-protein-mediated signaling in striatonigral neurons during training. These data demonstrate that cAMP-dependent signaling in direct-pathway neurons play a well-defined role in reward-related behavior; that is, they modulate the plasticity required for the retention of task-specific information that is used to improve performance on future renditions of the task.

Figure 1.

Decision-making training and viral injection. a, Illustration of the training and preference test components of the decision-making task. Each session consists of a maximum of 40 forced trials and 40 choice trials. b, Drawing adapted from plate 17 (0.2 mm from bregma) of the Paxinos and Watson (1998) rat atlas illustrating the target region of viral injections on one coronal brain section. Rats with viral injection tracts outside of the target area (designated by gray ovals) were excluded from analysis (3 of 92). c, d, Not reversing the lever assignment from the previous session (NR) in trained rats has no effect on the number of trials needed to reach criterion (c) or on preference for the HR lever (d) compared with reversing the lever assignment (R). p > 0.05. n = 4 per group.

Figure 2.

Increasing G_i/o-mediated signaling in direct-pathway neurons has no effect on decision-making task performance. Rats showed a significant decrease in the number of trials needed to reach criterion (a) and in preference for the HR lever (b) over training sessions; p < 0.0001. However, CNO-mediated activation (1 mg/kg, i.p.) of hM₄Di receptors had no effect on these two measures in previously trained rats (a, b). p > 0.05. Pre, Pretest, no injection; VEH, vehicle injection; CNO, CNO injection. n = 8 per group.

Figure 3.

Increasing G_i/o-mediated signaling in direct-pathway neurons impairs stable retention of task information. CNO-mediated activation of hM₄Di receptors had no effect on the number of trials needed to reach criteria during training sessions (a), on overall preference for the HR lever (b), and on preference for the HR lever percentage during the first four trial blocks in early, mid, or late training sessions (c). p > 0.05. However, rats that had been treated with CNO during training showed a significant increase in the number of trials needed to reach criterion during a preference test (Pref test) conducted 1 week after the last training session in the absence of CNO treatment (a; ***p = 0.003 vs vehicle-treated group), as well as a significant reduction in overall preference for the HR lever (b; **p = 0.01 vs vehicle-treated group) and a significant reduction in preference for the HR lever during the third trial block (c; *p < 0.05 vs vehicle-treated group). n = 7–8 per group. White symbols represent animals that received vehicle (VEH) during training, and black symbols represent animals that received CNO during training.

Figure 4.

Increasing G_i/o-mediated signaling in direct-pathway neurons has no effect on early task retention. CNO-mediated activation of hM₄Di receptors had no effect on the number of trials needed to reach criteria during training sessions (a), on overall preference for the HR lever (b), and on preference for the HR lever during the first four trial blocks in early, mid, or late training sessions (c). p > 0.05. When the preference test (Pref test) was conducted 24 h after the last training session, there were no group differences on these three measures (a–c). p > 0.05. n = 6–10 per group. White symbols represent animals that received vehicle (VEH) during training, and black symbols represent animals that received CNO during training.

Figure 5.

Increasing G_i/o-mediated signaling in direct-pathway neurons immediately after each training session has no effect on task retention. CNO-mediated activation of hM₄Di receptors after training had no effect on the number of trials needed to reach criteria during training sessions and during the preference test (Pref test; a), on overall preference for the HR lever (b) and on preference for the HR lever during the first four trial blocks in early, mid, or late training sessions or during the preference test (c). p > 0.05. n = 8 per group. White symbols represent animals that received vehicle (VEH) immediately after training session, and black symbols represent animals that received CNO immediately after each training session.

Figure 6.

pDYN–rM₃Ds viral vector construction and expression. a, Illustration of the HSV HA-tagged pDYN–rM3Ds transgene amplicon. b, pDYN–rM3Ds receptors were selectively expressed in striatonigral MSNs (95% of HA-positive cells were substance P positive, 157 of 166 cells) Green, HA; red, substance P; yellow, colocalization of neurons. Scale bar, 25 μm. c, CNO-mediated activation of pDYN–rM₃Ds receptors significantly increased the number of amphetamine-induced Fos cells in dorsomedial striatum (DM) compared with pDYN–GFP controls (**p = 0.01) but had no effect in dorsolateral striatum (DL; p > 0.05). n = 4 per group. d, Representative sections of Fos immunohistochemistry (red) are shown from pDYN–GFP (GFP) and pDYN–rM₃Ds (rM₃Ds) infused striatum. Scale bar, 100 μm. AmpR, Ampicillin resistance gene; ori S, HSV origin of replication; IE, immediate-early.

Figure 7.

Increasing G_s-mediated signaling in direct-pathway neurons enhances retention of task-specific information. CNO-mediated activation of rM₃Ds receptors had no effect on the number of trials needed to reach criteria during training sessions (a), on overall preference for the HR lever (b), and on preference for the HR lever during the first four trial blocks in early, mid, or late training sessions (c). p > 0.05. However, rats that had been treated with CNO during training showed a significant decrease in the number of trials needed to reach criterion during a preference test (Pref test) conducted 1 week after the last training session in the absence of CNO treatment (a; *p = 0.03 vs vehicle-treated group), as well as a significant increase in overall preference for the HR lever (b; **p = 0.005 vs vehicle-treated group). n = 13–17 per group. White symbols represent animals that received vehicle (VEH) during training, and black symbols represent animals that received CNO during training.