Mouse Behavior on the Trial-Unique Nonmatching-to-Location (TUNL) Touchscreen Task Reflects a Mixture of Distinct Working Memory Codes and Response Biases.

The trial-unique nonmatching to location (TUNL) touchscreen task shows promise as a translational assay of working memory (WM) deficits in rodent models of autism, ADHD, and schizophrenia. However, the low-level neurocognitive processes that drive behavior in the TUNL task have not been fully elucidated. In particular, it is commonly assumed that the TUNL task predominantly measures spatial WM dependent on hippocampal pattern separation, but this proposition has not previously been tested. In this project, we tested this question using computational modeling of behavior from male and female mice performing the TUNL task (N = 163 across three datasets; 158,843 trials). Using this approach, we empirically tested whether TUNL behavior solely measured retrospective WM, or whether it was possible to deconstruct behavior into additional neurocognitive subprocesses. Overall, contrary to common assumptions, modeling analyses revealed that behavior on the TUNL task did not primarily reflect retrospective spatial WM. Instead, behavior was best explained as a mixture of response strategies, including both retrospective WM (remembering the spatial location of a previous stimulus) and prospective WM (remembering an anticipated future behavioral response) as well as animal-specific response biases. These results suggest that retrospective spatial WM is just one of a number of cognitive subprocesses that contribute to choice behavior on the TUNL task. We suggest that findings can be understood within a resource-rational framework, and use computational model simulations to propose several task-design principles that we predict will maximize spatial WM and minimize alternative behavioral strategies in the TUNL task.SIGNIFICANCE STATEMENT Touchscreen tasks represent a paradigm shift for assessment of cognition in nonhuman animals by automating large-scale behavioral data collection. Their main relevance, however, depends on the assumption of functional equivalence to cognitive domains in humans. The trial-unique, delayed nonmatching to location (TUNL) touchscreen task has revolutionized the study of rodent spatial working memory. However, its assumption of functional equivalence to human spatial working memory is untested. We leveraged previously untapped single-trial TUNL data to uncover a novel set of hierarchically ordered cognitive processes that underlie mouse behavior on this task. The strategies used demonstrate multiple cognitive approaches to a single behavioral outcome and the requirement for more precise task design and sophisticated data analysis in interpreting rodent spatial working memory.

High sucrose diet does not impact spatial cognition in rats using advanced touchscreen technology.

INTRODUCTION: Western diets, including those consisting of saturated fats, simple sugars and processed foods, is rising at an unprecedented rate. These lead to obesity and metabolic diseases, and possibly cognitive deficits. Exploring this, recent studies demonstrate marked impairment in spatial learning in rodents exposed to high-sugar diets. We utilised advanced touchscreen technology to assess several spatial and non-spatial components of cognition in rats chronically exposed to a high sucrose diet. METHODS: Male Wistar rats received 70 ml of 10% sucrose solution each day, or control tap water, persisting for the experiment duration (total n = 32). After 5 weeks of diet, rats performed Pairwise Discrimination, Location Discrimination, or Progressive Ratio tasks on automated touchscreens, and performance compared between groups. RESULTS: Sucrose rats consumed all the sugar solution provided to them, and had significantly increased caloric intake, compared to controls (p < 0.0001). However, in all tests, we found no significant difference in cognitive performance between Sucrose and Control treated rats. This included the number of trials for acquisition, and reversal, in Pairwise Discrimination, and number of trials required to complete Location Discrimination (p > 0.05 for all outcomes). No differences were observed in perseverative behaviour, motivation levels, or processing speed. CONCLUSION: Our study found no evidence to suggest that chronic consumption of sucrose impairs cognition, including both spatial and non-spatial learning tasks. These findings suggest that not all aspects of spatial cognition are negatively impacted by high sugar diet in rodents, and that particular use of touchscreen technology may probe different aspects of cognition than traditional tasks.

MK-801 impairs working memory on the Trial-Unique Nonmatch-to-Location test in mice, but this is not exclusively mediated by NMDA receptors on PV+ interneurons or forebrain pyramidal cells.

NMDA receptors (NMDAr) are widely expressed throughout the brain on many cell types, and loss of function of these receptors (ie: NMDAr hypofunction) is a candidate mechanism explaining working memory impairment in schizophrenia. However, the cellular source driving the working memory deficits caused by NMDAr hypofunction has not been explored. The aim of this study was to assess the contribution of NMDAr on pyramidal cells and parvalbumin (PV+) interneurons to impairments in working memory induced by NMDAr hypofunction. We excised GluN1 - the gene encoding the obligatory subunit of the NMDAr - from PV + interneurons or CaMKIIα+ pyramidal cells using Cre-lox technology. Adult male PV GluN1 KO (n = 10) and CaMKIIα GluN1 KO mice (n = 9) and WT controls (n = 10 and n = 13) were trained to perform the Trial-Unique Nonmatching-to-Location (TUNL) task of working memory. Once trained, mice received the NMDAr antagonist MK-801 (0.1 and 0.3 mg/kg ip), and working memory assessed. Neither task acquisition nor working memory differed between the two transgenic lines and WT littermates. MK-801 dose-dependently decreased working memory accuracy in all strains (p < 0.001). PV GluN1 KO mice were sensitised to the impairing effects of MK-801 (p = 0.04), whereas CaMKIIα GluN1 KO mice showed equivalent working memory deficits as WT. Developmental NMDAr hypofunction at either PV+ interneurons or forebrain pyramidal cells is not sufficient to impair working memory, and neither of these cell types exclusively mediates working memory impairment caused by NMDAr antagonism. Reduced NMDAr signalling at PV+ interneurons could predispose circuits to NMDAr hypofunction magnifying deficits in working memory.

NMDA receptors on parvalbumin-positive interneurons and pyramidal neurons both contribute to MK-801 induced gamma oscillatory disturbances: Complex relationships with behaviour.

BACKGROUND: NMDAr antagonists induce disturbances to gamma frequency oscillations, including increasing ongoing gamma activity and reducing evoked gamma oscillations. We sought to investigate the role parvalbumin (PV+) neurons and CaMKIIα+ pyramidal cells in NMDAr antagonist-induced disturbances in gamma oscillatory activity and relate these to common behavioural consequences of these drugs by selectively deleting the obligatory GluN1 subunit from these cells in mice. METHODS: Adult mice (total n = 99) with GluN1 deleted from PV interneurons (PV:GluN1 KO) or CaMKIIα+ pyramidal cells (CaMKIIα:GluN1 KO), and WT littermates, were used. We assessed effects of the NMDAr antagonist MK-801 on prepulse inhibition (PPI) and locomotor behaviour. Then, mice were implanted with electrodes in the prefrontal cortex (mPFC) and hippocampus (dHPC), and the effects of MK-801 on gamma oscillations assessed. RESULTS: In WT mice, MK-801 increased ongoing gamma power, reduced evoked gamma power and increased gamma coherence. These changes were accompanied by hyperlocomotion and deficient PPI. The consequences of NMDAr antagonism were differentially regulated in the transgenic mice. The MK-801-induced increase in ongoing gamma power was significantly attenuated in both transgenic strains, but deficits to evoked gamma activity were unaffected by genotype. Deficient PPI was not affected by genotype, and only in PV:GluN1 KO mice was the hyperlocomotor phenotype of MK-801 attenuated. The emergence of abnormal gamma band hyperconnectivity between the mPFC and dHPC was absent in CaMKIIα:GluN1 KO mice. CONCLUSION: This study suggests that the effects of NMDAr antagonism on gamma band responses and behaviour have complex relationships, and rely on different populations of neurons.

The mGluR2/3 agonist LY379268 reverses NMDA receptor antagonist effects on cortical gamma oscillations and phase coherence, but not working memory impairments, in mice.

BACKGROUND: Abnormalities in neural oscillations that occur in the gamma frequency range (30-80 Hz) may underlie cognitive deficits in schizophrenia. Both cognitive impairments and gamma oscillatory disturbances can be induced in healthy people and rodents by administration of N-methyl-D-aspartate receptor (NMDAr) antagonists. AIMS: We studied relationships between cognitive impairment and gamma abnormalities following NMDAr antagonism, and attempted to reverse deficits with the metabotropic glutamate receptor type 2/3 (mGluR2/3) agonist LY379268. METHODS: C57/Bl6 mice were trained to perform the Trial-Unique Nonmatching to Location (TUNL) touchscreen test for working memory. They were then implanted with local field potential (LFP) recording electrodes in prefrontal cortex and dorsal hippocampus. Mice were administered either LY379268 (3 mg/kg) or vehicle followed by the NMDAr antagonist MK-801 (0.3 or 1 mg/kg) or vehicle prior to testing on the TUNL task, or recording LFPs during the presentation of an auditory stimulus. RESULTS: MK-801 impaired working memory and increased perseveration, but these behaviours were not improved by LY379268 treatment. MK-81 increased the power of ongoing gamma and high gamma (130-180 Hz) oscillations in both brain regions and regional coherence between regions, and these signatures were augmented by LY379268. However, auditory-evoked gamma oscillation deficits caused by MK-801 were not affected by LY379268 pretreatment. CONCLUSIONS: NMDA receptor antagonism impairs working memory in mice, but this is not reversed by stimulation of mGluR2/3. Since elevations in ongoing gamma power and regional coherence caused by MK-801 were improved by LY379268, it appears unlikely that these specific oscillatory abnormalities underlie the working memory impairment caused by NMDAr antagonism.