Vulnerability and resilience to prenatal stress exposure: behavioral and molecular characterization in adolescent rats.

Exposure to stress can lead to long lasting behavioral and neurobiological consequences, which may enhance the susceptibility for the onset of mental disorders. However, there are significant individual differences in the outcome of stress exposure since only a percentage of exposed individuals may show pathological consequences, whereas others appear to be resilient. In this study, we aimed to characterize the effects of prenatal stress (PNS) exposure in rats at adolescence and to identify subgroup of animals with a differential response to the gestational manipulation. PNS adolescent offspring (regardless of sex) showed impaired emotionality in different pathological domains, such as anhedonia, anxiety, and sociability. However, using cluster analysis of the behavioral data we could identify 70% of PNS-exposed animals as vulnerable (PNS-vul), whereas the remaining 30% were considered resilient (PNS-res). At the molecular level, we found that PNS-res males show a reduced basal activation of the ventral hippocampus whereas other regions, such as amygdala and dorsal hippocampus, show significant PNS-induced changes regardless from vulnerability or resilience. Taken together, our results provide evidence of the variability in the behavioral and neurobiological effects of PNS-exposed offspring at adolescence. While these data may advance our understanding of the association between exposure to stress during gestation and the risk for psychopathology, the investigation of the mechanisms associated to stress vulnerability or resilience may be instrumental to develop novel strategies for therapeutic intervention.

A systematic review and multilevel meta-analysis of the prenatal and early life stress effects on rodent microglia, astrocyte, and oligodendrocyte density and morphology.

Exposure to stress during early development may lead to altered neurobiological functions, thus increasing the risk for psychiatric illnesses later in life. One potential mechanism associated with those outcomes is the disruption of glial density and morphology, despite results from rodent studies have been conflicting. To address that we performed a systematic review and meta-analysis of rodent studies that investigated the effects of prenatal stress (PNS) and early life stress (ELS) on microglia, astrocyte, and oligodendrocyte density and morphology within the offspring. Our meta-analysis demonstrates that animals exposed to PNS or ELS showed significant increase in microglia density, as well as decreased oligodendrocyte density. Moreover, ELS exposure induced an increase in microglia soma size. However, we were unable to identify significant effects on astrocytes. Meta-regression indicated that experimental stress protocol, sex, age, and type of tissue analyzed are important covariates that impact those results. Importantly, PNS microglia showed higher estimates in young animals, while the ELS effects were stronger in adult animals. This set of data reinforces that alterations in glial cells could play a role in stress-induced dysfunctions throughout development.

Effects of early life stress on brain cytokines: A systematic review and meta-analysis of rodent studies.

Exposure to early life stress (ELS) may lead to long-lasting neurobiological and behavioral impairments. Alterations in the immune system and neuroinflammatory state induced by ELS exposure are considered risk factors for developing psychiatric disorders. Here, we performed a systematic review and meta-analysis of rodent studies investigating the short and long-term effects of ELS exposure on anti and pro-inflammatory cytokines in brain tissues. Our analysis shows that animals exposed to ELS present an increase in pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α. On the other hand, no alteration was observed in the anti-inflammatory cytokine IL-10. Meta-regression revealed that alterations were more prominent in the hippocampus of adult animals that were exposed to more extended periods of ELS. These inflammatory effects were not permanent since few alterations were identified in aged animals. Our findings suggest that ELS exposure alters pro-inflammatory cytokines expression and may act as a primer for a secondary challenge that may induce lifelong immune alterations. Moreover, the actual evidence is insufficient to comprehend the relationship between anti-inflammatory cytokines and ELS fully.

Early environmental enrichment rescues memory impairments provoked by mild neonatal hypoxia-ischemia in adolescent mice.

Hypoxia-ischemia (HI) is a consequence of a lack of oxygen and glucose support to the developing brain, which causes several neurodevelopmental impairments. Environmental enrichment (EE) is considered an option to recover the alterations observed in rodents exposed to HI. The aim of this study was to investigate the impact of early EE on memory, hippocampal volume and brain-derived neurotrophic factor (Bbnf) and glucocorticoid receptor (Nr3c1) gene expression of mice exposed to HI. At P10, pups underwent right carotid artery permanent occlusion followed by 35 min of 8% O2 hypoxic environment. Starting at P11, animals were reared in EE or in standard cage (HI-SC or SHAM-SC) conditions until behavioral testing (P45). SHAM pups did not undergo carotid ligation and hypoxic exposure. Memory performance was assessed in the Y-maze, Novel object recognition, and Barnes maze. Animals were then sacrificed for analysis of hippocampal volume and Bdnf and Nr3c1 gene expression. We observed that animals exposed to HI performed worse in all three tests compared to SHAM animals. Furthermore, HI animals exposed to EE did not differ from SHAM animals in all tasks. Moreover, HI decreased hippocampal volume, while animals reared in early EE were not different compared to SHAM animals. Animals exposed to HI also showed upregulated hippocampal Bdnf expression compared to SHAM animals. We conclude that early EE from P11 to P45 proved to be effective in recovering memory impairments and hippocampal volume loss elicited by HI. Nevertheless, Bdnf expression was not associated with the improvements in memory performance observed in animals exposed to EE after a hypoxic-ischemic event.

Long-term Effects of Maternal Separation on Anxiety-Like Behavior and Neuroendocrine Parameters in Adult Balb/c Mice.

Introduction: Disruption of maternal care using maternal separation (MS) models has provided significant evidence of the deleterious long-term effects of early life stress. Several preclinical studies investigating MS showed multiple behavioral and biomolecular alterations. However, there is still conflicting results from MS studies, which represents a challenge for reliability and replicability of those findings. Objective: To address that, this study was conducted to investigate whether MS would affect anxiety-like behaviors using a battery of classical tasks, as well as central and peripheral stress-related biomarkers. Methods: Male Balb/c mice were exposed to MS from postnatal day (PND) 2 to 14 for 180-min per day. Two independent cohorts were performed to evaluate both baseline and anxiety-like behavior responses to MS at PND60. We performed composite scores to evaluate MS effects on anxiety and risk assessment phenotypes. Also, we assessed mRNA gene expression in the medial pre-frontal cortex (mPFC) of glucocorticoid and mineralocorticoid receptors (GR and MR) using real-time PCR and peripheral corticosterone levels (CORT) to investigate possible neurobiological correlates to anxiety behaviors. Results: We found increased anxiety-like behavior and decreased risk assessment and exploratory behaviors in MS mice. The animals exposed to MS also presented a decrease in MR mRNA expression and higher levels of CORT compared to controls. Conclusions: Our findings reinforce the body of evidence suggesting that long-term MS induces effects on anxiety and risk assessment phenotypes following the exposure to a standardized MS protocol. Moreover, MS affected the expression of MR mRNA and induced significant changes on CORT response. This data highlights that the reprograming MS effects on HPA axis could be mediate by MR gene expression in mPFC and chronic overactivity of peripheral CORT levels.

Acute neuroinflammation elicited by TLR-3 systemic activation combined with early life stress induces working memory impairments in male adolescent mice.

Toll-like Receptors (TLRs) are implicated with the pathogenesis of cognitive impairment induced by inflammation. Early life stress is associated with altered trajectories of neuroimmune signaling with implications for cognitive development. However, effects of TLR-3 activation on early life stress-related cognitive outcomes are understudied. We investigated the effects of maternal separation (MS) during postnatal development and a viral immune challenge during adolescence on working memory performance. BALB/c mice exposed to MS were separated from their dams daily for 180-min from postnatal day (PND) 2 to 15. At PND 45, animals were challenged with a single i.p. injection of either Poly (I:C) or sterile saline, and then subjected to a spatial working memory test in a Y-maze apparatus. Gene expression was determined by qPCR. Protein levels of oxidative stress markers were also assessed. A single peripheral administration of a TLR-3 agonist was able to induce working memory impairments in adolescent mice exposed to MS. At a molecular level, exposure to MS was associated with lower mRNA levels of Tlr3 in the medial prefrontal cortex (mPFC). However, when MS animals were exposed to Poly (I:C), a more robust activation of Tlr3, Il6 and Nfkb1 gene transcription was observed in these mice compared with control animals. These modifications did not result in oxidative stress. Finally, higher mRNA levels of Nfkb1 in the mPFC were correlated with lower working memory performance, suggesting that altered NF-κB signaling might be related with poor cognitive functioning. These results have implications for how ELS affects neuroimmune signaling in the mPFC.