Inheritable effect of unpredictable maternal separation on behavioral responses in mice.

The long-term impact of early stress on behavior and emotions is well documented in humans, and can be modeled in experimental animals. In mice, maternal separation during early postnatal development induces poor and disorganized maternal care, and results in behavioral deficits that persist through adulthood. Here, we examined the long-term effect of unpredictable maternal separation combined with maternal stress on behavior and its transmissibility. We report that unpredictable maternal separation from birth to postnatal day 14 in C57Bl/6J mice has mild behavioral effects in the animals when adult, but that its combination with maternal stress exacerbates this effect. Further, the behavioral deficits are transmitted to the following generation through females, an effect that is independent of maternal care and is not affected by cross-fostering. The combined manipulation does not alter basic components of the hypothalamic-pituitary-adrenal axis but decreases the expression of the corticotropin releasing factor receptor 2 (CRFR2) in several nuclei of the amygdala and the hypothalamus in the brain of maternal-separated females. These results suggest a non-genomic mode of transmission of the impact of early stress in mice.

Epigenetic transmission of the impact of early stress across generations.

BACKGROUND: Traumatic experiences in early life are risk factors for the development of behavioral and emotional disorders. Such disorders can persist through adulthood and have often been reported to be transmitted across generations. METHODS: To investigate the transgenerational effect of early stress, mice were exposed to chronic and unpredictable maternal separation from postnatal day 1 to 14. RESULTS: We show that chronic and unpredictable maternal separation induces depressive-like behaviors and alters the behavioral response to aversive environments in the separated animals when adult. Most of the behavioral alterations are further expressed by the offspring of males subjected to maternal separation, despite the fact that these males are reared normally. Chronic and unpredictable maternal separation also alters the profile of DNA methylation in the promoter of several candidate genes in the germline of the separated males. Comparable changes in DNA methylation are also present in the brain of the offspring and are associated with altered gene expression. CONCLUSIONS: These findings highlight the negative impact of early stress on behavioral responses across generations and on the regulation of DNA methylation in the germline.

Effect of social isolation on stress-related behavioural and neuroendocrine state in the rat.

The present study investigated the effects of post-weaning social isolation (SI) on behavioural and neuroendocrine reactivity to stress of male and female rats. Innate aspects of fear and anxiety were assessed in the open field and elevated plus maze tests. Spontaneous startle reflex and conditioned fear response were further investigated. The neuroendocrine response of isolates was examined by measuring basal and stress release of ACTH and corticosterone and by evaluating the mRNA expression of mineralocorticoid (MR) and glucocorticoid (GR) receptors using in situ hybridization. Locomotor activity in the open field was not modified by chronic SI. In males, but not females, SI produced an anxiogenic profile in the elevated plus maze. Male isolates showed a trend towards increased startle reflex amplitude relative to socially-reared controls. Moreover, SI in males produced alterations of the HPA axis functioning as reflected by higher basal levels of ACTH, and enhanced release of ACTH and corticosterone following stress. In contrast, startle response or HPA axis functioning were not altered in female isolates. Social isolates from both genders showed reduced contextual fear-conditioning. Finally, the mRNA expression of MR and GR was not modified by SI. The results of the present study suggest that chronic SI increases emotional reactivity to stress and produces a hyperfunction of the HPA axis in adult rats, particularly in males.

Dissociable effects of isolation rearing and environmental enrichment on exploration, spatial learning and HPA activity in adult rats.

Male Lister hooded rats were reared from weaning either singly or in groups of three in either barren or enriched cages (n=9 each) to study effects of isolation rearing and environmental enrichment on open-field activity, object exploration, activity in the Light/Dark box (L/D box), spatial learning and memory in the Morris water maze, and hypothalamic-pituitary-adrenal (HPA) activity in response to restraint stress. Regardless of inanimate background, isolation rearing mainly enhanced activity under several conditions of environmental novelty. By contrast, environmental enrichment, regardless of social background, primarily accelerated habituation to novelty and improved spatial learning and memory. None of the treatments significantly altered basal and response levels of plasma ACTH and corticosterone. Furthermore, rats reared singly in barren cages showed persistent activity in the L/D box, indicating an interaction between isolation-induced hyperactivity and reduced habituation due to barren caging. These results show that isolation rearing and environmental enrichment affect behaviour selectively, while at the same time revealing biologically relevant interactions between social and inanimate stimulation. It is concluded that systematic variation of social and inanimate stimulation can help distinguish between effects that generalise across variation in environmental background and effects that are idiosyncratic to a specific environmental background.