Cinnamaldehyde, a major bioactive component of cinnamon bark, enhances social approach behavior associated with a liver–brain FGF21–isotocin axis in zebrafish

Abstract

Cinnamaldehyde is a major bioactive component of cinnamon bark and is widely consumed as a food-derived compound. However, its effects on social behavior and the underlying regulatory mechanisms remain poorly understood. In this study, we investigated the effects of cinnamon bark supplementation and cinnamaldehyde exposure on social behavior in adult zebrafish and investigated potential molecular and endocrine mechanisms. Adult zebrafish were fed a cinnamon bark-supplemented diet or exposed to cinnamaldehyde and subjected to a three-chamber social interaction test. Anxiety-like behavior, aggression, and spatial cognition were evaluated using the novel tank, aggression, and Y-maze tests, respectively. Gene expression and pharmacological analyses were performed to examine the involvement of neuroendocrine and metabolic signaling pathways. Cinnamon bark supplementation significantly enhanced heterospecific-directed social approach and interaction behaviors. Similarly, cinnamaldehyde exposure promoted social approach behavior without affecting locomotor activity or aggression. In addition, cinnamaldehyde reduced anxiety-like behavior and selectively upregulated isotocin- and GABA-related genes in the brain. Furthermore, cinnamaldehyde increased hepatic fgf21 expression and upregulated fgfr1 and klb in the brain. Intraperitoneal administration of FGF21 mimicked the behavioral and molecular effects of cinnamaldehyde, whereas pharmacological inhibition attenuated the effects of cinnamaldehyde. These findings suggest that cinnamon bark and its major component cinnamaldehyde may enhance social approach behavior through mechanisms involving a liver–brain FGF21–isotocin-related pathway in zebrafish. Our results highlight the potential of cinnamon-derived bioactive compounds as functional food-related ingredients for improving social functioning and mental well-being.