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Development of affective disorders: The legacy of prenatal stress Stefania
Maccari The origin of certain affective disorders is the subject of much neurobiological research and a new hypothesis is currently gaining ground. It is based on the idea of "in utero programming" of adult diseases, thus revealing the decisive importance of the nine months of pregnancy for the rest of the child’s life, and that of the adult it will become. All sorts of early environmental influences can leave indelible imprints and influence the development of offspring. It would certainly seem that environmental factors significantly influence cerebral ontogenesis during the critical prenatal and postnatal periods. Nonetheless, the true impact of these factors remains difficult to assess. We have been interested in this phenomenon, in its broader sense, for some years, wondering about the possible long-term consequences for the fetus of modifications to the maternal environment. In humans, these modifications can be engendered after a period of maternal stress during pregnancy, a situation known to be responsible for delayed neurological development, hyperemotivity, and sleep disorders in children. The psychological state of the mother, in particular her anxiety level during pregnancy, can influence the development of the fetus. Our study of the influence of prenatal stress in rodents is based on an animal model developed by my team in the Bordeaux laboratory of Professor Le Moal (INSERM Unit 259 "Psychobiology of adaptive behaviors"). We showed that rats subjected to stress during the prenatal period exhibit greater vulnerability to drugs at an adult age and higher levels of anxiety (correlated with high levels of corticosterone) following a stress event. These effects due to prenatal stress continue as the subject ages. Studies carried out on circadian rhythms indicate a modification in the activity of the biological clock in rats subjected to stress in utero: an increase in the duration of paradoxical sleep is observed in these animals. These behavioral effects result from permanent modifications to the functioning of the brain. In the research we have carried out into the neurobiological mechanisms responsible for such dysfunctions, we have shown that the hypothalamic-pituitary-adrenal (HPA) axis is hyperstimulated after a prenatal stress event. These animals also show a deficiency in the feedback mechanisms of the HPA axis: the secretion of corticosterone is prolonged and associated with a reduction in the capacity of the central receptors to bind with glucocorticoids. Our recent results also show that rats subjected to stress during the prenatal period show a phase-advance in the circadian rhythm of corticosterone. Dysfunction of the HPA axis may be due to modifications in the synthesis and/or release of certain neurotransmitters such as acetylcholine. All of these results show that prenatal stress in rats leads to behavioral and neuroendocrinal dysfunctions which bear certain similarities to those encountered in human depression (sleep fragmentation, increased anxiety, drug-taking behavior, deficiency in the retrocontrol mechanisms of the HPA axis, hyperactivity of the cholinergic system). Within the context of the development of new therapeutic strategies to combat depression, a number of studies have highlighted the importance of validating animal models. The fact is that in healthy subjects most antidepressants are not very effective. The animal model affected by "prenatal stress syndrome" is an interesting model of depression because of the behavioral, hormonal and neurobiological disturbances it produces in the long term. We therefore studied, by means of various behavioral tests, the effects on prenatal stress of tianeptine and imipramine, two leading antidepressants. These two antidepressants seem to be effective in reversing the effects of prenatal stress in a forced swimming test (Porsolt test). We also tested the effect of a melatonin agonist on rats subjected to stress during their fetal development. This agonist proved to be as effective as leading antidepressants, suggesting the possible usefulness of this type of molecule in treating depression. Another line of research is dedicated to the study of the mechanisms by which stress experienced by the mother can engender these effects in her offspring. The working hypothesis is that modifications linked to maternal stress in the hormonal environment of the fetus, lead to short and long term neurobiological modifications in the offspring by means of placental and hematoencephalic exchange, together with aspects of the postnatal environment (maternal milk and behavior). We have shown that certain long-term effects of prenatal stress seem to be secondary in importance to the increase in maternal corticosterone during prenatal stress. These results are in line with the work carried out in humans showing that a correlation exists between maternal and fetal cortisol levels. Maternal behavior after birth also seems to play an important role. We have shown that adoption or a change in maternal environment after birth reduces the effects induced by prenatal stress and that this is due, in part, to an “increase” in maternal behavior on the part of the adoptive mothers. Stéfania Maccari Laboratory of Behavioral Neurosciences ("Laboratoire des neurosciences du comportement") University of Lille 1, Villeneuve d'Ascq Tel: +33 3 20 43 40 83 Email: Stefania.Maccari@univ-lille1.fr
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