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
| Autor: | David M. Thomson, Clotilde Mannoury la Cour, Marianna Kouskou, Judith A. Pratt, Rebecca L. Openshaw, Millan Mark, Emma J Mitchell, Brian J. Morris |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Striatum Receptors G-Protein-Coupled Mice 03 medical and health sciences Behavioral Neuroscience Cognition Risk-Taking 0302 clinical medicine Reward Thalamus Genetics Animals Prefrontal cortex Radial arm maze Working memory Motor Cortex Cognitive flexibility Iowa gambling task Corpus Striatum Associative learning Mice Inbred C57BL Memory Short-Term 030104 developmental biology Neurology Psychology Neuroscience Gene Deletion 030217 neurology & neurosurgery |
| Zdroj: | Genes, Brain and Behavior. 20 |
| ISSN: | 1601-183X 1601-1848 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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