Glucocorticoid-sensitive period of corticotroph development -- implications in early life stress

Abstract

Corticotrophs are intermediaries in the hypothalamic-pituitary-adrenal (HPA) axis, which plays a crucial role in vertebrates stress response. The HPA axis displays an intricate mode of negative feedback regulation, whereby the peripheral effector, cortisol inhibits the secretion of its upstream regulator, adrenocorticotropic hormone (ACTH) from proopiomelanocortin (POMC)-expressing cells in the pituitary. While the feedback regulation of the HPA axis is well characterized in the adult organism, the effect of feedback regulation on the development of corticotrophs is poorly understood. Here, we study the effect of glucocorticoids on the development of POMC-expressing cells in the zebrafish pituitary. The development of POMC cells displayed striking robustness in terms of their steady increase in numbers between 2-6 days post fertilization. Inhibition of endogenous glucocorticoid synthesis resulted in an increase in POMC cell number due to reduced developmental feedback inhibition of cortisol on POMC cells. Conversely, addition of exogenous dexamethasone at a critical developmental window led to a decrease in POMC cell number, mimicking greater feedback control. Finally, developmental dysregulation of ACTH levels resulted in impaired anxiety-like and stress-coping behaviours. Hence, we identified a sensitive developmental window for the effect of glucocorticoids on corticotrophs and demonstrate the downstream effect on stress-responsive behaviour.