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

Abstract

Part of the natural aging process is a decline in memory and executive function, even in the absence of disease. The dopaminergic system has been implicated in age associated alterations in cognitive flexibility and working memory. Here we examine the relationship between cognitive performance and dopamine function of young-adult and aging zebrafish (Danio rerio). We reveal an age-related decrease in working memory and cognitive flexibility when faced with a negative feedback loop for informing search strategies in the Free-Movement Pattern (FMP) Y-maze. We additionally found a selective role for dopamine D1-like receptor activation, by treatment with partial D1/D5 receptor agonist SKF-38393, for enhancing working memory performance in aged zebrafish, but not for restoring behavioural flexibility. We additionally noted that baseline performance levels were critical to the effect of SKF-38393 on cognitive flexibility. This reduction in behavioural plasticity was accompanied by a down-regulation of the dopamine transporter (dat) and a decrease in metabolic activity. Together, these findings suggest a selective role for cognitive enhancement via dopamine D1 receptors; however, beneficial effects are dependent on behavioural task and baseline performance, emphasising the need for caution when treating cognitive deficits with dopamine agonists to improve cognitive impairment of some tasks. This study further supports the use of zebrafish as a model of aging and cognitive decline.

Behavioral profile of adult zebrafish acutely exposed to a selective dopamine uptake inhibitor, GBR 12909

“…Poorer habituation in zebrafish treated by 1 mg/L GBR 12909, seen in the present study, strikingly recapitulates reduced spatial working memory reported in the DAT knockout mice (Li et al, 2010). Somewhat similar working memory decline is also observed in adult zebrafish with reduced DAT expression following a dopamine D1/D5 receptor agonist SKF-38393 treatment at young ages (Cleal et al, 2021a). Natural rise of zebrafish locomotion in the habituation test was reduced by GBR 12909 at all doses used here (Supplemental Table S1), paralleling similar effects of a relatively novel DAT inhibitor, CE-123, thus attenuating an alcohol-induced hyperactivity in rats (Gibula-Tarlowska et al, 2021).…”

The effects of two stressors on working memory and cognitive flexibility in zebrafish (Danio rerio): The protective role of D1/D5 agonist on stress responses

“…The FMP Y-maze has shown that different species such as zebrafish, rats and humans adopt alternations (rlrl or lrlr) as the main strategy to escape from the maze (Cleal et al, 2020). In zebrafish, during 1 hour of testing, the animals tend to increase their alternations up to 40 minutes (peak of activity) which then reduces due to the energy demanding nature of the task (Cleal et al, 2021;Cleal et al, 2020). Researchers have concluded the percentage of alternations during the test is correlated with overall working memory, with changes in behavior over the course of the task reflective of behavioral adaptability and cognitive flexibility (Cleal et al 2020).…”