Ferulic acid eicosyl ester enhances cognitive flexibility and modulates arousal-related neural circuits in mice

Cognitive deficits are a major contributor to disability in numerous neuropsychiatric and neurodegenerative disorders, yet effective pharmacological treatments remain limited. Ferulic acid eicosyl ester (FAE-20), a natural constituent of the plant Rhodiola rosea, has previously been identified as an enhancer of simple forms of Pavlovian conditioning in flies, bees, and mice. Here, we investigated whether FAE-20 has further potential to enhance cognitive flexibility, working memory, or spatial learning in mice, and explored potential neurobiological mechanisms underlying such enhancement. Cognitive flexibility was assessed using the attentional set-shifting task (ASST). Subchronic FAE-20 treatment significantly improved ASST performance in both male and female young adult mice, indicating enhanced cognitive flexibility. In contrast, no effects were observed on spatial working memory, assessed by spontaneous alternations in the Y-maze, or on spatial learning in the Barnes maze in either young or aged mice. Notably, FAE-20 enabled spatial learning in the Barnes maze in a subgroup of aged mice that failed to learn the task under vehicle treatment. Histological analyses using c-Fos immunohistochemistry as a marker of neural activity and doublecortin expression and spine density as markers of hippocampal plasticity revealed sex-specific effects on components of the ascending arousal system. FAE-20 increased the activation of orexinergic neurons in the lateral hypothalamus of male mice, whereas it reduced the activity of cholinergic neurons in the laterodorsal tegmental nucleus of females. No effects were detected on hippocampal neurogenesis or dendritic spine density. These findings suggest that the cognitive effects of FAE-20 are selective, depending on the cognitive demands of the task and the baseline cognitive abilities of the animals, and may be mediated, at least in part, by modulation of arousal-related neural circuits.