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Séminaire - Stefania Maccari Grandma's curse in the prenatal stress rat model

Abstract :

Early life stress may program offspring susceptibility to lifelong health problems and there is increasing evidence that developmental programming by an altered intrauterine environment can be passed across generations. In rats, we have previously shown that prenatal restraint stress (PRS) induces long-lasting biochemical and behavioral changes, which result into expression of an anxious/depressive phenotype. In mice PRS increases expression of type-1 DNA methyl transferase in the frontal cortex and induces epigenetic changes in mGlu2/3 metabotropic glutamate receptors. 

Here we examined the transgenerational effect of PRS in rats by mating first-generation (F1) PRS females rats with naïve males. Remarkably, most of the behavioral and neurobiological alterations associated with PRS persisted in the second-generation (F2), despite the fact that these males were reared normally (i.e not directly exposed to stress in utero). We observed enhanced anxiety-like behavior, prolonged corticosterone response to stress, and increased BDNF and reduced mGlu2/3 receptor expression in the hippocampus in both F1 and F2 rats. In addition, we identified several genes stably regulated by PRS that were transmitted to F2 generation by a microarray analysis of the hippocampal transcriptome and we observed a hypomethylation of the BDNF promoter and a hypermethylation of the MR glucocorticoid receptors.

Since vulnerability to stress-related disorders can be epigenetically programmed by maternal behavior we scored dams exposed to the repeated restraint stress during gestation (F0, grandmothers) as well as in their female offspring (F1, mothers). Gestational stress in grandmothers markedly reduced the amount of nursing and licking/grooming behavior, and enhanced anxiety during and after lactation. Interestingly, PRS stress affected very mildly maternal behavior in F1 dams and had no effect on their anxiety-like profile. Our results show that the pathological programming induced by PRS in rats can be transmitted across generations and that transmission involves at least in part mechanisms independent of maternal behavior.

Selected publications

1: Marrocco J, Mairesse J, Bucci D, Lionetto L, Battaglia G, Consolazione M, Ravasi L, Simmaco M, Morley-Fletcher S, Maccari S, Nicoletti F. Early life stress causes refractoriness to haloperidol-induced catalepsy. Mol Pharmacol. 2013 Aug;84(2):244-51.

2: Marrocco J, Mairesse J, Ngomba RT, Silletti V, Van Camp G, Bouwalerh H, Summa M, Pittaluga A, Nicoletti F, Maccari S, Morley-Fletcher S. Anxiety-like behavior of prenatally stressed rats is associated with a selective reduction of glutamate release in the ventral hippocampus. J Neurosci. 2012 Nov 28;32(48):17143-54.

3: Laloux C, Mairesse J, Van Camp G, Giovine A, Branchi I, Bouret S, Morley-Fletcher S, Bergonzelli G, Malagodi M, Gradini R, Nicoletti F, Darnaudéry M, Maccari S. Anxiety-like behaviour and associated neurochemical and endocrinological alterations in male pups exposed to prenatal stress. Psychoneuroendocrinology. 2012 Oct;37(10):1646-58.

4: Mairesse J, Silletti V, Laloux C, Zuena AR, Giovine A, Consolazione M, van Camp G, Malagodi M, Gaetani S, Cianci S, Catalani A, Mennuni G, Mazzetta A, van Reeth O, Gabriel C, Mocaer E, Nicoletti F, Morley-Fletcher S, Maccari S. Chronic agomelatine treatment corrects the abnormalities in the circadian rhythm of motor activity and sleep/wake cycle induced by prenatal restraint stress in adult rats. Int J Neuropsychopharmacol. 2013 Mar;16(2):323-38.

5: Matrisciano F, Tueting P, Maccari S, Nicoletti F, Guidotti A. Pharmacological activation of group-II metabotropic glutamate receptors corrects a schizophrenia-like phenotype induced by prenatal stress in mice. Neuropsychopharmacology. 2012 Mar;37(4):929-38.

6: Maccari S, Nicoletti F. Agomelatine: protecting the CNS from the effects of stress. CNS Neurosci Ther. 2011 Oct;17(5):269-70.

7: Zuena AR, Mairesse J, Casolini P, Cinque C, Alemà GS, Morley-Fletcher S, Chiodi V, Spagnoli LG, Gradini R, Catalani A, Nicoletti F, Maccari S. Prenatal restraint stress generates two distinct behavioral and neurochemical profiles in male and female rats. PLoS One. 2008 May 14;3(5):e2170.

8: Darnaudéry M, Maccari S. Epigenetic programming of the stress response in male and female rats by prenatal restraint stress. Brain Res Rev. 2008 Mar;57(2):571-85.