Dopaminergic modulation of working memory and cognitive flexibility in a zebrafish model of aging-related cognitive decline.

Healthy aging is associated with a decline in memory and executive function, which have both been linked with aberrant dopaminergic signaling. We examined the relationship between cognitive performance and dopamine function of young and aging zebrafish (Danio rerio). We revealed age-related decreases in working memory and cognitive flexibility in the Free-Movement Pattern (FMP) Y-maze. An increase in drd5 gene expression in aging adults coincided with a decrease in cognitive performance. Treatment with a D1/D5 receptor agonist (SKF-38393, 35 µM) 30 minutes prior to behavioral assessment resulted in improved working memory in aging zebrafish, but no effect in younger adults. However, an "overdosing" effect caused by agonist treatment resulted in downregulation of dat expression in 6-month old, treated zebrafish. The translational relevance of these findings was tested in humans by analyzing exploratory behavior in young-adult, 18-35-year olds, and aged adults, 70+ year olds, in a virtual FMP Y-maze. Our findings revealed similar age-related decline in working memory. Thus, strongly supporting zebrafish as a translational model of aging and cognitive decline.