Abstract
Cognitive flexibility is a critical ability for adapting to an ever-changing environment in humans and animals. Deficits in cognitive flexibility are observed in most schizophrenia patients. Previous studies reported that the medial prefrontal cortex-to-ventral striatum and orbital frontal cortex-to-dorsal striatum circuits play important roles in extra- and intra-dimensional strategy switching, respectively. However, the precise function of striatal subregions in flexible behaviors is still unclear. N-methyl-D-aspartate receptors (NMDARs) are major glutamate receptors in the striatum that receive glutamatergic projections from the frontal cortex. The membrane insertion of Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) depends on NMDAR activation and is required in learning and memory processes. In the present study, we measured set-shifting and reversal learning performance in operant chambers in rats and assessed the effects of blocking NMDARs and Ca2+-permeable AMPARs in striatal subregions on behavioral flexibility. The blockade of NMDARs in the nucleus accumbens (NAc) core by AP5 impaired set-shifting ability by causing a failure to modify prior learning. The suppression of NMDAR-mediated transmission in the NAc shell induced a deficit in set-shifting by disrupting the learning and maintenance of novel strategies. During reversal learning, infusions of AP5 into the NAc shell and core impaired the ability to learn and maintain new strategies. However, behavioral flexibility was not significantly affected by blocking NMDARs in the dorsal striatum. We also found that the blockade of Ca2+-permeable AMPARs by NASPM in any subregion of the striatum did not affect strategy switching. These findings suggest that NMDAR-mediated glutamate transmission in the NAc contributes more to cognitive execution compared with the dorsal striatum.
Highlights
Strategy switching as a cognitive ability is critical for adapting to and surviving in an ever-changing environment
Twentyfour hours later, 15 rats were infused with AP5 into the nucleus accumbens (NAc) core before the set-shifting task, and 36 rats were infused with the corresponding saline vehicle
The present study revealed that the blockade of N-methylD-aspartate receptors (NMDARs) in the NAc core impaired set-shifting performance by increasing perseverative errors
Summary
Strategy switching as a cognitive ability is critical for adapting to and surviving in an ever-changing environment. Impaired cognitive flexibility is one of the core symptoms of schizophrenia (Orellana and Slachevsky, 2013). The striatum is one of the major brain regions to which frontal cortex glutamatergic neurons project (Reynolds and Zahm, 2005; Xu and Südhof, 2013), but the role of this region in cognitive flexibility is not well-known. Subchronic treatment with the noncompetitive NMDAR antagonist ketamine reduces perseverative errors during extradimensional set-shifting but impairs intradimensional reversal learning (Floresco et al, 2009). Setshifting ability is impaired by subchronic treatment with the NMDAR antagonist phencyclidine (Egerton et al, 2008). The phenotypes induced by these treatments closely resemble heterogeneous symptoms in schizophrenia patients (Jentsch and Roth, 1999), implying that NMDARs in the brain participate in the process of replacing old strategies with new ones.
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