Contributions of striatal dopamine signaling to the modulation of cognitive flexibility

Abstract

Background: Although cognitive flexibility is mediated by different areas of the prefrontal cortex, evidence from patients with Parkinson's disease suggests an additional involvement of striatal dopamine (DA) signaling. Because both dorsal and ventral striatum receive prefrontal cortex projections, it is unclear whether DA signaling to either one or both of these regions is required for cognitive flexibility.

Methods: Cognitive flexibility was examined with a water U-maze paradigm in which mice had to shift from an initially acquired escape strategy to a new strategy or to reverse the initially learned strategy. We tested mice with conditionally inactive tyrosine hydroxylase genes that can be activated by Cre recombinase. With region-specific viral gene therapy we selectively restricted DA signaling to either dorsal or ventral striatum.

Results: Restricting DA signaling to the ventral striatum did not impair learning of the initial strategy or reversal-learning but strongly disrupted strategy-shifting. In contrast, mice with DA signaling restricted to the dorsal striatum had intact learning of the initial strategy, reversal-learning, and strategy-shifting.

Conclusions: Dopamine signaling in both dorsal and ventral striatum is sufficient for reversal-learning, whereas only DA signaling in the dorsal striatum is sufficient for the more demanding strategy-shifting task.

Figure 1

Restriction of dopaminergic signaling to the striatum of vrDDDorsal and vrDD-Ventral mice. Tyrosine hydroxylase (TH) (red) immunostaining was visualized in coronal sections of the striatum from control and vrDD mice. (A) Schematic illustration of the Th-restoration strategy, depicting viral injections into the dorsal and ventral striatum of vrDD and control mice. (B) TH expression pattern in sham control mice. (C) TH expression found in vrDD-Dorsal mice. Expression was restricted to the dorsal striatum with strong immunostaining in both lateral and medial regions. (D) TH expression found in vrDD-Ventral mice. Expression was strongest in the nucleus accumbens with some immunostaining in the dorsomedial striatum and the olfactory tubercle.

Figure 2

Cognitive flexibility by sham and vrDD mice. (A) Escape latencies and (B) percentage of correct trials/training day during pretraining of the turn-based strategy. Sham control, vrDD-Dorsal, and vrDD-Ventral mice reached > 80% correct trials on the third training day. Escape latencies by vrDD mice were elevated compared with sham control mice. (C) Escape latencies and (D) percentage of correct trials/training day during reversal-learning. Although vrDD mice performed slower than sham control mice, all groups reached > 80% correct trials on the fourth training day. (E) Escape latencies and (F) percentage of correct trials/training day during pretraining of the turn-based strategy. Strategy-shifting was impaired in vrDD-Ventral mice. Sham-control and vrDD-Dorsal mice reached > 80% correct trials on the third training day; vrDD-Ventral mice required 6 training days to reach this criterion. Significant main effects of group (**p < .01; *p < .05). Data are means ± SEM.