The Neuropeptide Fam19a5a/tafa5a Regulates Inflammation and Influences Anxiety‐Like Behaviours in Zebrafish

Anxiety is a future-oriented mood state that consists of a complex cognitive, affective, physiological and behavioural response system that prepares individuals for perceived or anticipated threats. Although the neural circuits underlying anxiety behaviours have been extensively studied, how inflammatory factors influence anxiety and the molecular links between them remains poorly understood. To gain novel insights into these mechanisms, we investigated the role of fam19a5a, a zebrafish ortholog of the human FAM19A5 gene, which encodes a secreted peptide, in anxiety-like responses. Gene expression analyses revealed widespread fam19a5a expression in anxiety-associated brain regions, including the septum, pallial amygdala and habenula. Using multiple behavioural assays and both loss-of-function and gain-of-function genetic models, we found that the loss of fam19a5a significantly reduced anxiety-like responses. Interestingly, neuronal overexpression of fam19a5a also reduced anxiety-like responses. Neuronal activity analysis showed altered activity in the septum, pallial amygdala and habenula in fam19a5a-knockout brain without changes in neurotransmitter levels. However, increased neuronal activity was observed in the preoptic area of neuronal fam19a5a-overexpressing zebrafish. Transcriptomic analyses revealed upregulation of anti-inflammatory chemokines and cytokines and downregulation of proinflammatory factors, in both fam19a5a-knockout and neuronal fam19a5a-overexpressing brains. All together, these findings suggest that fam19a5a regulates anxiety-like behaviours in zebrafish by modulating the anti-inflammatory chemokine/cytokine signalling pathways.