Acute stress modulates the outcome of traumatic brain injury-associated gene expression and behavioral responses.

Psychological stress and traumatic brain injury (TBI) result in long-lasting emotional and behavioral impairments in patients. So far, the interaction of psychological stress with TBI not only in the brain but also in peripheral organs is poorly understood. Herein, the impact of acute stress (AS) occurring immediately before TBI is investigated. For this, a mouse model of restraint stress and TBI was employed, and their influence on behavior and gene expression in brain regions, the hypothalamic-pituitary-adrenal (HPA) axis, and peripheral organs was analyzed. Results demonstrate that, compared to single AS or TBI exposure, mice treated with AS prior to TBI showed sex-specific alterations in body weight, memory function, and locomotion. The induction of immediate early genes (IEGs, e.g., c-Fos) by TBI was modulated by previous AS in several brain regions. Furthermore, IEG upregulation along the HPA axis (e.g., pituitary, adrenal glands) and other peripheral organs (e.g., heart) was modulated by AS-TBI interaction. Proteomics of plasma samples revealed proteins potentially mediating this interaction. Finally, the deletion of Atf3 diminished the TBI-induced induction of IEGs in peripheral organs but left them largely unaltered in the brain. In summary, AS immediately before brain injury affects the brain and, to a strong degree, also responses in peripheral organs

The Role of the Intestinal Microbiome in Chronic Psychosocial Stress-Induced Pathologies in Male Mice

Chronic psychosocial stress is a risk factor for the development of physical and mental disorders accompanied or driven by an activated immune system. Given that chronic stress-induced systemic immune activation is lacking in germ-free and antibiotics-treated mice, a causal role of the gut microbiome in the development of stress-related disorders is likely. To address this hypothesis in the current study we employed the chronic subordinate colony housing (CSC, 19 days) paradigm, a pre-clinically validated mouse model for chronic psychosocial stress, known to alter the gut microbial signature and to induce systemic low-grade inflammation, as well as physical and mental abnormalities. In detail, we investigated if (i) CSC-induced alterations can be prevented by repeated transplantation of feces (FT) from non-stressed single-housed control (SHC) mice during CSC exposure, and (ii) if the transplantation of a “stressed” CSC microbiome is able to induce CSC effects in SHC mice. Therefore, we repeatedly infused SHC and CSC recipient mice rectally with SHC donor feces at days 4 and 11 of the CSC paradigm and assessed anxiety-related behavior on day 19 as well as physiological, immunological, and bone parameters on day 20. Furthermore, SHC and CSC recipient mice were infused with CSC donor feces at respective days. To exclude effects of rectal infusions per se, another set of SHC and CSC mice was infused with saline, respectively. Our results showed that transplantation of SHC feces had mild stress-protective effects, indicated by an amelioration of CSC-induced thymus atrophy, anxiety, systemic low-grade inflammation, and alterations in bone homeostasis. Moreover, transplantation of CSC feces slightly aggravated CSC-induced systemic low-grade inflammation and alterations in bone homeostasis in SHC and/or CSC animals. In conclusion, our data provide evidence for a role of the host’s microbiome in many, but not all, adverse consequences of chronic psychosocial stress. Moreover, our data are consistent with the hypothesis that transplantation of healthy feces might be a useful tool to prevent/treat different adverse outcomes of chronic stress. Finally, our data suggests that stress effects can be transferred to a certain extend via FT, proposing therapeutic approaches using FT to carefully screen fecal donors for their stress/trauma history

Rural participants raised in the presence of farm animals show less immune activation following acute psychosocial stress

Urbanization is on the rise, although the urban environment is linked to an increased prevalence of both physical and mental disorders. Human and animal studies suggest that an over-reactive immune system not only accompanies stress-associated disorders, but might even be causally involved in their pathogenesis. Here we show in young (mean age, years, (SD): rural, 25.1 (0.78); urban, 24.5 (0.88)) healthy human volunteers that urban upbringing in the absence of pets (n=20), relative to rural upbringing in the presence of farm animals (n=20), was associated with an exaggerated systemic immune activation following psychosocial stress. Questionnaires, plasma cortisol, and salivary alpha-amylase, however, indicated that the experimental protocol was more stressful and anxiogenic for rural participants. In detail, in response to the Trier Social Stress Test (TSST), participants with an urban versus rural upbringing showed a more pronounced increase in the number of peripheral blood mononuclear cells (PBMCs) and plasma interleukin (IL)-6 concentrations. Moreover, ex vivo cultured PBMCs from urban versus rural participants secreted more IL-6 in response to the T cell-specific mitogen concanavalin A (ConA). In turn, anti-inflammatory IL-10 secretion was suppressed following TSST in urban versus rural participants, suggesting immunoregulatory deficits in urban participants following social stress. Together, our findings support the hypothesis that urban upbringing in the absence of pets, in contrast to rural upbringing in the presence of farm animals, increases the vulnerability for stress-associated physical and mental disorders by compromising adequate resolution of systemic immune activation following social stress and, in turn, aggravating stress-associated systemic immune activation

Different Patterns of Inappropriate Antimicrobial Use in Surgical and Medical Units at a Tertiary Care Hospital in Switzerland: A Prevalence Survey

Audits of individual patient care provide important data to identify local problems in antimicrobial prescription practice. In our study, antimicrobial prescriptions without indication, and divergence from institutional guidelines were frequent errors. Based on these results, we will tailor education, amend institutional guidelines and further develop the infectious diseases consultation service

Association of the Salivary Microbiome With Animal Contact During Early Life and Stress-Induced Immune Activation in Healthy Participants

The prevalence of stress-associated somatic and psychiatric disorders is increased in environments offering a narrow relative to a wide range of microbial exposure. Moreover, different animal and human studies suggest that an overreactive immune system not only accompanies stress-associated disorders, but might even be causally involved in their pathogenesis. In support of this hypothesis, we recently showed that urban upbringing in the absence of daily contact with pets, compared to rural upbringing in the presence of daily contact with farm animals, is associated with a more pronounced immune activation following acute psychosocial stressor exposure induced by the Trier Social Stress Test (TSST). Here we employed 16S rRNA gene sequencing to test whether this difference in TSST-induced immune activation between urban upbringing in the absence of daily contact with pets (n = 20) compared with rural upbringing in the presence of daily contact with farm animals (n = 20) is associated with differences in the composition of the salivary microbiome. Although we did not detect any differences in alpha or beta diversity measures of the salivary microbiome between the two experimental groups, statistical analysis revealed that the salivary microbial beta diversity was significantly higher in participants with absolutely no animal contact (n = 5, urban participants) until the age of 15 compared to all other participants (n = 35) reporting either daily contact with farm animals (n = 20, rural participants) or occasional pet contact (n = 15, urban participants). Interestingly, when comparing these urban participants with absolutely no pet contact to the remaining urban participants with occasional pet contact, the former also displayed a significantly higher immune, but not hypothalamic-pituitary-adrenal (HPA) axis or sympathetic nervous system (SNS) activation, following TSST exposure. In summary, we conclude that only urban upbringing with absolutely no animal contact had long-lasting effects on the composition of the salivary microbiome and potentiates the negative consequences of urban upbringing on stress-induced immune activation.</p

Using Stress-Based Animal Models to Understand the Mechanisms Underlying Psychiatric and Somatic Disorders

Chronic or repeated stress, particularly psychosocial stress, is an acknowledged risk factor for numerous affective and somatic disorders in modern societies. Thus, there is substantial evidence showing that chronic stress can increase the likelihood of major depressive disorder and anxiety disorders, as well as cardiovascular diseases, irritable bowel syndrome and pain syndromes, to name but a few, in vulnerable individuals. Although a number of pharmacological agents are available to treat such stress-related disorders, many patients do not respond to them, and those who do often report a number of side effects. Therefore, a major emphasis in modern basic research is to uncover the underlying aetiology of these disorders, and to develop novel efficacious treatment strategies. This has led to a resurgence in developing, and using, appropriate animal models to study a wide variety of stress-related disorders. Thus, the aim of this research topic “Using stress-based animal models to understand the mechanisms underlying psychiatric and somatic disorders” was to bring together novel research articles and comprehensive review articles from prominent stress researchers. In addition to describing the insights such models have provided relating to the aetiology of psychiatric and somatic disorders, these articles also encompass mechanisms that are believed to underlie stress resilience and stress-protection. Finally, given the current prominence on the role of the brain-gut axis in health and disease, the research topic covers the emerging evidence showing how the gut, particularly the microbiota, influences affective behaviour and physiology

Effects of CSC on hippocampal GR and MR mRNA and cytoplasmic protein expression as well as on nuclear GR protein expression under basal conditions and in response to EPF exposure.

<p>Following decapitation on day 20 hippocampi of both SHC and CSC mice were removed. Afterwards, either RNA of SHC (n = 13) and CSC (n = 19) mice was extracted and reversely transcribed into cDNA for quantification of GR and MR mRNA expression [arbitrary units] via qPCR using TaqMan technology normalized to the mRNA expression of the housekeeping gene GAPDH (A/D), or protein was extracted from the hippocampi of SHC (GR: n = 8; MR: n = 6) and CSC (GR: n = 6; MR: n = 6) mice for determination of cytoplasmic GR (B/C) and MR (E/F) protein expression [grey density] normalized to the loading control ß-Tubulin and for determination of basal nuclear GR (G/H) protein expression (SHC: n = 6, CSC: n = 5) normalized to the loading control TATA binding protein (TBP). Another set of SHC and CSC mice was exposed to an elevated platform (EPF) for 5 min on day 20 of CSC. 10 min after termination of EPF exposure, SHC (n = 6) and CSC (n = 7) mice were decapitated, hippocampi were removed and protein was extracted for determination of nuclear GR protein expression [grey density] normalized to the loading control TBP (G/H). Grey bars represent SHC, black bars CSC mice. Data represent the mean + SEM. * represent <i>P</i> < 0.05 vs. respective SHC mice; ^# represent <i>P</i> < 0.05 vs. respective basal. Representative images of bands detected for cytoplasmic GR (~ 86 kDa; C) or MR (~ 107 kDa; F) and respective loading control ß-Tubulin (~ 50 kDa; C/F) are shown for SHC and CSC mice. Representative images of bands detected for nuclear GR (~ 86 kDa; H) and the loading control TBP (~ 36 kDa; B) are shown for SHC and CSC mice under basal and EPF conditions.</p

Effects of CSC on absolute adrenal weight and plasma CORT and ACTH concentrations.

<p>Following decapitation on day 20 of CSC between 0800 and 1000 h under basal conditions the left and right adrenals of SHC (n = 36) and CSC (n = 42) mice were removed, pruned of fat, pooled, and weighed. Depicted is the absolute weight [mg] of the left and right adrenal (sum of both, A). Furthermore, plasma CORT [ng/ml] (SHC: n = 47; CSC: n = 53; B) and ACTH [pg/ml] (SHC and CSC: n = 5; C) concentrations were determined in trunk blood following decapitation. Grey bars represent SHC, black bars CSC mice. Data represent the mean + SEM. * represent <i>P</i> < 0.05, *** represent <i>P</i> < 0.001 vs. respective SHC mice.</p