Effects of D1 agonist on working memory and cognitive flexibility in a zebrafish model of aging

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.