When considering postnatal stimulus saliency, maternal interactions with offspring are paramount. Interactions between the mother and offspring are complex, and not only are they important for meeting the nutritional requirements of the offspring, they also provide warmth and tactile stimulation. Considerable literature exists regarding the importance of maternal contact on the psychological development of primates; however, more recent attention has focused on how important maternal and peer contact are for the developing endocrine (12
) and immune systems (see review, ref. 26
). Mitogen-induced lymphocyte proliferation is reduced in monkeys that as infants were subjected to early separation (i.e., maternal or peer). In-depth analyses of the effects of early rearing environments on immune functioning reveal that 2-year-old rhesus monkeys that had been reared in a nursery have reduced CD8+
cell numbers and lowered NK cell cytotoxicity, but increased mitogen-induced lymphocyte proliferation up to 2.5 years of age, relative to controls that were reared by their mothers (26
). Monkeys that had been separated on multiple occasions from their mothers early in life also showed long-term suppression of cell-mediated immune responses. However, the data also differentiate between the impact of rearing conditions and that of intermittent maternal separation. It is difficult to confirm whether increased immune responses seen in offspring reared under nursery conditions might also reflect differences in pathogen exposure early in life compared with mother-raised infants. It is also uncertain whether the increase in cell-mediated activity reflects the removal of maternal influences or stress. Analysis of the immediate impact of maternal separation on lymphocyte proliferation in infant primates reveals that immune disturbances are most notable in those infants that displayed greater behavioral responses to the separation procedure. Over a 14-day separation, mitogen-induced lymphocyte proliferation responses drop significantly relative to preseparation base-line levels in infant bonnet monkeys. Levels return to base line once these infants are reunited with their mothers (26
). In addition to exogenous in vitro measures of immune activity, maternal separation has also been shown to disrupt the normal balance of intestinal microflora in infant rhesus monkeys (27
). Those infants displaying the strongest emotional reactions to separation were found to display the greatest drop in microflora and to be more susceptible to opportunistic bacterial infections. Maternal separation thus appears to be stressful for primates and to alter the risk of disease both immediately during and after the separation and far into adulthood.
Rodent models investigating the importance of maternal factors in development of endocrine and immune systems have largely used maternal separation/deprivation or neonatal handling paradigms. What is interesting about these neonatal manipulations is that they exert opposing effects on HPA function. “Handling” involves separation of the dam from the nest for 15–20 minutes per day. Following handling sessions, dams generally exhibit increased nesting bouts and manipulation of offspring, and it has been suggested that this increase in maternal behavior is the determining factor mediating the long-term effects of handling on development of the HPA axis and stress responsiveness (12
). This observation is further supported by data indicating that HPA stress responses to maternal separation in rat pups can be altered by tactile stimulation (28
). Stroking rat pups with a brush while they are separated from their mother dampens ACTH responses, while feeding alters both corticosterone and ACTH responses (28
). These data suggest that maternal interactions with pups during early development represent more than maintenance of nest temperature and provision of milk, i.e., that manipulation of offspring and maternal behaviors are important factors that can modulate the impact of early life stress. Maccari and colleagues (29
) elegantly demonstrate the importance of maternal behavior in determining endocrine development in a study where offspring from prenatally stressed dams were cross-fostered/adopted to other dams. These authors found that, regardless of the prenatal stress condition, cross-fostering increased maternal interactions with offspring, reversing the effects of prenatal stress on HPA stress responsivity. Consequently, it appears that plasticity, at least with respect to HPA development in rodents, extends to the first weeks of life and that postnatal events can have opposing effects to prenatal pressures on developing neuroendocrine systems.
As adults, neonatally handled animals generally exhibit dampened HPA stress responses, and greater negative feedback regulation of HPA responses than nonhandled animals (see ref. 5
). Neonatal handling in mice enhances cell-mediated immune responses such as NK cell cytotoxicity and mitogen-induced lymphocyte proliferation in adult mice (30
). In contrast, differences in immune responsiveness between handled and nonhandled rats were not as pronounced or have not been consistently observed for either antibody responses or predisposition to tumors (31
). However, the long-term effects of handling on neuro-immune interactions become more obvious when the animals are stressed. Thus, following exposure to either acute cold stress or chronic intermittent cold stress, the plaque-forming response to sheep erythrocytes is decreased to a similar extent for both handled and nonhandled animals (31
). If, however, the chronically stressed animals are re-exposed to the stressor, immune responses are suppressed even further in the nonhandled animals, but no further suppression is seen for the handled animals (31
), suggesting that while antibody responses are suppressed in the chronically stressed handled animals, they are better able to contend with subsequent stress exposure than are nonhandled animals.
The effects of neonatal handling with respect to susceptibility to disease are more difficult to interpret. Handling increases susceptibility to experimental allergic encephalomyelitis (EAE), increasing both incidence and severity of the clinical signs of the pathology (33
). In addition to dampening HPA responses, handling may promote long-lasting alterations in the cellular and molecular environments in the brain that increase susceptibility to EAE in adult life (34
). However, neonatal handling does not appear to alter susceptibility to another autoimmune condition, adjuvant-induced arthritis (AA) (11
). It might be expected that animals with lower HPA activity would prove more susceptible or exhibit more severe inflammation, but circulating levels of corticosterone and altered peptide expression within the paraventricular nucleus of the hypothalamus in response to the AA inflammation are similar in handled and nonhandled animals, a finding that may account for the similar symptom profiles observed between these two experimental groups (11
In contrast to the neonatal handling effects, adult animals maternally deprived or exposed to a longer duration of maternal separation during development generally display increased HPA responses to stress as adults (see review, ref. 13
) and decreased plaque-forming cell responses. Laban et al. (35
) have noted that maternal deprivation exerts the opposite effects on susceptibility to EAE, where both the neurological and the histological signs of the inflammation are suppressed compared with those in control animals. However, these researchers also observed that early weaning of pups exacerbated both the clinical signs and the histological lesions of EAE. Maternal factors and early life stress may, therefore, interact and alter long-term predisposition to inflammation as a consequence of increased HPA activity.
Administration of dexamethasone to neonatal rats has also been found to exert long-term effects changing susceptibility to inflammatory disease. Bakker and colleagues (36
) injected rat pups with dexamethasone or saline during the first week of life. When the animals were 8 weeks of age, the researchers assessed the HPA responses to acute inflammatory challenge (i.e., an LPS injection), macrophage cytokine production, and induced EAE. They observed that animals administered dexamethasone as neonates had significantly lower plasma corticosterone responses to LPS challenge and that macrophages from these animals produced lower levels of inflammatory cytokines, whereas splenocytes expressed greater increased levels of mRNA for IFN-γ and TNF-β. Interestingly, these animals exhibited increased incidence and severity of EAE relative to saline treated controls. These researchers also suggest that exposure to glucocorticoid during early development may have implications for intrathymic T cell selection events resulting in long-term changes in immune reactivity. These data further illustrate the interactive nature of the endocrine and immune systems during development and that exposure to synthetic glucocorticoids can exert permanent programming effects on the neuro-immune interface.
In addition to behavioral variables, milk-borne factors should not be ruled out as having an important role in the development of neuro-immune interactions. Lactation is unique to the mammalian species and not only serves to provide nutrition to offspring but plays an important role in the development of immune and possibly endocrine function. Both breast milk and colostrum are complex matrices containing hormones, lymphocytes, antibodies, and cytokines. These immune and endocrine signals are transferred to offspring and are thought to prepare the developing organism to deal with environmental challenges and pathogens. Glucocorticoids and other steroids present in milk are important for the offspring’s normal respiratory, gut, endocrine, and CNS development. Corticosterone administered to lactating dams can be passed to offspring and elevate circulating steroid levels in rat pups (37
). As adults, these animals show dampened corticosterone stress responses, increased central steroid receptor levels, and altered behavior. The permanent alterations seen in these animals are strikingly similar to profiles seen in neonatally handled animals, and it could be suggested that mild stress due to handling procedures might provoke maternal HPA responses and thus contribute to handling effects on development of offspring. The observation that maternal glucocorticoids influence endocrine development in offspring also suggests that postnatal maternal stress could alter CNS, endocrine, and possibly immune development. Postnatal maternal immune activity may similarly alter development of progeny. In particular, induction of EAE prior to pregnancy or during lactation reduced susceptibility to EAE in offspring (38
). These effects do not depend on the disease severity in the dams, and the greatest protection is seen for animals where the dam was immunized shortly after delivery, when the refractory period was during lactation. Only pups nursed by immunized dams were protected, whether born to immunized or nonimmunized dams. Protection therefore does not appear to be related to antibody passively transferred to the neonate, suggesting that other immune or even endocrine factors transferred via colostrum or milk can affect susceptibility to inflammation over the long term.
Most of the attention concerning long-term effects of early life environment has been on how endocrine or behavioral factors influence the development of the immune system and neuroendocrine regulation of immune function. However, given the bidirectional communication between the two systems, stimuli that elicit an immune response may similarly program the developing CNS and endocrine systems. Administration of IL-1β to mouse pups during the first week of life has been shown to alter corticosterone and ACTH levels in adult mice and to increase splenocyte responses to allogeneic antigens (39
). Neonatal rats treated with a low dose of endotoxin during the first week of life exhibit increased HPA stress responsiveness as adults (10
). Adult animals that had been administered endotoxin during development show greater corticosterone and ACTH stress responses, perhaps reflecting both increased drive of the HPA axis by increased hypothalamic peptide release and less efficient negative feedback inhibition consequent to lower glucocorticoid receptor levels in the CNS (10
). Basal secretion patterns are also increased in adult animals that have been exposed to endotoxin as neonates, and these animals exhibit increased anxiety and behavioral stress reactivity (11
). However, the most striking feature of these animals is that, as adults, they do not develop paw inflammation subsequent to induction of AA, although, like control animals, their levels of corticosterone increase and hypothalamic corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) mRNA expression are altered following adjuvant administration (11
). Exposure to acute inflammatory stimuli during development, while obviously altering HPA regulation and stress responsiveness, thus appears to also alter the regulation of inflammation by neuroendocrine factors. Consistent with this view, splenocyte proliferation to LPS is more sensitive to stress factors when the cells are collected from adult animals that had been neonatally exposed to endotoxin. Corticosterone responses to intravenous injection of LPS are also accelerated in these animals relative to controls (11
It is apparent, therefore, that both prenatal and postnatal environmental factors can influence HPA development, alter stress responsiveness, and alter predisposition to inflammation. Predisposition to inflammation appears to be tightly linked to the responsivity of the HPA axis. While regulation of the onset of inflammation and predisposition to autoimmune disease are multifaceted, it has been suggested that in adult animals immune factors (e.g., tolerance) affect disease susceptibility, whereas HPA responsiveness dictates disease severity (4
). However, as is apparent from the developmental literature, endocrine activity can alter the developing immune system and might, therefore, also dictate disease vulnerability.