Assessment of mGluR5 KO mice under conditions of low stress using a rodent touchscreen apparatus reveals impaired behavioural flexibility driven by perseverative responses

Jisoo Lim,Benjamin U Phillips,Timothy J Bussey,Eosu Kim,Dong Goo Kim,Christopher J Heath,Shinwon Kang,Lisa Saksida,Chul Hoon Kim,Hyun Jong Noh

doi:10.1186/s13041-019-0441-8

Abstract

Genetic and pharmacological manipulations targeting metabotropic glutamate receptor 5 (mGluR5) affect performance in behavioural paradigms that depend on cognitive flexibility. Many of these studies involved exposing mice to highly stressful conditions including electric foot shocks or water immersion and forced swimming. Because mGluR5 is also implicated in resilience and stress responses, however, apparent impairments in inhibitory learning may have been an artifact of manipulation-induced changes in affective state. To address this, we present here a characterization of cognitive flexibility in mGluR5 knockout (KO) mice conducted with a rodent touchscreen cognitive assessment apparatus in which the animals experience significantly less stress.Our results indicate a significant reversal learning impairment relative to wild-type (WT) controls in the two-choice Visual Discrimination-Reversal (VDR) paradigm. Upon further analysis, we found that this deficit is primarily driven by a prolonged period of perseveration in the early phase of reversal. We also observed a similar perseveration phenotype in the KO mice in the Extinction (EXT) paradigm. In addition, mGluR5 KO mice show higher breakpoints in the touchscreen Progressive Ratio (PR) and altered decision making in the Effort-related Choice (ERC) tasks. Interestingly, this impairment in PR is an additional manifestation of an increased propensity to perseverate on the emission of relatively simplistic behavioural outputs.Together, these findings suggest that under conditions of low stress, mGluR5 KO mice exhibit a pronounced perseverative phenotype that blunts cognitive flexibility.

Highlights

Behavioural flexibility is a key cognitive ability required for effectively addressing the demands of a constantly changing environment
We evaluated the cognitive flexibility of metabotropic glutamate receptor 5 (mGluR5) KO and WT littermates using a rodent touchscreen cognitive assessment apparatus [15, 16]
Results mGluR5 KO mice exhibit impaired reversal in the touchscreen two-choice Visual Discrimination-Reversal (VDR) task To evaluate the importance of mGluR5 in cognitive flexibility under low-stress conditions, we assessed a cohort of mGluR5 KO mice and WT littermates in the touchscreen two-choice VDR task using the ‘fan’ and ‘marbles’ stimuli (Fig. 1a) [16]

Summary

Introduction

Behavioural flexibility is a key cognitive ability required for effectively addressing the demands of a constantly changing environment. We evaluated the cognitive flexibility of mGluR5 KO and WT littermates using a rodent touchscreen cognitive assessment apparatus [15, 16] This platform exclusively uses appetitive reinforcement to avoid stress-related confounding effects. The use of computerized task delivery, data recording, and analysis ensures full standardization between chambers, as well as robust paradigm stability between sessions and the elimination of experimenter/ scorer bias within and across studies [16,17,18,19,20] These attributes contribute to high data reproducibility that enables direct comparisons of studies both within and between research groups [19, 21]

Methods

Results

Conclusion