Increased expression of the 5-HT6 receptor by viral mediated gene transfer into posterior but not anterior dorsomedial striatum interferes with acquisition of a discrete action-outcome task

Abstract

Serotonin plays a role in reinforcement learning; however, it is not known which serotonin receptors mediate these effects. Serotonin 6 (5-HT(6)) receptors are abundant in the striatum, a brain area that is involved in reinforcement learning. We previously found that 5-HT(6) receptors in the dorsomedial striatum (DMS) affect reinforcement learning or consolidation over several days. We use viral-mediated gene transfer to discern the role that 5-HT(6) receptors play in mediating post-synaptic responses in anterior versus posterior DMS. Male Long-Evans rats were used to study learning acquisition during a single session of 100 trials on a fixed interval of 20 seconds. In a discrete action-outcome learning task, rats had 10 seconds to press a lever to induce lever retraction and sucrose pellet delivery. In another group of rats, the task had a lever that was continuously extended but only active every 20 seconds, allowing for repetitive, mostly non-reinforced, lever pressing. Results demonstrate that increased expression of 5-HT(6) receptors in the posterior DMS interferes with earning sucrose pellets in only the former task. We take this to indicate that 5-HT(6) receptor signaling in the posterior DMS interferes with acquisition of discrete action-outcome responding.

Figure 1

Rat atlas figures showing injection targets as shaded areas in (A) anterior dorsomedial striatum (aDMS) and (B) posterior dorsomedial striatum (pDMS). (C) A typical injection site in the DMS shows expression of enhanced green fluorescent protein in neuron somas and processes. Scale bar = 200 µm.

Figure 2

Increased expression of 5-HT₆ receptors in the dorsomedial striatum (DMS) does not affect reward learning. There were no differences in rats’ sucrose consumption in the operant chamber during the pre-test in any of the four groups (group sizes included rats from both tasks). (A) aDMS: enhanced green fluorescent protein (eGFP) n = 16, 5-HT₆ n = 24; pDMS: eGFP n = 15, 5-HT₆ n = 21). Orientation to the pellet receptacle during the continuously extended task was unaffected by treatment. (B) aDMS: eGFP n = 8, 5-HT₆ n = 7; (C) pDMS (both groups n = 8). All error bars represent SEM.

Figure 3

Increased expression of 5-HT₆ receptors in the posterior dorsomedial striatum (pDMS) impairs the ability to acquire a discrete action–outcome task using the inserting/retracting (IR) task. (A) Performance on the IR task is not affected by increased expression of 5-HT₆ receptors in the aDMS as compared to enhanced green fluorescent protein (eGFP) controls (n = 8 per group). (B) However, increased expression of 5-HT₆ receptors in the pDMS significantly altered rats’ ability to earn sucrose pellets (eGFP n = 16, 5-HT₆ n = 13). (C) The impaired performance of rats with increased expression of 5-HT₆ receptors in the pDMS is seen over the course of the session. *p < 0.05; **p < 0.01. All error bars represent SEM.

Figure 4

Motor skills necessary to perform a lever-pressing task are not impaired by increased expression of 5-HT₆ receptors in anterior or posterior dorsomedial striatum (aDMS/pDMS). The number of sucrose pellets earned is not affected by increased expression of 5-HT₆ receptors in (A) aDMS (eGFP n = 8, 5-HT₆ n = 7) or (C) pDMS (n = 8 per group). Rats in all groups were able to distinguish the active lever from the inactive lever, aDMS (B), pDMS (D). **p < 0.01; ***p < 0.001. All error bars represent SEM.