Early Life Stress Increases Disease Susceptibility in Adulthood

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Early life stress modulates neural and neuroendocrine mechanisms in host defence and autoimmunity, thereby predisposing to adult disease susceptibility. Here, we reported on opposing effects of MD and HA on a diversity of diseases like asthma, multiple sclerosis, and periodontitis. Summarizing, MD increases, whereas HA decreases, disease susceptibility to all investigated disease models. Furthermore, HA prolongs the pain threshold, decreases anxiety-like behavior, and improves motor function and explorative behaviors, whereas MD induces more or less opposite-like effects. Denenberg and Karas (1959) summarized different experiments and stated that handled animals weighed most, learned best, and lived longest. The question is, how are these effects mediated?

First, postnatal handling and maternal deprivation have been shown to program adult HPA responsiveness (Ladd et al., 2000). However, based on our data, we are tempted to conclude that the demonstrated effects are far beyond oppositional directed changes of the HPA axis but rather due to complex modifications of several regulatory systems that contribute to an altered stress responsiveness and disease susceptibility in adulthood. Otherwise, it would not be allegeable that HA decreases whereas MD increases disease susceptibility of all investigated diseases, because corticosterone should exert protective effects on asthma as well as on multiple sclerosis, while it should aggravate the course of periodontitis. In addition, ACTH levels increased in handled rats during the course of the asthma-like inflammation, thereby protecting from increased symptoms. Therefore, the hypothesis that MD leads to a higher stress responsiveness and HPA axis activity has to be revised. More recently, other regulatory systems such as the gonadal axis and the peripheral nervous system have also come into focus (Straub and Cutolo, 2001; Bedoui et al., 2003) and are worthy of further investigation.

Second, postnatal experiences are powerful enough to induce long-term immunological changes, as indicated by different disease susceptibility, but little is known about possible mediators. Before we started the various experiments, we hypothesized MD induces a Th1-Th2 shift. But we had to abandon our hypothesis, because we observed that EAE was aggravated, though a Th2 shift should have had protective effects. Also, the cytokine profiles have not been consistent during the course of different diseases.

Third, it has been reported that postnatal stress effects CNS plasticity (McEwen, 2001), possibly via different BDNF expression profiles (Kuma et al., 2004; Roceri et al., 2004). Another mediator of altered neurogenesis in adulthood after MD has been suggested by Mirescu and collegues (2004), who reported that maternally deprived rats show "a decrease in cell proliferation and immature neuron production" in the dentate gyrus. They hypothesized "that early adverse experience inhibits structural plasticity via hypersensitivity to glucocorticoids and diminishes the ability of the hippocampus to respond to stress in adulthood." Furthermore, the long-term adaptations in glucocorticoid receptor and mineralocorticoid receptor have been recently decribed by Ladd and colleagues (2004). Moreover, there are many implications of postnatal manipulations—or even rearing conditions—for maturation of regulatory systems, cognition, and growth.

Interestingly, we were able to rescue from aggravated diseases by treating maternally deprived rats with imipramine. Because imipramine is an antidepressant drug, it raises the question of whether MD is really a model for schizophrenia—as Ellenbrook and Cools suggested (2004)—or a model for depression-like diseases. During the daily deprivation session, maternally deprived rats huddle together in a corner of the cage and remain there totally inactive. In contrast, handled rats are active, even as young pups, showing directed movements, running around, sniffing, and licking similar to older pups when their eyes were opened. After the short period of separation, handled pups and their dams are reunited, which may be interpreted as a reward for their searching behavior. As a hypothesis, one can argue that MD induces a "learned helplessness-like" phenotype while handled rats exhibit "learned competence-like" responses.

Summarizing, the postnatal environment causes a complex interplay of endocrine and immunological parameters, as well as of maturation and plasticity that induces long-term effects that program the individual to show altered disease susceptibility in adulthood.

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