Impaired working memory, cognitive flexibility and reward processing in mice genetically lacking Gpr88: Evidence for a key role for Gpr88 in multiple cortico‐striatal‐thalamic circuits,Genes, Brain and Behavior

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Impaired working memory, cognitive flexibility and reward processing in mice genetically lacking Gpr88: Evidence for a key role for Gpr88 in multiple cortico‐striatal‐thalamic circuits
Genes, Brain and Behavior ( IF 2.4 ) Pub Date : 2020-10-19 , DOI: 10.1111/gbb.12710
David M Thomson ₁ , Rebecca L Openshaw ₁ , Emma J Mitchell ₁ , Marianna Kouskou ₁ , Mark J Millan ₂ , Clotilde Mannoury la Cour ₂ , Brian J Morris ₃ , Judith A Pratt ₁

Affiliation

The GPR88 orphan G protein‐coupled receptor is expressed throughout the striatum, being preferentially localised in medium spiny neurons. It is also present in lower densities in frontal cortex and thalamus. Rare mutations in humans suggest a role in cognition and motor function, while common variants are associated with psychosis. Here we evaluate the influence of genetic deletion of GPR88 upon performance in translational tasks interrogating motivation, reward evaluation and cognitive function. In an automated radial arm maze ‘N‐back’ working memory task, Gpr88 KO mice showed impaired correct responding, suggesting a role for GPR88 receptors in working memory circuitry. Associative learning performance was similar to wild‐type controls in a touchscreen task but performance was impaired at the reversal learning stage, suggesting cognitive inflexibility. Gpr88 KO mice showed higher breakpoints, reduced latencies and lengthened session time in a progressive ratio task consistent with enhanced motivation. Simultaneously, locomotor hyperactivity was apparent in this task, supporting previous findings of actions of GPR88 in a cortico‐striatal‐thalamic motor loop. Evidence for a role of GPR88 in reward processing was demonstrated in a touchscreen‐based equivalent of the Iowa gambling task. Although both Gpr88 KO and wild‐type mice showed a preference for an optimum contingency choice, Gpr88 KO mice selected more risky choices at the expense of more advantageous lower risk options. Together these novel data suggest that striatal GPR88 receptors influence activity in a range of procedures integrated by prefrontal, orbitofrontal and anterior cingulate cortico‐striatal‐thalamic loops leading to altered cognitive, motivational and reward evaluation processes.

中文翻译：

Gpr88基因缺失小鼠的工作记忆、认知灵活性和奖励处理受损：Gpr88在多个皮质-纹状体-丘脑回路中的关键作用的证据

GPR88 孤儿 G 蛋白偶联受体在整个纹状体中表达，优先定位于中等多刺神经元中。它也以较低的密度存在于额叶皮层和丘脑中。人类罕见的突变表明在认知和运动功能中起作用，而常见的变异与精神病有关。在这里，我们评估了 GPR88 基因缺失对翻译任务中表现的影响，包括动机、奖励评估和认知功能。在自动径向臂迷宫“N-back”工作记忆任务中，Gpr88KO 小鼠的正确反应受损，表明 GPR88 受体在工作记忆电路中发挥作用。联想学习表现与触摸屏任务中的野生型对照相似，但在逆向学习阶段表现受损，表明认知不灵活。Gpr88 KO 小鼠在与增强的动机一致的渐进比例任务中表现出更高的断点、减少的延迟和延长的会话时间。同时，在这项任务中，运动过度活跃很明显，这支持了 GPR88 在皮质-纹状体-丘脑运动环中的作用的先前发现。GPR88 在奖励处理中的作用的证据在基于触摸屏的爱荷华州赌博任务中得到证明。虽然Gpr88KO 和野生型小鼠表现出对最佳应急选择的偏好，Gpr88 KO 小鼠选择了风险更大的选择，而牺牲了更有利的低风险选择。这些新数据共同表明，纹状体 GPR88 受体影响一系列由前额叶、眶额叶和前扣带回皮质-纹状体-丘脑环整合的程序中的活动，从而导致认知、动机和奖励评估过程的改变。

更新日期：2020-10-19

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