Short-term effects and long-term consequences of neonatal HPA activation

Abstract

The stress hyporesponsive period (SHRP) is a time of relative quiescence of the hypothalamic-pituitary-adrenal (HPA) axis spanning postnatal days (P) 3--14, during which the HPA axis is actively inhibited from responding to most stresses. It is unclear how repeated, brief isolation activates the neonatal stress response. The goal of this thesis was to answer several questions about the corticosterone response produced on P9 by repeated episodes of isolation: (1) is this paradigm effective at stimulating the neonatal HPA axis when it falls entirely within the SHRP? (2) is the corticosterone response associated with ACTH release? (3) does this manipulation have consequences for adult stress responsiveness? and (4) is 5-HT an important mediator of HPA activation during the SHRP? The current work demonstrated that as few as 5 episodes of brief isolation induce an ACTH response to isolation stress on P9, and that it is also sufficient to induce a corticosterone response in females. Thus, the female adrenal may be more sensitive to modest plasma ACTH elevations during the SHRP. Adult rats isolated as neonates exhibit heightened behavioral responses to stressful stimuli. Following 1 hour restraint stress neonatal isolates selectively avoid the center of an open field, and female isolates exhibit fewer rears. On the elevated plus maze isolates explored the open arms less than the closed arms, further suggesting a more anxious behavioral profile for isolated rats. This increased anxiety did not translate into altered HPA function in these rats, either at baseline or in response to 20 minutes of restraint stress. Additionally, the current work shows that a single injection of a 5-HT2A/2C agonist can significantly stimulate all levels of the HPA axis on P9 without significant disruption of maternal care. However, this manipulation is insufficient to have enduring consequences on adult behavior or HPA function. Finally, we present evidence that 5,7-DHT may be severely toxic to neonatal rats, and that this toxicity may be unrelated to any 5-HT depletion. This work indicates the type of stress experienced early in life is a critical determinant in the behavioral stress profile of the adult rat.