Gut microbiome and telomere length in gull hatchlings

In many animals, recent evidence indicates that the gut microbiome may be acquired during early development, with possible consequences on newborns' health. Thus, it has been hypothesized that a healthy microbiome protects telomeres and genomic integrity against cellular stress. However, the link between the early acquired microbiome and telomere dynamics has not hitherto been investigated. In birds, this link may also be potentially modulated by the transfer of maternal glucocorticoids, since these substances dysregulate microbiome composition during postnatal development. Here, we examined the effect of the interplay between the microbiome and stress hormones on the telomere length of yellow-legged gull hatchlings by using a field experiment in which we manipulated the corticosterone content in eggs. We found that the hatchling telomere length was related to microbiome composition, but this relationship was not affected by the corticosterone treatment. Hatchlings with a microbiome dominated by potential commensal bacteria (i.e. Catellicoccus and Cetobacterium ) had larger telomeres, suggesting that an early establishment of the species-specific microbiome during development may have important consequences on offspring health and survival.

Corticosterone Enhances Formation of Neutral but Not Fear Memory During Infectious Illness

Survivors of critical illness often report traumatic memories of their illness period, and these memories are thought to contribute to development of neuropsychiatric disorders, such as PTSD. Many patients are treated with high doses of glucocorticoids for their vasoactive and anti-inflammatory properties, and glucocorticoids have also been shown to prevent the development of PTSD after trauma. Due to their activity in the hippocampus and amygdala, the putative protective effect of glucocorticoids may occur via memory formation during illness. To examine the effect of glucocorticoids on memory formation during acute infectious illness, male and female C57BL/6 mice (N=80, 40 male/40 female) underwent cecal ligation and puncture and were treated with either corticosterone (16 mg/kg) or vehicle in the early afternoon daily for five days beginning on the day of surgery. All mice were habituated to a neutral object in their home cage for five days and underwent one 30-minute footshock/no shock training session during the illness period. After physiologic recovery (2 weeks), the mice underwent behavioral testing including open field exploration, object recognition testing in which they were presented with both the familiar (habituated) object and a novel object, and testing in the shock context. The results showed that drug treatment had no effect on behavior in the open field, including time spent in the center (VEH: 20.19±10.81 vs CORT: 22.32±12.87 sec; P=0.476). Drug treatment increased overall object exploration (12.28±10.79 vs 19.17±15.88 sec; P=0.049). Corticosterone-treated mice showed a preference for the familiar object (60.9±23.0% of total exploration time with familiar object; P=0.015), while vehicle-treated mice did not (54.1±23.3%; P=0.378). The increase in overall object exploration seen in corticosterone-treated mice could be accounted for by an increase in exploration of the familiar object. History of footshock increased freezing in the training context (3.96±2.54% vs 36.08±15.42%; P<0.0001) and corticosterone treatment had no effect (18.06±17.65% vs 22.16±21.19%; P=0.557). In conclusion, administration of corticosterone during infectious illness facilitated memory of a neutral object from the illness period, and recovered mice exhibited a preference for this object over a novel one. Corticosterone treatment had no impact on fear memory formed during illness. This is consistent with human literature suggesting that hydrocortisone decreases PTSD symptoms without impacting traumatic memories. These findings suggest that glucocorticoids selectively enhance the formation, consolidation, and/or recall of neutral but not fear memories during illness, which may rely on hippocampal circuitry. We further suggest that accurate memories of the illness period may influence patients’ perception of this experience and alter their risk for psychiatric sequelae.

Chronic stress and corticosterone exacerbate alcohol-induced tissue injury in the gut-liver-brain axis

Alcohol use disorders are associated with altered stress responses, but the impact of stress or stress hormones on alcohol-associated tissue injury remain unknown. We evaluated the effects of chronic restraint stress on alcohol-induced gut barrier dysfunction and liver damage in mice. To determine whether corticosterone is the stress hormone associated with the stress-induced effects, we evaluated the effect of chronic corticosterone treatment on alcoholic tissue injury at the Gut-Liver-Brain (GLB) axis. Chronic restraint stress synergized alcohol-induced epithelial tight junction disruption and mucosal barrier dysfunction in the mouse intestine. These effects of stress on the gut were reproduced by corticosterone treatment. Corticosterone synergized alcohol-induced expression of inflammatory cytokines and chemokines in the colonic mucosa, and it potentiated the alcohol-induced endotoxemia and systemic inflammation. Corticosterone also potentiated alcohol-induced liver damage and neuroinflammation. Metagenomic analyses of 16S RNA from fecal samples indicated that corticosterone modulates alcohol-induced changes in the diversity and abundance of gut microbiota. In Caco-2 cell monolayers, corticosterone dose-dependently potentiated ethanol and acetaldehyde-induced tight junction disruption and barrier dysfunction. These data indicate that chronic stress and corticosterone exacerbate alcohol-induced mucosal barrier dysfunction, endotoxemia, and systemic alcohol responses. Corticosterone-mediated promotion of alcohol-induced intestinal epithelial barrier dysfunction and modulation of gut microbiota may play a crucial role in the mechanism of stress-induced promotion of alcohol-associated tissue injury at the GLB axis.

Corticosterone Induces HMGB1 Release in Primary Cultured Rat Cortical Astrocytes: Involvement of Pannexin-1 and P2X7 Receptor-Dependent Mechanisms

A major risk factor for major depressive disorder (MDD) is stress. Stress leads to the release of high-mobility group box-1 (HMGB1), which in turn leads to neuroinflammation, a potential pathophysiological basis of MDD. The mechanism underlying stress-induced HMGB1 release is not known, but stress-associated glucocorticoids could be involved. To test this, rat primary cultured cortical astrocytes, the most abundant cell type in the central nervous system (CNS), were treated with corticosterone and HMGB1 release was assessed by Western blotting and ELISA. Significant HMGB1 was released with treatment with either corticosterone or dexamethasone, a synthetic glucocorticoid. HMGB1 translocated from the nucleus to the cytoplasm following corticosterone treatment. HMGB1 release was significantly attenuated with glucocorticoid receptor blocking. In addition, inhibition of pannexin-1, and P2X7 receptors led to a significant decrease in corticosterone-induced HMGB1 release. Taken together, corticosterone stimulates astrocytic glucocorticoid receptors and triggers cytoplasmic translocation and extracellular release of nuclear HMGB1 through a mechanism involving pannexin-1 and P2X7 receptors. Thus, under conditions of stress, glucocorticoids induce astrocytic HMGB1 release, leading to a neuroinflammatory state that could mediate neurological disorders such as MDD.

Corticosterone Induces Depressive-Like Behavior in Female Peri-Pubescent Rats, but Not in Pre-Pubescent Rats

Background There are no data on the effect of exogenous corticosterone on depressive-like behavior in juvenile rats. Furthermore, it has not been tested whether the effects of corticosterone in female rats is different before or after puberty. Objective We tested the effect of corticosterone treatment on female pre- and peri-pubescent juvenile rats on depressive-like behavior. Methods Female juvenile rats were divided into pre-pubescent (post-natal day 7–27) or peri-pubescent (post-natal day 28–48) groups and administered daily corticosterone (40 mg kg−1 day−1) for 21 days. Depressive-like behavior was assessed using a modified forced swim test and the sucrose preference test. After behavioral assessment, brains were analyzed to determine if there were changes in cell proliferation and newborn neuron survival in the dentate gyrus of the dorsal hippocampus. Results Chronic corticosterone treatment did not affect behavior or neurogenesis in female pre-pubescent juvenile rats. However, female peri-pubescent rats injected with corticosterone showed increased depressive-like behavior as well as a decrease in cell proliferation in the subgranular zone. Furthermore, there was an inverse correlation between time spent immobile in the forced swim test and cell proliferation in the granule cell layer in peri-pubescent rats. Conclusions Corticosterone induces depressive-like behavior in peri-pubescent, but not in pre-pubescent female rats. Finally, our results suggest that depressive-like behavior may be associated with a decrease in hippocampal cell proliferation in female peri-pubescent rats.