CD4+/IL­4+ lymphocytes of the lamina propria and substance P promote colonic protection during acute stress.

Life stress may influence symptom onset and severity in certain gastrointestinal disorders in association with a dysregulated intestinal barrier. It has been widely accepted that stress triggers the hypothalamus­pituitary­adrenal (HPA) axis, releasing corticosterone, which promotes intestinal permeability. In response, colonic inflammation alters mucosal immune homeostasis and destroys the colonic architecture, leading to severe intestinal diseases. Endogenous substance P (SP) does not inhibit the initial extent of the HPA axis response to restraint stress, but it reduces the duration of the stress, suggesting that SP plays an important role in the transition between acute and chronic stress. The present study aimed to investigate the effect of two groups of mice exposed to stress, including acute and chronic stress. The corticosterone was evaluated by ELISA, colon samples were obtained to detected polymorphonuclear cells by hematoxylin and eosin staining, goblet and mast cells were identified by immunocytochemistry and cytokine­producing CD4+ T cells were analyzed by flow cytometry assays, adhesion proteins in the colon epithelium by western blotting and serum SP levels by ELISA. The results demonstrated an increase in the number of polymorphonuclear, goblet and mast cells, a decrease in claudin­1 expression and an elevation in E­cadherin expression during acute stress. Increased E­cadherin expression was also detected during chronic stress. Moreover, it was found that acute stress caused a shift towards a predominantly anti­inflammatory immune response (T helper 2 cells), as shown by the increase in the percentage of CD4+/IL­6+ and CD4+/IL4+ lymphocytes in the lamina propria and the increase in serum SP. In conclusion, this response promoted colonic protection during acute stress.

Acutely increased ß-hydroxybutyrate plays a role in the prefrontal cortex to escape stressful conditions during the acute stress response.

Ketone bodies can be increased in the blood under certain physiological conditions, but their role under such conditions remains to be clarified. In the present study, we found the increment and usage of ß-hydroxybutyrate (BHB) in the prefrontal cortex (PFC) during acute stress. BHB levels increased in the blood and PFC after 30-min acute immobilization stress, and BHB dehydrogenase 1 increased in the PFC simultaneously, but not in the hippocampus. Moreover, increased levels of acetyl-CoA, pyruvate carboxylase, and glutamate dehydrogenase 1 were found in the PFC, implicating the metabolism of increased BHB in the brain. Thus, we checked the levels of glutamate, glutamine, and GABA and found increased levels of glutamate and glutamine in the stressed group compared with that in the control group in the PFC. Exogenous administration of BHB enhanced struggling behaviors under stressful conditions. Our results suggest that the metabolism of BHB from peripheral blood in the PFC may contribute to acute stress responses to escape stressful conditions.

The impact of acute stress disorder on gallbladder interstitial cells of Cajal.

Physical and psychological stress exerts a substantial effect on gastrointestinal motility disorders, where trauma enhances symptoms of digestive dysfunction. Interstitial cells of Cajal (ICCs) act as pacemakers for gastrointestinal motility regulation and are likely important in stress-associated gastrointestinal motility disorders. This study explored the mechanisms underlying gallbladder ICCs function under acute stress conditions using a rabbit chest puncture and cholecystectomy model. The stem cell factor (SCF)/c-kit pathway is essential for the development of ICCs, and gene expression was investigated to identify stress-induced transcriptional alterations. Immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end labeling assays were used to determine ICCs apoptosis, whereas western blot analysis and reverse-transcription polymerase chain reaction were used to detect changes in the SCF/c-kit signaling pathway. These methods revealed a reduction in ICCs via apoptosis following stress, and ICCs increased over time after stressor removal. Therefore, this study demonstrates the impact of stress on ICCs development and survival and further confirms the link between stress and gastrointestinal motility.

High cortisol awakening response in the aftermath of workplace violence exposure moderates the association between acute stress disorder symptoms and PTSD symptoms.

Although a majority of people will be exposed to a traumatic event over the course of their lifespan, only a minority will develop post-traumatic stress disorder. Better understanding the factors contributing to the development of this psychopathology is of high importance and could significantly reduce the societal and human costs associated with PTSD. Acute stress disorder symptoms, which refers to clinical manifestations experienced in the aftermath of a traumatic event, have been shown to be associated with subsequent PTSD symptoms. Yet, many people who develop PTSD do not meet criteria for acute stress disorder in the first place, highlighting the need to refine the predictors of PTSD. The secretion of the stress hormone cortisol is dysregulated in PTSD patients. Whether combining clinical and biological measures in the aftermath of trauma could help to better explain subsequent PTSD symptoms remains to be tested. The current prospective study recruited 51 adults who were exposed to a traumatic event in their work setting, i.e. a psychiatric hospital. Acute stress disorder symptoms and cortisol awakening responses were assessed one to five weeks following trauma exposure (Time 1). PTSD symptoms were measured two months following trauma exposure. Results revealed a significant interaction between acute stress disorder symptoms and cortisol awakening response in predicting later PTSD symptoms. The results suggest that higher cortisol awakening response is a protective factor in that it abolishes the relationship between acute stress disorder symptoms and subsequent PTSD symptoms. These results point to the importance of considering multi-level information in the aftermath of trauma, such as clinical and biological measures, in order to better identify individuals who are at higher risk of developing PTSD.

Topical fluorometholone treatment and desiccating stress change inflammatory protein expression in tears.

PURPOSE: It was hypothesized that tear protein biomarkers could predict the effects of topical steroid treatment and desiccating stress in patients with dry eye disease (DED). To test this concept, a randomized, double-masked, controlled clinical trial with 41 patients was conducted. METHODS: The patients were treated topically with either 0.1% fluorometholone (FML) or polyvinyl alcohol (PA). Tear samples were collected using 1 µl glass capillaries at recruitment into the study and after a 3-week treatment period, both before and after 2 h exposure to desiccating stress, in a controlled environment chamber. Relative quantification of tear proteins was conducted by NanoLC-MSTOF using sequential window acquisition of all theoretical mass spectra (SWATH). Ocular surface integrity (corneal and conjunctival staining and conjunctival hyperemia) was selected as the key DED-related sign and analyzed with proteomic data. Analysis of covariance (ANCOVA) and linear models were used to analyze the data with R. RESULTS: 758 proteins were identified and relatively quantified from each tear sample. Analysis revealed 9 differentially expressed proteins between FML and PA treatments after 3 weeks and 7 after desiccating stress (P < 0.05). We also identified several differentially expressed proteins at the initial collection, which could be used to predict changes of conjunctival and corneal staining and conjunctival hyperemia after FML treatment and after desiccating stress. These proteins include complement C3 (C3) and calmodulin like 5 (CALML5), which could also differentiate the severity of DED at baseline. CONCLUSIONS: The identified proteins could be further used as biomarkers to identify patients most benefiting from FML treatment.

Depletion of adult neurogenesis using the chemotherapy drug temozolomide in mice induces behavioural and biological changes relevant to depression.

Numerous studies have examined links between postnatal neurogenesis and depression using a range of experimental methods to deplete neurogenesis. The antimitotic drug temozolomide (TMZ) has previously been used successfully as an experimental tool in animals to deplete adult neurogenesis and is used regularly on human patients as a standard chemotherapy for brain cancer. In this study, we wanted to evaluate whether TMZ as a model for chemotherapy treatment could affect parameters related to depression in an animal model. Prevalence rates of depression in patients is thought to be highly underdiagnosed, with some studies reporting rates as high as 90%. Results from this study in mice, treated with a regimen of TMZ similar to humans, exhibited behavioural and biochemical changes that have relevance to the development of depression. In particular, behavioural results demonstrated robust deficits in processing novelty and a significant increase in the corticosterone response. Quantification of neurogenesis using a novel sectioning method, which clearly evaluates dorsal and ventral neurogenesis separately, showed a significant correlation between the level of ventral neurogenesis and the corticosterone response. Depression is a complex disorder with discoveries regarding its neurobiology and how it relates to behaviour being only in their infancy. The findings presented in this study demonstrate that chemotherapy-induced decreases in neurogenesis results in previously unreported behavioural and biochemical consequences. These results, we argue, are indicative of a biological mechanism, which may contribute to the development of depression in patients being treated with chemotherapy and is separate from the mental distress resulting from a cancer diagnosis.

Acute stress-induced antinociception is cGMP-dependent but heme oxygenase-independent

Endogenous carbon monoxide (CO), which is produced by the enzyme heme oxygenase (HO), participates as a neuromodulator in physiological processes such as thermoregulation and nociception by stimulating the formation of 3′,5′-cyclic guanosine monophosphate (cGMP). In particular, the acute physical restraint-induced fever of rats can be blocked by inhibiting the enzyme HO. A previous study reported that the HO-CO-cGMP pathway plays a key phasic antinociceptive role in modulating noninflammatory acute pain. Thus, this study evaluated the involvement of the HO-CO-cGMP pathway in antinociception induced by acute stress in male Wistar rats (250-300 g; n=8/group) using the analgesia index (AI) in the tail flick test. The results showed that antinociception induced by acute stress was not dependent on the HO-CO-cGMP pathway, as neither treatment with the HO inhibitor ZnDBPG nor heme-lysinate altered the AI. However, antinociception was dependent on cGMP activity because pretreatment with the guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxaline-1-one (ODQ) blocked the increase in the AI induced by acute stress.

Acute stress-induced antinociception is cGMP-dependent but heme oxygenase-independent.

Endogenous carbon monoxide (CO), which is produced by the enzyme heme oxygenase (HO), participates as a neuromodulator in physiological processes such as thermoregulation and nociception by stimulating the formation of 3',5'-cyclic guanosine monophosphate (cGMP). In particular, the acute physical restraint-induced fever of rats can be blocked by inhibiting the enzyme HO. A previous study reported that the HO-CO-cGMP pathway plays a key phasic antinociceptive role in modulating noninflammatory acute pain. Thus, this study evaluated the involvement of the HO-CO-cGMP pathway in antinociception induced by acute stress in male Wistar rats (250-300 g; n=8/group) using the analgesia index (AI) in the tail flick test. The results showed that antinociception induced by acute stress was not dependent on the HO-CO-cGMP pathway, as neither treatment with the HO inhibitor ZnDBPG nor heme-lysinate altered the AI. However, antinociception was dependent on cGMP activity because pretreatment with the guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxaline-1-one (ODQ) blocked the increase in the AI induced by acute stress.

Possible association of Toll-like receptor 9 polymorphisms with cytokine levels and posttraumatic symptoms in individuals with various types of orthopaedic trauma: early findings.

BACKGROUND: Although TLR9 polymorphisms may be associated with cytokine dysregulation, its role in regulation of cytokines due to bodily trauma or in relation to acute stress symptoms or posttraumatic stress symptoms (ASS/PTS) has not been evaluated. AIMS: To assess serum cytokine levels and levels of ASS and PTS in relation to four common TLR9 single-nucleotide polymorphisms (SNPs) in individuals with various types of orthopaedic trauma. METHODS: Forty-eight accident-injured individuals, aged 20-60 years were studied. Serum cytokine levels and TLR9 SNPS (1486T/C, 1237T/C, 1174G/A and 2848G/A) were assessed together with intensity of ASS and PTS symptoms. RESULTS: Statistically significant higher serum levels of IL-12 and IL-1ß (p<.05) were found in individuals heterozygous for TLR9-1237 (TC) than in individuals expressing the most common TLR9-1237 type (TT), while differences in levels of IL-6 were not significant. Also, marginally significant levels of IL-6 were found in individuals expressing the common TLR9-1174 (GG) compared with individuals homozygous (AA) or heterozygous (GA) for this SNP. They also had non-significant higher intensity of ASS symptoms. A trend of higher PTS levels in individuals expressing the most common type TLR9-1174 (GG) was found, contrary to homozygous (AA) and heterozygous individuals (GA). CONCLUSIONS: The results of this pilot study suggest that accident-injured individuals with certain TLR9 polymorphisms express higher levels of pro-inflammatory cytokines (IL-1ß, IL-6 and IL-12). The associations of TLR9 SNPSs with increased risk of ASS or PTS should be further studied in larger groups of such patients.

Acute stress exposure preceding global brain ischemia accelerates decreased doublecortin expression in the rat retrosplenial cortex.

BACKGROUND: Psychological distress is a risk factor of stroke in humans and worsens the behavioral and neurological outcomes. In rats, acute stress exposure preceding ischemic events attenuates learning and memory. The retrosplenial cortex (RS) plays an important role in these functions, and global brain ischemia (GBI) or acute stress exposure can induce a decrease in expression of the immature neuronal marker, doublecortin (DCX), in the RS. However, little is known about the DCX expression in the RS after stress exposure prior to GBI. METHODS: Eighteen male Sprague-Dawley rats were used. Acute stress exposure was applied as the forced swim paradigm and GBI was induced by bilateral common carotid arterial occlusion for 10 min. The rats were divided into three groups: GBI model preconditioned by stress (n = 6, Group P), GBI model preconditioned by non-stress (n = 6, Group G), and controls (n = 6, Group C). We performed immunohistochemistry to observe and analyze the DCX-expressing cells and Fluoro-Jade B (FJB) staining to detect cell death in the RS after GBI in each group. RESULTS: The total number of DCX-expressing cells was 1,032, 1,219, and 1,904 in Group P, Group G, and Group C, respectively. The mean number of DCX-expressing cells per unit area was significantly lower in Group P and Group G than in Group C (P < 0.001). Moreover, the number was significantly lower in Group P than in Group G (P < 0.05). In each group, no FJB positive cells were observed. CONCLUSION: DCX plays an important role in various cytoskeletal changes. Preconditioning by acute stress exposure accelerated the decrease in DCX expression in the RS after GBI.

Early altered resting-state functional connectivity predicts the severity of post-traumatic stress disorder symptoms in acutely traumatized subjects.

The goal of this study was to investigate the relationship between resting-state functional connectivity and the severity of post-traumatic stress disorder (PTSD) symptoms in 15 people who developed PTSD following recent trauma. Fifteen participants who experienced acute traumatic events underwent a 7.3-min resting functional magnetic resonance imaging scan within 2 days post-event. All the patients were diagnosed with PTSD within 1 to 6 months after trauma. Brain areas in which activity was correlated with that of the posterior cingulate cortex (PCC) were assessed. To assess the relationship between the severity of PTSD symptoms and PCC connectivity, contrast images representing areas positively correlated with the PCC were correlated with the subject's Clinician-Administered PTSD Scale scores (CAPS) when they were diagnosed. Furthermore, the PCC, medial prefrontal cortex and bilateral amygdala were selected to assess the correlation of the strength of functional connectivity with the CAPS. Resting state connectivity with the PCC was negatively correlated with CAPS scores in the left superior temporal gyrus and right hippocampus/amygdala. Furthermore, the strength of connectivity between the PCC and bilateral amygdala, and even between the bilateral amygdala could predict the severity of PTSD symptoms later. These results suggest that early altered resting-state functional connectivity of the PCC with the left superior temporal gyrus, right hippocampus and amygdala could predict the severity of the disease and may be a major risk factor that predisposes patients to develop PTSD.

Brain environment interactions: stress, posttraumatic stress disorder, and the need for a postmortem brain collection.

Stress, especially the extreme stress of traumatic events, can alter both neurobiology and behavior. Such extreme environmental situations provide a useful model for understanding environmental influences on human biology and behavior. This paper will review some of the evidence of brain alterations that occur with exposure to environmental stress. This will include recent studies using neuroimaging and will address the need for histological confirmation of imaging study results. We will review the current scientific approaches to understanding brain environment interactions, and then make the case for the collection and study of postmortem brain tissue for the advancement of our understanding of the effects of environment on the brain. Creating a brain tissue collection specifically for the investigation of the effects of extreme environmental stressors fills a gap in the current research; it will provide another of the important pieces to the puzzle that constitutes the scientific investigation of negative effects of environmental exposures. Such a resource will facilitate new discoveries related to the psychiatric illnesses of acute stress disorder and posttraumatic stress disorder, and can enable scientists to correlate structural and functional imaging findings with tissue abnormalities, which is essential to validate the results of recent imaging studies.