Variations in maternal care affect the development of individual differences in neuroendocrine responses to stress in rats. As adults, the offspring of mothers that exhibited more licking and grooming of pups during the first 10 days of life showed reduced plasma adrenocorticotropic hormone and corticosterone responses to acute stress, increased hippocampal glucocorticoid receptor messenger RNA expression, enhanced glucocorticoid feedback sensitivity, and decreased levels of hypothalamic corticotropin-releasing hormone messenger RNA. Each measure was significantly correlated with the frequency of maternal licking and grooming (all r's > -0.6). These findings suggest that maternal behavior serves to "program" hypothalamic-pituitary-adrenal responses to stress in the offspring.

The mothers of infant rats show individual differences in the frequency of licking͞grooming and archedback nursing (LG-ABN) of pups that contribute to the development of individual differences in behavioral responses to stress. As adults, the offspring of mothers that exhibited high levels of LG-ABN showed substantially reduced behavioral fearfulness in response to novelty compared with the offspring of low LG-ABN mothers. In addition, the adult offspring of the high LG-ABN mothers showed significantly (i) increased central benzodiazepine receptor density in the central, lateral, and basolateral nuclei of the amygdala as well as in the locus ceruleus, (ii) increased ␣ 2 adrenoreceptor density in the locus ceruleus, and (iii) decreased corticotropin-releasing hormone (CRH) receptor density in the locus ceruleus. The expression of fear and anxiety is regulated by a neural circuitry that includes the activation of ascending noradrenergic projections from the locus ceruleus to the forebrain structures. Considering the importance of the amygdala, notably the anxiogenic influence of CRH projections from the amygdala to the locus ceruleus, as well as the anxiolytic actions of benzodiazepines, for the expression of behavioral responses to stress, these findings suggest that maternal care during infancy serves to ''program'' behavioral responses to stress in the offspring by altering the development of the neural systems that mediate fearfulness.The development of responses to stress in the rat is influenced by the early postnatal environment (for reviews see refs. 1-3). Thus, postnatal handling during the first week of life decreases behavioral fearfulness and hypothalamic-pituitary-adrenal (HPA) responses under conditions of stress. These effects persist throughout the life of the animal (4, 5) and form a basis for vulnerability to stress-related disease (6).The handling paradigm reflects the remarkable plasticity that exists within neural systems that mediate responses to stress. The manipulation is actually rather subtle. Handled pups are simply removed from the nest for 3-15 min and then reunited with the mother. Handling does not represent a period of maternal deprivation, because over the course of the day mothers are routinely off their nests for periods of 20-25 min (see refs. 7-9). At the same time the artificial and nonspecific nature of the handling paradigm is unsettling (see refs. 10 and 11). Under natural conditions, development in the rat typically occurs in the rather dark, tranquil confines of a burrow where the major source of stimulation is that of the mother and littermates: there is little here that resembles the disruption associated with human handling. However, several studies have shown that postnatal handling actually alters the behavior of the mother toward her pups, leading to the idea that the effects of postnatal handling may be mediated by changes in mother-pup interactions (1, 12, 13).In the Norway rat, mother-pup contact occurs primarily within the context of a nest-bout, which b...