Early life challenge enhances cortisol regulation in zebrafish larvae

The hypothalamic-pituitary-adrenal (HPA) axis in mammals or hypothalamic-pituitary-interrenal (HPI) axis in fish is thought to function as an open system that adapts to the environment during development. We used larval zebrafish to explore how early life challenge (ELC) impacts the early stage of this process. ELC, induced by sustained involuntary swimming at 5 days post-fertilization (dpf), altered subsequent stress responsiveness. At 6 dpf, larvae exposed to ELC showed similar baseline cortisol levels but reduced cortisol reactivity to an initial stressor. Notably, they also showed increased cortisol reactivity to a second stress event within a 30-minute refractory period, when the cortisol response is usually suppressed. Whole-body qPCR revealed upregulation of genes involved in cortisol metabolism and stress modulation, including hsd11b2, cyp11c1, star, crh, oxt, crhr1, pomca, nr3c2, nr3c1, and fkbp5. Challenged larvae also showed fewer crh-, avp-, and oxt-positive cells in the nucleus preopticus (NPO), homologous to the mammalian paraventricular nucleus, with diminished co-expression of crh and avp. Altogether, the results suggest that at the early stage of HPI axis adaptation, ELC optimizes cortisol regulation by preventing excess levels while ensuring adequate release during homotypic stress. Follow-up work should examine the impact of ELC on steroidogenic interrenal cell activity and the maturation of stress circuits in the NPO.