with behaviour disorders such as attention deficits, schizophrenia, anxiety and depression; self-reported maternal stress is associated with a higher irritability, emotional and attentional problems. there is growing evidence that prenatal stress can affect hpa regulation in humans. children who were stressed prenatally may show altered cortisol rhythms. for example, several studies have found an association between maternal depression during pregnancy and childhood cortisol levels. prenatal stress has also been implicated in a tendency toward depression and short attention span in childhood. early life stress the role of early life stress in programming the hpa axis has been well-studied in animal models. exposure to mild or moderate stressors early in life has been shown to enhance hpa regulation and promote a lifelong resilience to stress. in contrast, early-life exposure to extreme or prolonged stress can induce a hyper-reactive hpa axis and may contribute to lifelong vulnerability to stress. in one widely replicated experiment, rats subjected to the moderate stress of frequent human handling during the first two weeks of life had reduced hormonal and behavioral hpa-mediated stress responses as adults, whereas rats subjected to the extreme stress of prolonged periods of maternal separation showed heightened physiological and behavioral stress responses as adults. several mechanisms have been proposed to explain these findings in rat models of early-life stress exposure. there may be a critical period during development during which the level of stress hormones in the bloodstream contribute to the permanent calibration of the hpa axis. one experiment has shown that, even in the absence of any environmental stressors, early-life exposure to moderate levels of corticosterone was associated with stress resilience in adult rats, whereas exposure to high doses was associated with stress vulnerability. another possibility is that the effects of early-life stress on hpa functioning are mediated by maternal care. frequent human handling of the rat pups may cause their mother to exhibit more nurturant behavior, such as licking and grooming. nurturant maternal care, in turn, may enhance hpa functioning in at least two ways. first, maternal care is crucial in maintaining the normal stress hypo responsive period (shrp), which in rodents, is the first two weeks of life during which the hpa axis is generally non-reactive to stress. maintenance of the shrp period may be critical for hpa development, and the extreme stress of maternal separation, which disrupts the shrp, may lead to permanent hpa dysregulation. another way that maternal care might influence hpa regulation is by causing epigenetic changes in the offspring. for example, increased maternal licking and grooming has been shown to alter expression of the glutocorticoid receptor gene implicated in adaptive stress response. at least one human study has identified maternal neural activity patterns in response to video stimuli of mother-infant separation as being associated with decreased glucocorticoid receptor gene methylation in the context of post-traumatic stress disorder stemming from early life stress. yet clearly, more research is needed to determine if the results seen in cross-generational animal models can be extended to humans. though animal models allow for more control of experimental manipulation, the effects of early life stress on hpa axis function in humans has also been studied. one population that is often studied in this type of research is adult survivors of childhood abuse. adult survivors of childhood abuse have exhibited increased acth concentrations in response to a psychosocial stress task compared to unaffected controls and subjects with depression but not childhood abuse. in one study, adult survivors of childhood abuse that are not depressed show increased acth response to both exogenous crf and normal cortisol release. adult survivors of childhood abuse that are depressed show a blunted acth response to exogenous crh. a blunted acth response is common in depression, so the authors of this work posit that this pattern is likely to be due to the participant's depression and not their exposure to early life stress. heim and colleagues have proposed that early life stress, such as childhood abuse, can induce a sensitization of the hpa axis, resulting in particular heightened neuronal activity in response to stress-induced crh release. with repeated exposure to stress, the sensitized hpa axis may continue to hypersecrete crh from the hypothalamus. over time, crh receptors in the anterior pituitary will become down-regulated, producing depression and anxiety symptoms. this research in human subjects is consistent with the animal literature discussed above. the hpa axis was present in the earliest vertebrate species, and has remained highly conserved by strong positive selection due to its critical adaptive roles. the programming of the hpa axis is strongly influenced by the perinatal and early juvenile environment, or "early-life environment". maternal stress and differential degrees of caregiving may constitute early life adversity, which has been shown to profoundly influence, if not permanently alter, the offspring's stress and emotional regulating systems. widely studied in animal models (e.g. licking and grooming/lg in rat pups), the consistency of maternal care has been shown to have a powerful influence on the offspring's neurobiology, physiology, and behavior. whereas maternal care improves cardiac response, sleep/wake rhythm, and growth hormone secretion in the neonate, it also suppresses hpa axis activity. in this manner, maternal care negatively regulates stress response in the neonate, thereby shaping his/her susceptibility to stress in later life. these programming effects are not deterministic, as the environment in which the individual develops can either match or mismatch with the former's "programmed" and genetically predisposed hpa axis reactivity. although the primary mediators of the hpa axis are known, the exact mechanism by which its programming can be modulated during early life remains to be elucidated. furthermore, evolutionary biologists contest the exact adaptive value of such programming, i.e. whether heightened hpa axis reactivity may confer greater evolutionary fitness. various hypotheses have been proposed, in attempts to explain why early life adversity can produce outcomes ranging from extreme vulnerability to resilience, in the face of later stress. glucocorticoids produced by the hpa axis have been proposed to confer either a protective or harmful role, depending on an individual's genetic predispositions, programming effects of early-life environment, and match or mismatch with one's postnatal environment. the predictive adaptation hypothesis (1), the three-hit concept of vulnerability and resilience (2) and the maternal mediation hypothesis (3) attempt to elucidate how early life adversity can differentially predict vulnerability or resilience in the face of significant stress in later life. these hypotheses are not mutually exclusive but rather are highly interrelated and unique to the individual. (1) the predictive adaptation hypothesis: this hypothesis is in direct contrast with the diathesis stress model, which posits that the accumulation of stressors across a lifespan can enhance the development of psychopathology once a threshold is crossed. predictive adaptation asserts that early life experience induces epigenetic change; these changes predict or "set the stage" for adaptive responses that will be required in his/her environment. thus, if a developing child (i.e., fetus to neonate) is exposed to ongoing maternal stress and low levels of maternal care (i.e., early life adversity), this will program his/her hpa axis to be more reactive to stress. this programming will have predicted, and potentially be adaptive in a highly stressful, precarious environment during childhood and later life. the predictability of these epigenetic changes is not definitive, however – depending primarily on the degree to which the individual's genetic and epigenetically modulated phenotype "matches" or "mismatches" with his/her environment (see: hypothesis (2)). (2) three-hit concept of vulnerability and resilience: this hypothesis states that within a specific life context, vulnerability may be enhanced with chronic failure to cope with ongoing adversity. it fundamentally seeks to explicate why, under seemingly indistinguishable circumstances, one individual may cope resiliently with stress, whereas another may not only cope poorly, but consequently develop a stress-related mental illness. the three "hits" – chronological and synergistic – are as follows: genetic predisposition (which predispose higher/lower hpa axis reactivity), early-life environment (perinatal – i.e. maternal stress, and postnatal – i.e. maternal care), and later-life environment (which determines match/mismatch, as well as a window for neuroplastic changes in early programming). (figure 1)6 the concept of match/mismatch is central to this evolutionary hypothesis. in this context, it elucidates why early life programming in the perinatal and postnatal period may have been evolutionarily selected for. specifically, by instating specific patterns of hpa axis activation, the individual may be more well equipped to cope with adversity in a high-stress environment. conversely, if an individual is exposed to significant early life adversity, heightened hpa axis reactivity may "mismatch" him/her in an environment characterized by low stress. the latter scenario may represent maladaptation due to early programming, genetic predisposition, and mismatch. this mismatch may then predict negative developmental outcomes such as psychopathologies in later life. ultimately, the conservation of the hpa axis has underscored its critical adaptive roles in vertebrates, so, too, various invertebrate species over time. the hpa axis plays a clear role in the production of corticosteroids, which govern many facets of brain development and responses to ongoing environmental stress. with these findings, animal model research has served to identify what these roles are – with regards to animal development and evolutionary adaptation. in more precarious, primitive times, a heightened hpa axis may have served to protect organisms from predators and extreme environmental conditions, such as weather and natural disasters, by encouraging migration (i.e. fleeing), the mobilization of energy, learning (in the face of novel, dangerous stimuli) as well as increased appetite for biochemical energy storage. in contemporary society, the endurance of the hpa axis and early life programming will have important implications for counseling expecting and new mothers, as well as individuals who may have experienced significant early life adversity.