Glucocorticoid‐sensitive period of corticotroph development—Implications for mechanisms of early life stress

Abstract

Corticotrophs are intermediaries in the hypothalamic–pituitary–adrenal (HPA) axis, which plays a crucial role in stress response in vertebrates. 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 studied the effect of glucocorticoids on the development of POMC‐expressing cells in the zebrafish pituitary. The development of POMC cells showed a 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 corticotroph cell number, mimicking greater feedback control due to increased cortisol levels. 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 leads to blunted stress‐response in larval zebrafish

“…We observed strong and selective suppression of pomca 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; Peles et al, 2023; To et al, 2007), demonstrating the effect of greater GC negative feedback control and that this group of pituitary pomca ‐expressing cells regulated by cortisol. This suppression of pomc a expression thus could be a contributing factor for the blunted GC phenotype possibly due to lack of ACTH release upon stressor exposure.…”

Advances in peptide modulation in systems physiology

“…Hernandez‐Perez et al 1 provide a novel example of how two neuropeptides, vasopressin and pituitary adenylate cyclase‐activating polypeptide (PACAP), interact to transmit prosocial need when the organism is under homeostatic challenge, by a circuit from the hypothalamus to the cortex via a ‘hub’ in the amygdaloid complex. In line with this, Peles et al 2 provide new evidence on shaping of the regulatory peptide architecture and action within the stress axis in the adult zebrafish, and what can be learned with this versatile model organism. Sabban et al 3 report potential benefits of intranasal neuropeptide Y administration in the treatment of post‐traumatic stress disorder (PTSD) using a rodent model, including sustained extinction of fear memory.…”