Accumbal Adenosine A2A Receptors Enhance Cognitive Flexibility by Facilitating Strategy Shifting

Abstract

The deficits of cognitive flexibility (including attentional set-shifting and reversal learning) concomitant with dysfunction of the striatum are observed in several neuropsychiatric disorders. Rodent and human studies have identified the striatum [particularly the dorsomedial striatum (DMS) and nucleus accumbens (NAc)] as the critical locus for control of cognitive flexibility, but the effective neuromodulator and pharmacological control of cognitive flexibility remains to be determined. The adenosine A 2A receptors (A 2A Rs) are highly enriched in the striatopallidal neurons where they integrate dopamine and glutamate signals to modulate several cognitive behaviors, but their contribution to cognitive flexibility control is unclear. In this study, by coupling an automated operant cognitive flexibility task with striatal subregional knockdown (KD) of the A 2A R via the Cre-loxP strategy, we demonstrated that NAc A 2A R KD improved cognitive flexibility with enhanced attentional set-shifting and reversal learning by decreasing regressive and perseverative errors, respectively. This facilitation was not attributed to mnemonic process or motor activity as NAc A 2A R KD did not affect the visual discrimination, lever-pressing acquisition, and locomotor activity, but was associated with increased attention and motivation as evident by the progressive ratio test (PRT). In contrast to NAc A 2A Rs, DMS A 2A Rs KD neither affected visual discrimination nor improved set-shifting nor reversal learning, but promoted the effort-related motivation. Thus, NAc and DMS A 2A Rs exert dissociable controls of cognitive flexibility with NAc A 2A Rs KD selectively enhancing cognitive flexibility by facilitating strategy shifting with increased motivation/attention.

Striatopallidal adenosine A2A receptor modulation of goal-directed behavior: Homeostatic control with cognitive flexibility

“…Increasing evidence from diverse learning paradigms suggest that the activation of striatopallidal A 2A R exerts a selective inhibitory control on various cognitive behaviors, including working memory ( Augusto et al, 2013 ; Li et al, 2018a ), instrumental learning ( Li et al, 2016 , 2018a ), reversal learning and set-shifting ( Zhou et al, 2019 ), Pavlovian fear conditioning ( Wei et al, 2014 ), and goal-directed behavior ( Emtage et al, 2022 ; Li et al, 2016 , 2018b ). Thus, the comparison of global, forebrain-specific and striatum-specific A 2A R knockout (KO) models shows that the inactivation of striatal A 2A R is sufficient to enhance a variety of cognitive processes including working memory ( Wei et al, 2011 ), reversal learning ( Wei et al, 2011 ), goal-directed behavior ( Yu et al, 2009 ), Pavlovian fear conditioning ( Wei et al, 2014 ), effort-related decision making and effort expenditure ( Mingote et al, 2008 ; Sun et al, 2023 ) without affecting spatial reference memory, motor function, and anxiety-like behaviors in ‘control’ rodents.…”

“…This homeostatic control of goal-directed behavior by A 2A R signaling may constrain behavior processes from reaching extreme values: this allostatic property of striatopallidal A 2A R may enforce rigidity control (either goal-directed or habit) and may underlie the ability of striatopallidal A 2A R antagonism to preferentially enhance cognitive flexibility. Indeed, exploiting the Cre-loxP-mediated focal knockdown of A 2A R in the DMS and NAc, allowed demonstrating that the knockdown of A 2A R selectively in the NAc enhances cognitive flexibility by increasing set-shifting as well as reversal learning ( Li et al, 2020 ; Zhou et al, 2019 ). While the reduced number of regressive errors facilitates a new strategy in the set-shifting phase, the suppression of the preservative errors inhibits the previous strategy in the reversal phase.…”

“…These two distinct processes suggest that NAc A 2A R dually control cognitive flexibility by distinctly controlling different glutamatergic inputs into the NAc, from medial prefrontal cortical and orbitofrontal cortex, respectively ( Birrell and Brown, 2000 ; Cui et al, 2018 ; McAlonan and Brown, 2003 ). Thus, the knockdown of NAc A 2A R selectively improves attentional set-shifting by increasing the ability of learning and maintaining the new extradimensional strategy ( Li et al, 2020 ; Zhou et al, 2019 ). This view is also consistent with the observations that A 2A R KO enhances strategy shifting in the water maze paradigm ( Wei et al, 2011 ), and that treatment with caffeine (a non-selective A 2A R antagonist) significantly improves attention and cognitive deficits in an animal model of attention deficit and hyperactivity disorder ( Pandolfo et al, 2013 ).…”