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.

Optogenetic induction of chronic glucocorticoid exposure in early-life impairs stress-response in larval zebrafish

“…We observed strong and selective suppression of pomc expression in the rostral pars distalis of the pituitary gland in transgenic larval zebrafish at 6 dpf. This is similar to reports wherein larval zebrafish were exogenously treated with dexamethasone, a selective GR agonist (Liu et al 2003; To et al 2007; Peles, Swaminathan, and Levkowitz 2022), demonstrating the effect of greater GC negative feedback control and that this group of pituitary pomc -expressing cells is involved in the control of interrenal steroidogenesis and cortisol synthesis. This suppression of pomc expression thus could be a contributing factor for the blunted GC phenotype owing possibly due to lack of ACTH release upon stressor exposure.…”

Altered glucocorticoid reactivity and behavioral phenotype in rx3-/- larval zebrafish

“…Avp is however also coexpressed in Crh cells ( 53 – 57 ), and those cells project to the adenohypophysis, which does form at least partially and would explain the sparse and faint innervation we see there. The specific loss of pomc expression in the rostral adenohypophyseal corticotrope cluster (rostral pomc -93%, caudal pomc +44%) was also observed after treatment with the GR agonist dexamethasone ( 8 , 9 , 58 ) and after chronic optogenetic interrenal steroidogenic cell activation ( 59 ).…”