¹Boehringer Ingelheim Pharma GmbH en Co.KG, Neuroscience & Mental Health, Biberach an der Riss, Germany

Background: The trial unique non-matched to location (TUNL) task is a touchscreen-based assay of working memory in rodents. While pharmacological impairment is widely used in rats, pharmacological enhancement of performance in rats or mice has not been demonstrated in literature.

Aims & Objectives: We employed a recently optimized mouse version of the TUNL task to test compounds modulating glutamatergic and cholinergic signaling.

Method: Performance was assessed across varying cognitive loads, and functional ultrasound imaging was used to probe neural circuit activity.

Results: The muscarinic antagonist scopolamine impaired performance to chance levels, whereas the glycine transporter 1 inhibitor bitopertin significantly improved accuracy. Both bitopertin and the acetylcholinesterase inhibitor donepezil enhanced performance under high cognitive demand, while scopolamine reduced performance even on easier trials. Bitopertin also rescued deficits induced by the NMDA receptor antagonist MK-801. Furthermore, functional ultrasound imaging revealed that bitopertin prevented ketamine-induced alterations in cerebral blood volume within prefrontal, hippocampal, and thalamic regions.

Discussion & Conclusions: These findings establish the mouse TUNL task as a sensitive tool for detecting pharmacological modulation of working memory in both improvements and impairments. Bitopertin and donepezil show promise as cognitive enhancers, with bitopertin additionally counteracting NMDA receptor–mediated impairments.