Adenosine A2A Receptors in the Rat Prelimbic Medial Prefrontal Cortex Control Delay-Based Cost-Benefit Decision Making.

Douglas T Leffa,António C Silva,Nélio Gonçalves,Attila Köfalvi,Henrique B Silva,Samira G Ferreira,Pablo Pandolfo,Nuno J Machado,Joana I Real,Carolina M De Souza,Rodrigo A Cunha

doi:10.3389/fnmol.2018.00475

Abstract

Adenosine A2A receptors (A2ARs) were recently described to control synaptic plasticity and network activity in the prefrontal cortex (PFC). We now probed the role of these PFC A2AR by evaluating the behavioral performance (locomotor activity, anxiety-related behavior, cost-benefit decision making and working memory) of rats upon downregulation of A2AR selectively in the prelimbic medial PFC (PLmPFC) via viral small hairpin RNA targeting the A2AR (shA2AR). The most evident alteration observed in shA2AR-treated rats, when compared to sh-control (shCTRL)-treated rats, was a decrease in the choice of the large reward upon an imposed delay of 15 s assessed in a T-maze-based cost-benefit decision-making paradigm, suggestive of impulsive decision making. Spontaneous locomotion in the open field was not altered, suggesting no changes in exploratory behavior. Furthermore, rats treated with shA2AR in the PLmPFC also displayed a tendency for higher anxiety levels in the elevated plus maze (less entries in the open arms), but not in the open field test (time spent in the center was not affected). Finally, working memory performance was not significantly altered, as revealed by the spontaneous alternation in the Y-maze test and the latency to reach the platform in the repeated trial Morris water maze. These findings constitute the first direct demonstration of a role of PFC A2AR in the control of behavior in physiological conditions, showing their major contribution for the control of delay-based cost-benefit decisions.

Highlights

Adenosine A2A receptors (A2ARs) are mostly known to control long-term synaptic plasticity throughout the brain, namely in the prefrontal cortex (PFC) where they facilitate long-term potentiation (LTP) in excitatory synapses onto fast spiking interneurons and control network activity (Kerkhofs et al, 2018)
We evaluated if the downregulation of A2AR in the prelimbic medial PFC (PLmPFC) impacted on locomotor activity
We have recently reported that A2AR in the PLmPFC control long-term plasticity of excitatory synaptic transmission onto fast spiking interneurons (Kerkhofs et al, 2018) and that they are necessary for dopamine-induced decrease in population activity (Real et al, 2018)

Summary

Introduction

Adenosine A2A receptors (A2ARs) are mostly known to control long-term synaptic plasticity throughout the brain (reviewed in Cunha, 2016), namely in the prefrontal cortex (PFC) where they facilitate long-term potentiation (LTP) in excitatory synapses onto fast spiking interneurons and control network activity (Kerkhofs et al, 2018). While optogenetic activation of A2AR signaling pathways in the medial PFC improves maintenance of spatial working memory (Li et al, 2018), there are still no direct evidence supporting a role for the endogenous activation of A2AR in the PFC to modulate behavior This is of particular relevance since A2AR are present in different areas of the forebrain (i.e., cerebral cortex, hippocampus and striatum) with different impacts on different behavioral outputs, as heralded by the striking opposite phenotypes resulting from the selective deletion of A2AR from only the striatum or forebrain neurons (Shen et al, 2008, 2013; Wei et al, 2014). Our findings reveal that the downregulation of A2AR in the PLmPFC decreased the choice of the large reward in a T-maze-based cost-benefit paradigm in which the cost was delay, suggesting an increase in impulsive decision making, a finding relevant for disorders with impaired decision making, such as Parkinson’s disease, schizophrenia, ADHD and addiction (Lee, 2013)

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Results

Conclusion