The Free-movement pattern Y-maze: A cross-species measure of working memory and executive function

Abstract

Numerous neurodegenerative and psychiatric disorders are associated with deficits in executive functions such as working memory and cognitive flexibility. Progress in developing effective treatments for disorders may benefit from targeting these cognitive impairments, the success of which is predicated on the development of animal models with validated behavioural assays. Zebrafish offer a promising model for studying complex brain disorders, but tasks assessing executive function are lacking. The Free-movement pattern (FMP) Y-maze combines aspects of the common Y-maze assay, which exploits the inherent motivation of an organism to explore an unknown environment, with analysis based on a series of sequential two-choice discriminations. We validate the task as a measure of working memory and executive function by comparing task performance parameters in adult zebrafish treated with a range of glutamatergic, cholinergic and dopaminergic drugs known to impair working memory and cognitive flexibility. We demonstrate the cross-species validity of the task by assessing performance parameters in adapted versions of the task for mice and Drosophila, and finally a virtual version in humans, and identify remarkable commonalities between vertebrate species' navigation of the maze. Together, our results demonstrate that the FMP Y-maze is a sensitive assay for assessing working memory and cognitive flexibility across species from invertebrates to humans, providing a simple and widely applicable behavioural assay with exceptional translational relevance.

Dopaminergic Modulation of Working Memory and Cognitive Flexibility in a Zebrafish Model of Aging-Related Cognitive Decline

“…Recording percentage-use of reoccurring patterns of four consecutive turn choices, known as tetragrams, over one hour of exploration gives rise to a 'global' search strategy. Similar exploration strategies, predominantly reliant on alternations, have been reported in rodents, both in the FMP Y-maze and T-maze using the same analysis (Cleal et al, 2020;Gross et al, 2011). Behavioural assessment of one hour of free exploration in the FMP Y-maze enables the identification of working memory abilities and cognitive flexibility, presenting the FMP Y-maze as a useful tool for assessing memory processing in animal models and potentially patients with disorders characterised by cognitive decline.…”

“…All other sequences were used at a level equivalent to chance selection. Prior wsork from our group has demonstrated that changes in global spatial activity patterns, particularly those relating to alternations and repetitions, are representative of changes in working memory processing (Cleal, et al, 2020). Previous work has also demonstrated similar patterns of alternations in young adult zebrafish ranging from 3-6-months old (Cleal & Parker, 2018;Fontana, Cleal, Clay, et al, 2019).…”

“…Fish were housed in groups of ~10-12 fish per 2.8L tank on a re-circulating system (Aquaneering Inc., San Diego, CA, USA), aquarium-water was maintained at pH 8.4 (±0.4). Previous work from our group and extensive pilot studies were used to calculate power analysis and inform sample sizes used in this study (Cleal et al, 2020;Cleal & Parker, 2018;Fontana, Cleal, Clay, et al, 2019). Room and tank temperatures were maintained at 25-27°C on a 14/10-hour light/dark cycle.…”

The cognitive and behavioral effects of D-amphetamine and nicotine sensitization in adult zebrafish

“…Here, we aimed to establish whether young-adult zebrafish develop cognitive or psychomotor sensitization to repeated administrations of AMPH and NIC, as assessed through the impact on working memory, locomotor activity, and cognitive flexibility. To do this, we used an established behavioral assay for zebrafish that has high translational relevance to humans, the FMP Y-maze (Cleal et al 2020). We assessed locomotor activity, working memory, and behavioral flexibility at four time points: baseline (prior to any drug exposure), chronic exposure (14 days of drug exposure), withdrawal (2 days without drug), and finally following drug challenge (single, repeat drug exposure).…”

Enhanced olfactory memory performance in trap-design Y-mazes allows the study of novel memory phenotypes inDrosophila

“…Y-maze setups allowing free movement are common in rodent studies to measure spatial working memory and exploratory behaviour (Kraeuter, Guest and Sarnyai, 2019) . Miniature single fly Y-mazes have been used in flies for the same purpose (Buchanan, Kain and de Bivort, 2015;Lewis et al , 2017;Cleal et al , 2020) . Y-mazes have also been used for naive and learned odour preferences in insects other than flies (Dupuy et al , 2006;Carcaud et al , 2009;Josens, Eschbach and Giurfa, 2009) .…”