Abstract
Anxiety refers to emotional responses triggered by discrete environmental factors that lead to defensive behaviors. Although the neural circuits underlying anxiety behaviors have been extensively studied, the molecular mechanisms involved in anxiety remain poorly understood. In this study, we explored the role of fam19a5a, a zebrafish ortholog of the human FAM19A5 gene encoding a secreted peptide, in anxiety responses. We conducted gene expression and behavioral analyses. Additionally, we measured the brain neuronal activity and analyzed the transcriptomes to elucidate the cellular and molecular mechanisms underlying the function of fam19a5a in anxiety-like responses. Gene expression analyses revealed a broad expression of zebrafish fam19a5a in anxiety-associated brain regions, including the septum, pallial amygdala, and habenula. Using multiple behavioral paradigms and genetic models for loss-of-function and gain-of-function studies, we demonstrated that loss of fam19a5asignificantly reduced anxiety-like behaviors, unlike those previously reported in Fam19a5 knockout mice. Moreover, neuronal overexpression of fam19a5a diminished anxiety-like responses. Neuronal activity analysis revealed altered activity in the septum, pallial amygdala, and habenula in the fam19a5a-knockout brain, without changes in neurotransmitter levels. However, elevated neuronal activity was observed in the preoptic area of the neuronal fam19a5a-overexpressing brain. Transcriptomic analyses revealed upregulation of anti-inflammatory chemokine/cytokine levels and downregulation of pro-inflammatory factor levels in both fam19a5a-knockout and neuronal fam19a5a-overexpressing brains. In summary, our findings suggest that fam19a5a regulates anxiety-like behaviors in zebrafish by modulating the anti-inflammatory chemokine/cytokine signaling pathways.