Accumbal Adenosine A2A Receptors Enhance Cognitive Flexibility by Facilitating Strategy Shifting.

Jianhong Zhou,Tingting Li,Yuwei Dai,Xingjun Chen,Beibei Wu,Xiangxiang Lin,Wu Zheng,Sergii Vakal,Wei Guo,Jiang-Fan Chen

doi:10.3389/fncel.2019.00130

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 A2A receptors (A2ARs) 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 A2AR via the Cre-loxP strategy, we demonstrated that NAc A2AR 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 A2AR 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 A2ARs, DMS A2ARs KD neither affected visual discrimination nor improved set-shifting nor reversal learning, but promoted the effort-related motivation. Thus, NAc and DMS A2ARs exert dissociable controls of cognitive flexibility with NAc A2ARs KD selectively enhancing cognitive flexibility by facilitating strategy shifting with increased motivation/attention.

Highlights

Cognitive flexibility is an essential executive function that enables individuals and species to adapt to new surroundings in the constantly changing environment and can be divided into two distinct components including attentional set-shifting and reversal learning
Optical intensity analysis of the A2A receptors (A2ARs) immunostaining confirmed that the expression level of A2AR in the nucleus accumbens (NAc) was decreased by 71% after transfection with AAV8-CAG-Cre-ZsGreen, as compared with the NAc transfected with AAV8-CAG-ZsGreen (Figure 1C)
The important finding in this study is that NAc A2AR KD enhances cognitive flexibility by increasing set-shifting as well as reversal learning

Summary

Introduction

Cognitive flexibility is an essential executive function that enables individuals and species to adapt to new surroundings in the constantly changing environment and can be divided into two distinct components including attentional set-shifting (extra-dimensional shifting) and reversal learning (intra-dimensional shifting). As the primary brain region receiving cortical glutamatergic inputs, striatum plays an essential role in neuronal control of cognitive flexibility. NAc has been shown to be critical to control cognitive flexibility (Haluk and Floresco, 2009; Ding et al, 2014; Cui et al, 2018). This NAc control of cognitive flexibility may be associated with NAc ability to modulate attention (Christakou et al, 2004; Salgado and Kaplitt, 2015), working memory (Takahashi et al, 2011; Laplante et al, 2012) and goal-directed behavior (Mannella et al, 2013). DMS has an important role in the control of cognitive flexibility and other cognitive behavior (Li et al, 2016, 2018; Kato et al, 2018; Zhu et al, 2018)

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Results

Conclusion