A comparison of stress reactivity between BTBR and C57BL/6J mice: an impact of early-life stress.

Early-life stress (ELS) is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and can increase the risk of psychiatric disorders later in life. The aim of this study was to investigate the influence of ELS on baseline HPA axis functioning and on the response to additional stress in adolescent male mice of strains C57BL/6J and BTBR. As a model of ELS, prolonged separation of pups from their mothers (for 3 h once a day: maternal separation [MS]) was implemented. To evaluate HPA axis activity, we assessed serum corticosterone levels and mRNA expression of corticotropin-releasing hormone (Crh) in the hypothalamus, of steroidogenesis genes in adrenal glands, and of an immediate early gene (c-Fos) in both tissues at baseline and immediately after 1 h of restraint stress. HPA axis activity at baseline did not depend on the history of ELS in mice of both strains. After the exposure to the acute restraint stress, C57BL/6J-MS mice showed less pronounced upregulation of Crh and of corticosterone concentration as compared to the control, indicating a decrease in stress reactivity. By contrast, BTBR-MS mice showed stronger upregulation of c-Fos in the hypothalamus and adrenal glands as compared to controls, thus pointing to greater activation of these organs in response to the acute restraint stress. In addition, we noted that BTBR mice are more stress reactive (than C57BL/6J mice) because they exhibited greater upregulation of corticosterone, c-Fos, and Cyp11a1 in response to the acute restraint stress. Taken together, these results indicate strain-specific and situation-dependent effects of ELS on HPA axis functioning and on c-Fos expression.

High-resolution MRI data of the brain of C57BL/6J and BTBR mice in three anatomical views.

The research on strain-, sex-, and stress-specific differences in structural and functional connectivity of the brain is important for elucidating various behavioral features and etiologies of psychiatric disorders. Socially impaired BTBR mice are considered a model of autism spectrum disorders. Here we present high-resolution magnetic resonance imaging data from the brain of 89 adolescent mice (C57BL/6J and BTBR) in axial, sagittal, and coronal views. The study [1] includes both females and males differed in early-life experience (normally reared or subjected to prolonged maternal separation: 3 h daily from postnatal day 2 to 15). The MRI data were obtained on a horizontal tomograph Biospec 117/16 instrument with a magnetic field strength of 11.7 T. Thus, multislice Turbo RARE T2-weighted images of the brain were captured in eight groups of mice. Altogether, these data allow to evaluate strain-, sex-, and stress-specific alterations in the volumes of various brain structures and to better understand the relation between brain structural differences and behavioral abnormalities.

Sex-specific behavioral and structural alterations caused by early-life stress in C57BL/6 and BTBR mice.

Lately, the development of various mental illnesses, such as depression, personality disorders, and autism spectrum disorders, is often associated with traumatic events in childhood. Nonetheless, the mechanism giving rise to this predisposition is still unknown. Because the development of a disease often depends on a combination of a genetic background and environment, we decided to evaluate the effect of early-life stress on BTBR mice, which have behavioral, neuroanatomical, and physiological features of autism spectrum disorders. As early-life stress, we used prolonged separation of pups from their mothers in the first 2 weeks of life (3 h once a day). We assessed effects of the early-life stress on juvenile (postnatal day 23) and adolescent (postnatal days 37-38) male and female mice of strains C57BL/6 (B6) and BTBR. We found that in both strains, the early-life stress did not lead to changes in the level of social behavior, which is an important characteristic of autism-related behavior. Nonetheless, the early-life stress resulted in increased locomotor activity in juvenile BTBR mice. In adolescent mice, the stress early in life caused a low level of anxiety in B6 males and BTBR females and increased exploratory activity in adolescent BTBR males and females. In addition, adolescent B6 male and female mice with a history of the early-life stress tended to have a thinner motor cortex as assessed by magnetic resonance imaging. As compared to B6 mice, BTBR mice showed reduced levels of social behavior and exploratory activity but their level of locomotor activity was higher. BTBR mice had smaller whole-brain, cortical, and dorsal hippocampal volumes; decreased motor cortex thickness; and increased ventral-hippocampus volume as compared to B6 mice, and these parameters correlated with the level of exploratory behavior of BTBR mice. Overall, the effects of early postnatal stress are sex- and strain-dependent.

Impact of mothers' experience and early-life stress on aggression and cognition in adult male mice.

The postnatal period is important for brain development and behavioral programming. Here, we hypothesized that females' stressful experience early in life can lead to disruption of mother-offspring interactions with their own progeny. The objective of this study was to assess the effects of mothers' stressful experience, early-life stress, or both on the behavior of adult male mice. In this study, female mice were allowed to raise their pups either without exposure to stress (normal rearing conditions, NC) or with exposure to maternal separation (3 hr/day, maternal separation, MS). Adult F1 female mice who had experienced MS (stressed mothers, SM) or had been reared normally (undisturbed mothers, UM) were used for generating F2 offspring, which was then exposed (or not exposed) to early-life stress. We assessed anxiety-like behavior, exploratory activity, locomotor activity, aggression, and cognition in four groups of adult F2 males (UM+NC, UM+MS, SM+NC, and SM+MS). We found that SM+MS males become more aggressive if agonistic contact is long enough; these results point to a change in their social coping strategy. Moreover, these aggressive males tended to show better long-term spatial memory. Overall, our findings suggest that mothers' early-life experience may have important implications for the adult behavior of their offspring.