Locomotor response to acute stressors requires hypothalamic-pituitary-interrenal axis activation and glucocorticoid receptor

When vertebrates face acute stressors, their bodies rapidly undergo a repertoire of physiological and behavioral adaptations, which is termed the stress response (SR). Rapid physiological changes in heart rates and blood sugar levels occur via the interaction of glucocorticoids and their cognate receptors following hypothalamic-pituitary-adrenal (HPA) axis activation. These physiological changes are observed within minutes of encountering a stressor and the rapid time domain rules out genomic responses that require gene expression changes. Although behavioral changes corresponding to physiological changes are commonly observed, it is not clearly understood to what extent HPA axis activation dictates adaptive behavior. We hypothesized that rapid locomotor response to acute stressors in zebrafish requires HPI axis activation. In teleost fish, interrenal cells (I) are functionally homologous to the adrenal gland cortical layer. We derived 8 frameshift mutants in genes involved in HPI axis function: two mutants in exon 2 of mc2r (adrenocorticotropic hormone receptor), two in each of exon 2 and exon 5 of nr3c1 (glucocorticoid receptor), and two in exon 2 of nr3c2 (mineralocorticoid receptor). Exposing larval zebrafish to mild environmental stressors, acute changes in salinity or light illumination, results in a rapid locomotor response. We show here that this locomotor response requires a functioning HPI axis via the action of mc2r (adrenocorticotropic hormone receptor) and the canonical glucocorticoid receptor encoded by nr3c1 gene, but not mineralocorticoid receptor ( nr3c2 ). Our rapid behavioral assay paradigm based on HPI axis biology may prove useful to screen for genetic, pharmacological, or environmental modifiers of the HPA axis.