Early-life stimulation (e.g., brief handling) attenuates the behavioral and neuroendocrine responses to stressors encountered in adulthood, particularly with respect to activation of hypothalamic-pituitary-adrenal (HPA) activity. In contrast, if neonates were subjected to a more severe stressor, such as protracted separation from the dam or exposure to an endotoxin, then the adult response to a stressor was exaggerated. These early-life experiences program HPA functioning, including negative feedback derived from stimulation of hippocampal glucocorticoid receptors, and corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) coexpression in PVN neurons, to modify the response to subsequent stressor experiences. The persistent variations of HPA activity observed in handled/stimulated animals may stem from alterations in dam-pup interactions (e.g. increased arched-back feeding, licking, grooming). In addition genetic makeup is critical in determining stress reactivity. For instance, BALB/cByJ mice are more reactive to stressors than C57BL/6ByJ mice, exhibiting greater HPA hormonal alterations and behavioral disturbances. BALB/cByJ also fail to acquire a spatial learning response in a Morris water-maze paradigm, which has been shown to be correlated with hippocampal cell loss associated with aging. Early-life handling of BALB/cByJ mice prevented these performance deficits and attenuated the hypersecretion of ACTH and corticosterone elicited by stressors. The stressor reactivity may have been related to maternal and genetic factors. When BALB/cByJ mice were raised by a C57BL/6ByJ dam, the excessive stress-elicited HPA activity was reduced, as were the behavioral impairments. However, cross-fostering the more resilient C57BL/6ByJ mice to a BALB/cByJ dam failed to elicit the behavioral disturbances. It is suggested that genetic factors may influence dam-pup interactive styles and may thus proactively influence the response to subsequent stressors among vulnerable animals. In contrast, in relatively hardy animals the early-life manipulations may have less obvious effects.

Following stressor exposure BALB/cByJ mice exhibit hypersecretion of corticosterone and marked brain catecholamine alterations. In addition, mice of this strain exhibit impairments of performance in a Morris water-maze, which may be exacerbated by footshock application. In the present investigation it was demonstrated that early-life handling of mouse pups (coupled with brief separation periods from the dam over the course of 21 days postpartum) reduced the learning impairments seen when mice were tested in the Morris water-maze at 120 days of age and also prevented stress-induced disturbances in this task. Likewise, cross-fostering BALB/cByJ mice with a C57BL/6ByJ dam prevented the performance deficits. In contrast, C57BL/6ByJ mice cross-fostered to a BALB/cByJ dam exhibited proficient performance. Thus, maternal factors may be important in determining the Morris water-maze disturbances, provided that this was applied on the BALB/cByJ genetic background. Stressor exposure exacerbated the performance disturbances in BALB/cByJ mice, while diazepam treatment disrupted Morris water-maze performance in both BALB/cByJ and C57BL/6ByJ mice. Paralleling the behavioral changes associated with handling, the stress-induced hypercorticosterone secretion characteristic of the BALB/cByJ mouse was attenuated by the early handling procedure. Stressor exposure also produced strain-dependent variations of NE and 5-HT, but these effects were not appreciably influenced by the handling procedure. These data are consistent with the proposition that performance disturbances of BALB/cByJ mice tested in the Morris water-maze task are associated with excessive hypothalamic-pituitary-adrenal reactivity. Moreover, it appears that the influence of early-life stimulation may interact with genetic factors in determining endocrine and behavioral stress responses.

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