N-methyl-D-aspartate receptor-mediated glutamate transmission in nucleus accumbens plays a more important role than that in dorsal striatum in cognitive flexibility

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.

Behavioral flexibility predicts increased ability to resist excessive methamphetamine self‐administration

“…After an initial learning phase, rats are tested repeatedly on the same set of rules that are alternated within and between sessions, and therefore they have to choose among strategies that they have already learned. In this respect, the procedure is different from other set‐shifting procedures in which flexibility is measured in a single session or two (Haluk & Floresco ; Dalton et al ; Ding et al ). It is possible that these procedures measure different aspects of behavioral flexibility; the former (Darrah et al and present work) models perseverative behavior and strategy selection and the latter (Haluk & Floresco ; Dalton et al ; Ding et al ) models the ability to rapidly adapt to new contingencies and to implement a novel behavioral strategy.…”

Impact of partial dopamine depletion on cognitive flexibility in BDNF heterozygous mice

“…3) Dopamine-glutamate interactions in the ventral striatum may be more important to maintaining higher forms of cognitive flexibility as opposed to the dorsal striatum. In this context, a recent study showed that infusions of AP5, a NMDA receptor antagonist, into the ventral striatum impaired strategy shifting (Ding et al 2014). A similar observation was reported by Haluk and Floresco (2009) when a D1 receptor antagonist was infused into the nucleus accumbens of rats.…”

The neural basis of reversal learning: An updated perspective

“…Ragozzino and colleagues found that these deficits were accompanied by decreases in acetylcholine efflux (Palencia and Ragozzino, 2006) and could be mimicked by blocking muscarinic M1 (via pirenzepine) or stimulating M2 (via oxotremorine sesquifumurate), but not by antagonizing nicotinic (via mecamylamine), acetylcholine receptors in the DMS (Tzavos et al, 2004, McCool et al, 2008, Ragozzino et al, 2009). Somewhat surprisingly, given this evidence of a key role for DMS NMDARs in reversal, a recent study found no effect of DMS NMDAR antagonism (via AP5) on a visual-cue reversal learning task that was impaired by NMDAR blockade in the NAc (Ding et al, 2014). It may be that differences in the way reversal was tested across these studies accounts for this discrepancy, but further investigation would be needed to draw any firm conclusions.…”