Chronic stress is generally accepted as the main risk factor in the development of cognitive decline; however, the underlying mechanisms remain unclear. Previous data have demonstrated that the levels of homocysteine (Hcy) are significantly elevated in the plasma of stressed animals, which suggests that Hcy is associated with stress and cognitive decline. To test this hypothesis, we analyzed the cognitive function, plasma concentrations of Hcy, and brain-derived neurotropic factor (BDNF) levels in rats undergoing chronic unpredicted mild stress (CUMS). The results showed that decreased cognitive behavioral performance and decreased BDNF transcription and protein expression were correlated with hyperhomocysteinemia (HHcy) levels in stressed rats. Diet-induced HHcy mimicked the cognitive decline and BDNF downregulation in the same manner as CUMS, while Hcy reduction (by means of vitamin B complex supplements) alleviated the cognitive deficits and BDNF reduction in CUMS rats. Furthermore, we also found that both stress and HHcy disturbed the DNA methylation process in the brain and induced DNA hypermethylation in the BDNF promoter. In contrast, control of Hcy blocked BDNF promoter methylation and upregulated BDNF levels in the brain. These results imply the possibility of a causal role of Hcy in stress-induced cognitive decline. We also used ten-eleven translocation (TET1), an enzyme that induces DNA demethylation, to verify the involvement of Hcy and DNA methylation in the regulation of BDNF expression and the development of stress-related cognitive decline. The data showed that TET1-expressing viral injection into the hippocampus inhibited BDNF promoter methylation and significantly mitigated the cognitive decline in HHcy rats. Taken together, novel evidence from the present study suggests that Hcy is likely involved in chronic stress-induced BDNF reduction and related cognitive deficits. In addition, the negative side-effects of HHcy may be associated with Hcy-induced DNA hypermethylation in the BDNF promoter. The results also suggest the possibility of Hcy as a target for therapy and the potential value of vitamin B intake in preventing stress-induced cognitive decline.
Animals ; Brain-Derived Neurotrophic Factor/metabolism* ; Cognitive Dysfunction/complications* ; DNA Methylation ; Homocysteine/metabolism* ; Hyperhomocysteinemia/metabolism* ; Rats ; Stress, Psychological/physiopathology*

OBJECTIVES: During pregnancy, pregnant women are prone to stress reactions due to external stimuli, affecting their own health and fetal development. At present, there is no good treatment for the stress reactions from pregnant women during pregnancy. This study aims to explore the effect of probiotics on abnormal behavior and hippocampal injury in pregnant stressed offspring. METHODS: SD pregnant rats were divided into a control group, a stress group, and a probiotics group, with 6 rats in each group. The control group was untreated; the stress group was given restraint stress on the 15th-20th day of pregnancy; the probiotics group was given both bifidobacterium trisporus capsules and restraint stress on the 15th-20th day of pregnancy, and the offspring continued to be fed with probiotics until 60 days after birth (P60). The offspring rats completed behavioral tests such as the open field test, the elevated plus maze test, the new object recognition test, and the barnes maze test at 60-70 d postnatally. Nissl's staining was used to reflect the injury of hippocampal neurons; immunohistochemical staining was used to detect the expression of microglia marker ionized calcium binding adapter molecule 1 (IBA-1) which can reflect microglia activation; ELISA was used to detect the content of plasma TNF-α and IL-1β; Western blotting was used to detect the expression of Bax, Bcl-2, and caspase-3. RESULTS: The retention time of offspring rats in the stress group in the central area of the open field was significantly less than that in the control group (P<0.01), and the retention time of offspring rats in the probiotic group in the central area of the open field was significantly more than that in the stress group (P<0.05). The offspring rats in the stress group stayed in the open arm for a shorter time than the control group (P<0.05) and entered the open arm less often than the control group (P<0.01); the offspring rats in the probiotic group stayed in the open arm for a longer time than the stress group and entered the open arm more often than the stress group (both P<0.05). The discrimination ratio for new to old objects in the offspring rats of the stress group was significantly lower than that of the control group (P<0.01), and the discrimination ratio for new to old objects in the offspring rats of the probiotic group was significantly higher than that of the stress group (P<0.05). The offspring rats in the stress group made significantly more mistakes than the control group (P<0.05), and the offspring rats in the probiotic group made significantly fewer mistakes than the stress group (P<0.05). Compared with the control group, the numbers of Nissl bodies in CA1, CA3, and DG area were significantly reduced in the offspring rats of the stress group (all P<0.001), the number of activated microglia in DG area of hippocampus was significantly increased (P<0.01), the contents of TNF-α and IL-1β in peripheral blood were significantly increased (P<0.05 or P<0.01), the protein expression level of Bcl-2 was significantly down-regulated, and the protein expression levels of Bax and caspase-3 were significantly up-regulated (all P<0.001). Compared with the stress group, the numbers of Nissl bodies in CA1, CA3, and DG area were significantly increased in the probiotic group offspring rats (P<0.001, P<0.01, P<0.05), the number of activated microglia in the DG area of hippocampus was significantly reduced (P<0.05), and the TNF-α and IL-1β levels in peripheral blood were significantly decreased (both P<0.05), the protein expression level of Bcl-2 was significantly up-regulated, and the protein expression levels of Bax and caspase-3 were significantly down-regulated (all P<0.001). CONCLUSIONS Probiotic intervention partially ameliorated anxiety and cognitive impairment in rats offspring of pregnancy stress, and the mechanism may be related to increasing the number of neurons, inhibiting the activation of hippocampal microglia, and reducing inflammation and apoptosis.
Animals ; Caspase 3/metabolism* ; Female ; Hippocampus/physiopathology* ; Humans ; Pregnancy ; Probiotics/therapeutic use* ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Rats ; Stress, Psychological/therapy* ; Tumor Necrosis Factor-alpha/metabolism* ; bcl-2-Associated X Protein/metabolism*

Restraint water-immersion stress (RWIS), a compound stress model, has been widely used to induce acute gastric ulceration in rats. A wealth of evidence suggests that the central nucleus of the amygdala (CEA) is a focal region for mediating the biological response to stress. Different stressors induce distinct alterations of neuronal activity in the CEA; however, few studies have reported the characteristics of CEA neuronal activity induced by RWIS. Therefore, we explored this issue using immunohistochemistry and in vivo extracellular single-unit recording. Our results showed that RWIS and restraint stress (RS) differentially changed the c-Fos expression and firing properties of neurons in the medial CEA. In addition, RWIS, but not RS, induced the activation of corticotropin-releasing hormone neurons in the CEA. These findings suggested that specific neuronal activation in the CEA is involved in the formation of RWIS-induced gastric ulcers. This study also provides a possible theoretical explanation for the different gastric dysfunctions induced by different stressors.
Action Potentials ; drug effects ; physiology ; Analysis of Variance ; Animals ; Central Amygdaloid Nucleus ; pathology ; Corticotropin-Releasing Hormone ; metabolism ; Disease Models, Animal ; Gastric Mucosa ; pathology ; Gene Expression Regulation ; physiology ; Neurons ; physiology ; Patch-Clamp Techniques ; Proto-Oncogene Proteins c-fos ; metabolism ; Rats ; Rats, Wistar ; Stress, Physiological ; physiology ; Stress, Psychological ; etiology ; physiopathology

PURPOSE: Fatigue is the third most common "extraintestinal" complaint of patients with irritable bowel syndrome (IBS), but it is still poorly understood. This study aimed to review characteristics of IBS-associated fatigue and to examine pooled frequency, severity of fatigue, and correlations of related factors with fatigue in IBS via meta-analyses. METHODS: Publications were searched in eight databases from 1995 to 2014. Random effects meta-analyses were applied with standard error, weighted effect size, and correlation-based measure of effect size. RESULTS: Twenty-four studies were included in systematic review. Seventeen studies were used for meta-analyses (2 studies were excluded in the frequency of fatigue analysis due to data unavailability). Using "tiredness" to define fatigue, and Fatigue Impact Scale to assess fatigue were the most frequently used across the studies. Gastrointestinal symptoms, psychological distress, and health-related quality of life were the most common correlates with fatigue. The pooled frequency of fatigue was 54.2% [95% confidence interval (38.5, 69.4)]. Metaregression on the frequency of fatigue showed positive and significant relations with tertiary care settings, female sex, and younger age. There was a negatively moderate relationship between the severity of fatigue and health-related quality of life score (correlation-based measure of effect size: -.378). CONCLUSIONS: Fatigue is prevalent among patients with IBS and commonly co-occurs with other symptoms. This is the first study to fully examine fatigue in IBS, which shed light on the comprehensive management of fatigue in this patient group. Future research is warranted to further explore fatigue-related factors and underlying mechanisms of fatigue in IBS.
Adult ; Age Factors ; Aged ; Fatigue/*etiology/*nursing ; Female ; Humans ; Irritable Bowel Syndrome/*complications/*physiopathology ; Male ; Middle Aged ; Prevalence ; *Quality of Life ; Severity of Illness Index ; Sex Factors ; Stress, Psychological

OBJECTIVETo establish social stress induced depression-like model in mice of C57BL/6 strain, and to assess its reliability using differenf behavioral methods.

METHODSTotally 20 male mice of C57BL/6 strain were divided into the normal group and the stress model group by random digit table,10 in each group. Another 10 CD1 mice were subjected to social stress. Mice in the normal control group received no stress, while those in the model group received social stress for 10 successive days. Behavioral assessment was performed using social interaction test (SIT), the elevated plus-maze (EPM) test, tail suspension test (TST), respectively. Serum cortisol level was detected by ELISA to assess the reliability of the model.

RESULTSIn the social interaction test when the social target (CDI mice) was inexistent, mice in the normal control group spent longer time in the social interaction zone and less time in the corner zone (P < 0.05); mice in the model group spent less time in the social interaction zone and more time in the corner zone (P < 0.05). Compared with the normal group when CDI mice existed, mice in the model group spent less time in the social interaction zone and more time in the corner zone (P < 0.05). Compared with the normal control group, the total times for entry into open arms, close arms, and the maze were obviously reduced (P < 0.05), and the proportion of entering open arms was significantly reduced (P < 0.05) in the model group. In TST, the motionless time within the last 4 mm was prolonged in the model group (P < 0.05). The serum cortisol level in the model group was obviously elevated (P < 0.01).

CONCLUSIONSocial stress induced depression-like animal model in mice of C57BL/6 straineasquite reliable and possibly suitable to be used in integrative medicine research of combination of disease and syndrome model.

Animals ; Behavior, Animal ; Depression ; physiopathology ; Disease Models, Animal ; Hydrocortisone ; blood ; Male ; Mice ; Mice, Inbred C57BL ; Social Behavior ; Stress, Psychological

PURPOSE: To determine the impact of noise on heart rate variability (HRV) in men, with a focus on the noise type rather than on noise intensity. MATERIALS AND METHODS: Forty college-going male volunteers were enrolled in this study and were randomly divided into four groups according to the type of noise they were exposed to: background, traffic, speech, or mixed (traffic and speech) noise. All groups except the background group (35 dB) were exposed to 45 dB sound pressure levels. We collected data on age, smoking status, alcohol consumption, and disease status from responses to self-reported questionnaires and medical examinations. We also measured HRV parameters and blood pressure levels before and after exposure to noise. The HRV parameters were evaluated while patients remained seated for 5 minutes, and frequency and time domain analyses were then performed. RESULTS: After noise exposure, only the speech noise group showed a reduced low frequency (LF) value, reflecting the activity of both the sympathetic and parasympathetic nervous systems. The low-to-high frequency (LF/HF) ratio, which reflected the activity of the autonomic nervous system (ANS), became more stable, decreasing from 5.21 to 1.37; however, this change was not statistically significant. CONCLUSION: These results indicate that 45 dB(A) of noise, 10 dB(A) higher than background noise, affects the ANS. Additionally, the impact on HRV activity might differ according to the noise quality. Further studies will be required to ascertain the role of noise type.
Adaptation, Psychological ; Confounding Factors (Epidemiology) ; Environment ; Heart Rate/*physiology ; Humans ; Male ; *Noise ; Questionnaires ; Stress, Psychological/physiopathology ; Young Adult

Stress cardiomyopathy is an atypical myocardial disease induced by emotional or physical stress, with the characteristic of left ventricular systolic dysfunction, transient imaging and electrocardiogram (ECG) changes. Sudden cardiac death can occur in severe cases. Clinical symptoms are likely to appear on acute myocardial infarction, but the exact pathological mechanism is unclear. In the present study, we perform a systematic review of the literature on the clinical manifestations, epidemiological characteristics, ECG, imaging and laboratory tests of stress cardiomyopathy, in order to provide the values for forensic pathology diagnosis.
Death, Sudden, Cardiac ; Diagnostic Imaging ; Electrocardiography ; Humans ; Myocardial Infarction ; Stress, Psychological ; Takotsubo Cardiomyopathy/physiopathology*

BACKGROUNDThe prevalence reported of maternal depression from the first to the third trimester was 7.4%, 12.8%, 12.0% respectively, which implies that around one-tenth of pregnant women suffer from psychological disorder during the whole pregnancy. It is assumed that during pregnancy the maternal-fetal circulation unit is also affected by maternal psychological status. The aim of this study is to explore the association between maternal psychological status and fetal dynamic blood flow circulation during pregnancy.

METHODSWe recruited 102 singleton low risk pregnant women between 30 to 33 gestational weeks. The Symptom Checklist-90 (SCL-90) was used to assess maternal psychological status. Ultrasound Doppler was used to measure blood flow changes in maternal-fetal circulation. Pulsatility index (PI) value was measured in umbilical artery (UA), fetal middle cerebral artery (MCA) and maternal uterine arteries (UTA). Peak systolic velocity (PSV) was measured in MCA and velocity was measured in umbilical vein (UV). Statistical analysis was performed with standard nonparametric Mann-Whitney U tests. Two-tailed P values <0.05 were considered statistical significance.

RESULTSOf the 102 pregnant women, 12 patients show high levels of poor mental health. Women with poor mental health have higher umbilical artery PI values than good mental health patients (P = 0.020). A higher MCA PI value is found in poor mental health patients but this does not reach statistical significance (P = 0.053). Women with hostility show lower placental scores (P = 0.030). Women with somatization demonstrate higher values in UA PI, MCA PI and MCA PSV (P = 0.049, 0.030 and 0.035 respectively). A higher MCA PSV value is also found in phobic anxiety patients (P = 0.046).

CONCLUSIONSPoor mental health during pregnancy is found to have an adverse effect on maternal-fetal circulation. Umbilical artery and fetal cerebral circulation are more sensitive and affected by maternal psychological disorder.

Adult ; Blood Flow Velocity ; physiology ; Female ; Fetus ; blood supply ; physiology ; Gestational Age ; Hemodynamics ; physiology ; Humans ; Pregnancy ; Pregnancy Trimester, Third ; Stress, Psychological ; physiopathology

PURPOSE: Our study aimed to examine the relationship between intelligence and health-related quality of life (HRQOL) in children (6-13 years old) diagnosed as having a brain tumor. MATERIALS AND METHODS: We administered a Korean version of the Wechsler Intelligence Scale for Children-III, the Pediatric Quality of Life Inventory, version 4.0 (PedsQL), the Korean version of the Parenting Stress Index-Short Form, and the Korean Version of the Parenting Sense of Competence (K-PSOC) scale before or after initial radiotherapy (T1) and after treatment termination (T2). In total, 13 patients completed both the T1 and T2 interviews. RESULTS: Scores significantly declined between T1 and T2 on the full-scale intelligence quotients (FIQ), verbal intelligence quotients (VIQ), performance intelligence quotients (PIQ), similarity and coding tests, as well as the K-PSOC, which measures parental anxiety. FIQ scores at T1 were correlated with the self-reported PedsQL total scores (r=0.739) and the parent proxy-report PedsQL scores for school functioning (r=0.706) at T2. Also, the FIQ scores at T2 were correlated with the self-reported PedsQL total scores (r=0.748) and scores for physical health (r=0.728) at T2. CONCLUSION: The cognitive ability and intelligence level of the patients significantly declined between on and off treatment periods, and higher intelligence functioning at both on and off treatment was correlated with long-term higher HRQOL. Further investigations that monitor intelligence, HRQOL and parenting stress over a longer period, using a greater number of participants, are needed.
Adolescent ; Anxiety ; Brain Neoplasms/complications/physiopathology/*psychology ; Child ; *Cognition ; Female ; Humans ; Intelligence Tests ; Longitudinal Studies ; Male ; Parenting ; Parents/psychology ; Prospective Studies ; *Quality of Life ; Stress, Psychological/*diagnosis ; Time Factors

Autistic Disorder ; complications ; psychology ; Child ; Child Development ; Communication ; Down Syndrome ; complications ; physiopathology ; psychology ; Follow-Up Studies ; Humans ; Interpersonal Relations ; Male ; Play and Playthings ; Singapore ; Social Behavior ; Stress, Psychological ; psychology