Chronic Psychological Stress Research Articles

Socioeconomic disadvantage, chronic stress, and proinflammatory phenotype: an integrative data analysis across the lifecourse.

Socioeconomic disadvantage confers risk for many chronic illnesses, and theories have highlighted chronic psychological stress and alterations to inflammatory processes as key pathways. Specifically, disadvantage can heighten chronic stress, which may promote a proinflammatory phenotype characterized by immune cells mounting exaggerated cytokine responses to challenge and being less sensitive to inhibitory signals. Importantly, lifecourse perspectives emphasize that such immune alterations should be more potent earlier in life during a sensitive period when bodily tissues are highly plastic to environmental inputs. However, examining these propositions is resource intensive, as they require cell-culturing approaches to model functional inflammatory activities, a wide age range, and longitudinal data. Here, we integrated data from five independent studies to create a diverse sample of 1,607 individuals (960 with longitudinal data; 8 to 64 years old; 359 Asian, 205 Black, and 151 Latino/a). Leveraging the resulting lifecourse data, rich interview assessments of disadvantage and stress, and ex vivo assessments of inflammation, we examined two questions: (1) Does chronic stress account for the link between disadvantage and proinflammatory phenotype? (2) Is there a developmental period during which inflammatory responses are more sensitive to disadvantage and chronic stress? Disadvantage was associated with higher chronic stress, which was linked with a proinflammatory phenotype cross-sectionally, longitudinally, and in terms of prospective change across 1.5 to 2 years. Consistent with the sensitive period hypothesis, the magnitude of these indirect associations was strongest in earlier decades and declined across the lifecourse. These findings highlight the importance of taking a lifecourse perspective in examining health disparities.

Psychological stress induces depressive-like behavior associated with bone marrow-derived monocyte infiltration into the hippocampus independent of blood–brain barrier disruption

BackgroundPsychological stress is one of the most important factors that trigger emotional disorders, such as depression and anxiety. Emerging evidence suggests that neuroinflammation exacerbated by bidirectional communication between the peripheral immune system and the central nervous system facilitates abnormal psychiatric symptoms. This study aimed to investigate the hippocampal migration of bone marrow (BM)-derived monocytes and its role in regulating depressive-like behaviors using the chronic psychological stress (CPS) mouse model. More importantly, whether the central migration of these peripheral BM-derived cells depend on the disruption of the blood–brain barrier (BBB) was also investigated.Methods and findingsGreen fluorescent protein-positive (GFP+) BM chimeric mice were used to distinguish BM-derived monocytes within the brain. A CPS mouse model was established to explore the effect of CPS on hippocampal migration of BM-derived monocytes and its role in the regulation of depressive-like behaviors. The results revealed that BM-derived GFP+ cells accumulated in the hippocampus and differentiated into microglia-like cells after exposure to CPS. Interestingly, this migration was not associated with BBB disruption. Furthermore, treatment with C–C chemokine receptor 2 (CCR2) antagonist (RS102895) suppressed the recruitment of BM-derived monocytes to the hippocampus and alleviated depressive-like symptoms.ConclusionThese findings indicate that monocyte recruitment to the hippocampus in response to psychological stress may represent a novel cellular mechanism that contributes to the development of depression.

Traditional Chinese medicine mediated tumor suppression via regulating psychological factors

Chronic psychological stress causes physiological stress and leads to disturbance in the body's internal environment. There is growing evidence that stress can promote cancer biological processes, including proliferation, genomic instability, angiogenesis, metastasis, immune evasion, and metabolic disorders, through neuroendocrine mechanisms, immune and inflammatory responses, and epigenetic alterations, and may even impact tumor therapy. In addition, as the tumor development process advances, the body also promotes depressive and anxiety-like behaviors through one or more of these mechanisms, generating a vicious cycle that contributes to the tumor's poor prognosis. However, psychosomatic behavioral interventions (PBI) and Chinese medicine can also effectively mitigate the effects of stress in cancer patients. In this review, we will explore the potential pathways of stress-tumor interactions.

Perceived stress and hair cortisol concentration in a study of Mexican and Icelandic women.

Hair cortisol concentration (HCC) represent a potential biomarker of chronic psychological stress. Previous studies exploring the association between perceived stress and HCC have been limited to relatively small and selected populations. We collected hair samples from 881 women from the Mexican Teachers' Cohort (MTC) and 398 women from the Icelandic SAGA pilot-cohort following identical protocols. HCC was quantified using liquid chromatography coupled with tandem mass spectrometry. The self-reported Perceived Stress Scale (PSS, 10 and 4 item, range 0-40 and 0-16) was used to assess psychological stress. We conducted multivariable linear regression analyses to assess the association between perceived stress and log-transformed HCC in the combined sample and in each cohort separately. MTC participants had slightly higher HCC and PSS scores than SAGA participants (median HCC 6.0pg/mg vs. 4.7pg/mg and mean PSS-10 score 12.4 vs. 11.7, respectively). After adjusting for sociodemographic factors and health behaviors, we observed a 1.4% (95% CI 0.6, 2.1) increase in HCC for each unit increase in the PSS-10 score in the combined sample. Furthermore, PSS-10 quintiles were associated with a 24.3% (95% CI 8.4, 42.6, mean logHCC 1.8 vs 1.6) increase in HCC when comparing the highest to the lowest quintile, after multivariable adjustment. Similar results were obtained when we analyzed each cohort separately and when using the PSS-4. Despite relatively small absolute differences, an association between perceived stress and HCC was found in a sample of women from two diverse geographical and cultural backgrounds supporting the hypothesis that HCC is a viable biomarker in studies of chronic psychological stress.

Prenatal chronic stress impairs the learning and memory ability via inhibition of the NO/cGMP/PKG pathway in the Hippocampus of offspring

Numerous clinical and animal studies have found that antenatal chronic stress can lead to pathological changes the hippocampal development from embryos to adult, but the mechanisms are not well understood. Proteomic analyses provide a new insight to explore the potential mechanisms of this impairment. In this study, gestating rats were subjected to chronic unpredictable mild stress (CUMS) during pregnant days using nine different stimulations, and the changes of the learning and memory performance and the expression of proteins in the hippocampus of offspring were measured. It was found that prenatal chronic stress led to growth retardation, impaired spatial learning and memory ability in the offspring. Furthermore, prenatal stress caused various degrees of damage to neurons, Nissl body, mitochondria and synaptic structures in hippocampal CA3 region of offspring. In addition, 26 significantly different expressed proteins (DEPs) were found between the two groups by using isoquantitative tag-based relative and absolute quantification (iTRAQ) proteomics analysis. Further analyses of these DEPs showed that involved with different molecular functions and several biological processes, such as biological regulation and metabolic processes. Among these, the KEGG pathway enrichment showed that learning and memory impairment was mainly associated with the cyclic guanosine monophosphate protein kinase G (cGMP-PKG) pathway. At the same time, compared with OPC group, the NO, nNOS and cGMP level were significantly decreased, and the expression of PKG protein was also dropped. All of these results suggested that pregnant rats exposed to chronic psychological stress might impair spatial learning and memory ability of offspring, by disturbing the NO/cGMP/PKG signaling pathway.

Salivary immune markers are not associated with self-reported childhood maltreatment or psychopathology in adults

BackgroundPsychological stress has repeatedly been found to be associated with pro-inflammatory markers in blood, and neuro-inflammation may play a role in the development of psychopathology after early life stress. Salivary immune testing is a novel method to non-invasively assess immune functioning. We examined a large range of salivary immune markers in relation to self-reported childhood maltreatment and psychopathology in an adult sample. MethodsParticipants (N = 118, 51% female, mean age = 46.6 yrs, range 22–64) were drawn from a cross-sectional three-generation study, and supplied 2 ml of saliva via passive drool. They reported on childhood maltreatment experiences and on psychopathological symptoms in the last 6 months. Hair cortisol was additionally assessed in a subsample (n = 68). Levels of IL1ß, IL6, IL8, IFNγ, TNFα, tIgE, sIgA, FLCƛ, and FLCƙ were assessed. ResultsLinear mixed model analyses showed that several salivary immune markers were associated with age (sIgA and IgE), BMI (sIgA, IL1ß, and IL6), sex (FLCs and IgE), and bad health (IL6, IL8, TNFα). No associations with (anti-inflammatory) medication use or oral health problems were found. Notably, no associations between the immune markers and self-reported childhood maltreatment, psychopathology, or hair cortisol were found. ConclusionsSalivary immune measures were found to be sensitive to individual differences in age, sex, health and BMI. However. in the current sample there was no indication of inflammation in relation to chronic psychological stress. Larger studies, including participants with higher stress levels, are needed to further examine associations between salivary immune markers and psychological stress.

Higher hair cortisol concentrations associated with shorter leukocyte telomere length in high-risk young adults

Chronic stress is associated with accelerated biological aging as indexed by short age-adjusted leukocyte telomere length (LTL). Exploring links of biological stress responses with LTL has proved challenging due to the lack of biological measures of chronic psychological stress. Hair cortisol concentration (HCC) has emerged as a measure of chronic hypothalamic pituitary adrenal (HPA) axis activation, allowing the examination of relationships between aggregate cortisol concentrations over time and LTL. Our sample includes 92 participants (38% women, Mage = 26 ± 3.7 years) from a high-risk sample of young adults with previous residential care placements. Two cm hair was collected for HCC, reflecting approximately eight weeks of cortisol secretion. LTL was measured with quantitative polymerase chain reaction (qPCR) in whole blood samples. All samples for LTL were run in triplicate and assayed twice. Linear and polynomial regression models were used to describe the association between HCC and LTL, adjusting for age and sex. HCC and LTL showed negative associations (std. ß = − 0.67, 95% CI [− 0.83, − 0.52], p < .001) in age- and sex-adjusted analyses, indicating that higher HCCs are associated with shorter LTL. Using polynomial regression, we found a curvilinear relationship indicating a stronger negative association at lower cortisol concentrations. Higher HCCs were associated with shorter LTL, supporting the hypothesized involvement of prolonged cortisol secretion in telomere attrition. Thus, HCC may prove useful as a biological indicator of chronic stress associated with aging-related processes in samples exposed to high levels of stress.

Cathepsin K Deficiency Prevented Kidney Damage and Dysfunction in Response to 5/6 Nephrectomy Injury in Mice With or Without Chronic Stress.

Background:Chronic psychological stress is a risk factor for kidney disease, including kidney dysfunction and hypertension. Lysosomal CatK (cathepsin K) participates in various human pathobiologies. We investigated the role of CatK in kidney remodeling and hypertension in response to 5/6 nephrectomy injury in mice with or without chronic stress.Methods:Male 7-week-old WT (wild type; CatK+/+) and CatK-deficient (CatK−/−) mice that were or were not subjected to chronic stress underwent 5/6 nephrectomy. At 8 weeks post-stress/surgery, the stress was observed to have accelerated injury-induced glomerulosclerosis, proteinuria, and blood pressure elevation.Results:Compared with the nonstressed mice, the stressed mice showed increased levels of TLR (Toll-like receptor)-2/4, p22phox, gp91phox, CatK, MMP (matrix metalloproteinase)-2/9, collagen type I and III genes, PPAR-γ (peroxisome proliferator-activated receptor-gamma), NLRP-3 (NOD-like receptor thermal protein domain associated protein 3), p21, p16, and cleaved caspase-8 proteins, podocyte foot process effacement, macrophage accumulation, apoptosis, and decreased levels of Bcl-2 (B cell lymphoma 2) and Sirt1, as well as decreased glomerular desmin expression in the kidneys. These harmful changes were retarded by the genetic or pharmacological inhibition of CatK. Consistently, CatK inhibition ameliorated 5/6 nephrectomy–related kidney injury and dysfunction. In mesangial cells, CatK silencing or overexpression, respectively, reduced or increased the PPAR-γ and cleaved caspase-8 protein levels, providing evidence and a mechanistic explanation of CatK’s involvement in PPAR-γ/caspase-8–mediated cell apoptosis in response to superoxide and stressed serum.Conclusions:These results demonstrate that CatK plays an essential role in kidney remodeling and hypertension in response to 5/6 nephrectomy or stress, possibly via a reduction of glomerular inflammation, apoptosis, and fibrosis, suggesting a novel therapeutic strategy for controlling kidney injury in mice under chronic psychological stress conditions.

Naringenin in Si-Ni-San formula inhibits chronic psychological stress-induced breast cancer growth and metastasis by modulating estrogen metabolism through FXR/EST pathway

IntroductionChronic psychological stress is a well-established risk factor for breast cancer development. Si-Ni-San (SNS) is a classical traditional Chinese medicine formula prescribed to psychological disorder patients. However, its action effects, molecular mechanisms, and bioactive phytochemicals against breast cancer are not yet clear. ObjectivesThis study aimed to explore the modulatory mechanism and bioactive compound of SNS in regulating estrogen metabolism during breast cancer development induced by chronic psychological stress. MethodsMouse breast cancer xenograft was used to determine the effect of SNS on breast cancer growth and metastasis. Metabolomics analysis was conducted to discover the impact of SNS on metabolic profile changes in vivo. Multiple molecular biology experiments and breast cancer xenografts were applied to verify the anti-metastatic potentials of the screened bioactive compound. ResultsSNS remarkably inhibited chronic psychological stress-induced breast cancer growth and metastasis in the mouse breast cancer xenograft. Meanwhile, chronic psychological stress increased the level of cholic acid, accompanied by the elevation of estradiol. Mechanistic investigation demonstrated that cholic acid activated farnesoid X receptor (FXR) expression, which inhibited hepatocyte nuclear factor 4α (HNF4α)-mediated estrogen sulfotransferase (EST) transcription in hepatocytes, and finally resulting in estradiol elevation. Notably, SNS inhibited breast cancer growth by suppressing estradiol level via modulating FXR/EST signaling. Furthermore, luciferase-reporting gene assay screened naringenin as the most bioactive compound in SNS for triggering EST activity in hepatocytes. Interestingly, pharmacokinetic study revealed that naringenin had the highest absorption in the liver tissue. Following in vivo and in vitro studies demonstrated that naringenin inhibited stress-induced breast cancer growth and metastasis by promoting estradiol metabolism via FXR/EST signaling. ConclusionThis study not only highlights FXR/EST signaling as a crucial target in mediating stress-induced breast cancer development, but also provides naringenin as a potential candidate for breast cancer endocrine therapy via promoting estradiol metabolism.

Abstract 24: The effect of chronic psychological stress during puberty and early adulthood on mammary gland development and mammary cancer risk in adulthood

Abstract Breast cancer is the second most common cancer among women in the United States. Puberty is a well-established sensitive period in women when breast cancer (BC) risk is increased by the physical environment for example exposure to chemical carcinogens, synthetic estrogens, endocrine disrupters, radiation, etc. However, relatively little is known about effects of exposure to chronic psychological stress from the social environment during this time period (puberty and early adulthood). In previous studies using the Sprague-Dawley rat model of spontaneous mammary cancer, chronically heightened glucocorticoid stress reactivity arising from imposed social isolation after weaning increased duration of glucocorticoid release in response to everyday stressors, impeded mammary gland ductal development, and caused earlier and more aggressive mammary gland cancer incidence during adulthood. However due to the period of isolation lasting from weaning to death, a critical time period in which these changes occurred was not established. Here we found that chronic social isolation only during puberty and early adulthood results in alterations in mammary gland gene expression patterns and preservation of mammary stem/progenitor cells. We have observed that social isolation beginning at five weeks and ending at 21 weeks leads to a 4-fold increase in the key metabolic lipogenic enzymes ATP citrate lyase (ACLY; p-value = 0.008), 2-fold increase in acetyl-CoA carboxylase (Acaca; p-value=0.01), and 1.88-fold change in stearoyl-CoA desaturase 1 (Scd1; p-value = 0.50). Interestingly, we have also observed that social isolation during this time period, leads to a slight decrease (0.70-fold change) in hexokinase 2 (HK2; p-value= 0.007). Regarding mammary stem/progenitor cell preservation, we found that social isolation beginning at five weeks and ending at 17 weeks leads to a significant increase in the number of mammary gland stem/progenitor cells (isolated by FACS sorting). This correlation was only observed in response to corticosterone reactivity, and null to exposure to estrogen or progesterone. In summary, our findings suggest that social isolation during puberty and early adulthood correlates to increased glucocorticoid exposure resulting in metabolic reprogramming in the mammary gland and inappropriate preservation of mammary stem/progenitor cells. Altogether these factors may increase the risk of mammary cancer occurrence later in adulthood. Citation Format: Briana Banks, Marianna Johnson, Joscelyn Hoffmann, Hannah You, Matt Piron, Suzanne Conzen, Martha McClintock, Matthew Brady. The effect of chronic psychological stress during puberty and early adulthood on mammary gland development and mammary cancer risk in adulthood [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 24.

Impact of Chronic Prenatal Stress on Maternal Neuroendocrine Function and Embryo and Placenta Development During Early-to-Mid-Pregnancy in Mice.

Psychological stress, both leading up to and during pregnancy, is associated with increased risk for negative pregnancy outcomes. Although the neuroendocrine circuits that link the stress response to reduced sexual motivation and mating are well-described, the specific pathways by which stress negatively impacts gestational outcomes remain unclear. Using a mouse model of chronic psychological stress during pregnancy, we investigated 1) how chronic exposure to stress during gestation impacts maternal reproductive neuroendocrine circuitry, and 2) whether stress alters developmental outcomes for the fetus or placenta by mid-pregnancy. Focusing on the stress-responsive neuropeptide RFRP-3, we identified novel contacts between RFRP-3-immunoreactive (RFRP-3-ir) cells and tuberoinfundibular dopaminergic neurons in the arcuate nucleus, thus providing a potential pathway linking the neuroendocrine stress response directly to pituitary prolactin production and release. However, neither of these cell populations nor circulating levels of pituitary hormones were affected by chronic stress. Conversely, circulating levels of steroid hormones relevant to gestational outcomes (progesterone and corticosterone) were altered in chronically-stressed dams across gestation, and those dams were qualitatively more likely to experience delays in fetal development. Together, these findings suggest that, up until at least mid-pregnancy, mothers appear to be relatively resilient to the effects of elevated glucocorticoids on reproductive neuroendocrine system function. We conclude that understanding how chronic psychological stress impacts reproductive outcomes will require understanding individual susceptibility and identifying reliable neuroendocrine changes resulting from gestational stress.

The anxiogenic effects of adolescent psychological stress in male and female mice

Adolescence is a period of transition during which there is extensive development of the brain and the hypothalamic-pituitary-adrenal axis. However, the term adolescence is broad and covers a number of important developmental periods ranging from pre-pubescence to sexual maturity. Using a predator stress model, we investigated the effects of chronic psychological stress on anxiety-like, depression-like, and social behaviours in male and female mice during early adolescence, when mice are pre-pubertal, and late adolescence, when mice are sexually mature. All stressed mice showed hyperactivity and increased anxiety-like behaviours. The anxiogenic effects were generally more pronounced in mice exposed to late, rather than early adolescent stress, but were clearly evident when stress was experienced at either timepoint. Risk assessment behaviours were also affected by the stress treatments, but the direction of these changes were sometimes sex- and age-specific. Surprisingly, mice stressed during adolescence showed no depressive-like behaviours as adults. This study provides evidence that adolescent psychological stress has pronounced long-term anxiogenic effects but that the precise behavioural phenotype differs based on sex and the sub-stage of adolescence during which the individual is exposed.

Maternal Chronic Perceived Stress, but Not Acute Stress Exposure, Is Associated With Ghrelin Levels Among Hispanic Pregnant Women With Overweight or Obesity

ObjectivesThe aim of this study is to test the effects of maternal chronic and acute psychological stress on plasma ghrelin levels among pregnant women with overweight or obesity.MethodsN = 33 Hispanic women without diabetes and a pre-pregnancy BMI of 25.0–34.9 Kg/m2 participated in a crossover study at 28–32 weeks’ gestation. Perceived stress levels over the past month were assessed by the Perceived Stress Scale. Women attended the lab in the fasted state on two separate days and consumed a breakfast shake immediately after a fasting blood and saliva sample collection on each visit, followed by a 15 minute task: friendly conversation (control) on visit 1 or the standardized Trier Social Stress Test on visit 2 to elicit acute stress. Six postprandial blood and saliva samples were collected at intervals up to 2 hours post-prandial and assayed for ghrelin and cortisol, respectively. The area-under-the-curve (AUC) for ghrelin and cortisol were computed. Differences in ghrelin AUC between visits were compared by paired t-tests and repeated measures ANOVA adjusting for gestational age at visit 2. Associations between perceived stress scores with fasting and ghrelin AUC, and between cortisol AUC and ghrelin AUC following acute stress exposure were analyzed by linear regression, adjusting for gestational age.ResultsPerceived stress score was positively associated with ghrelin levels both in the fasted (beta = 0.06, p = 0.02, 95% CI = 0.01, 0.12) and postprandial state (beta = 0.05, p = 0.02, 95% CI = 0.01, 0.09), which remained significant after adjusting for gestational age. Mean ghrelin AUC following a meal was lower after acute stress compared to the control condition (10.19 ± 0.37 vs 10.24 ± 0.40, p = 0.03), but this difference was not significant after adjusting for gestational age (p = 0.59). Salivary cortisol reactivity to acute stress was also not associated with ghrelin AUC (beta = −0.02, p = 0.92, 95% CI = −0.38, 0.35).ConclusionsChronic perceived stress in pregnant women with overweight and obesity may contribute to higher ghrelin levels both in the fasted state and after consuming a meal. Postprandial ghrelin is not affected by acute stress exposure in this population of women in the third trimester of pregnancy.Funding SourcesNational Institute of Child Health and Human Development.

Chronic Psychological Stress Disrupts Iron Metabolism and Enhances Hepatic Mitochondrial Function in Mice.

To explore the changes in iron metabolism and mitochondrial function exposed to chronic psychological stress, seventy-five male mice aged 5 ~ 6weeks were randomly sorted into 2 groups: control group and chronic psychological stress group. Mice were conducted by communication box to induce psychological stress for 21 consecutive days. The results showed that chronic psychological stress led to a significant reduction in average daily gain (P < 0.01) and the final weight (P < 0.05). Chronic psychological stress greatly increased plasma and duodenal iron level (P < 0.05), whereas markedly decreased hepatic iron content in mice (P < 0.05). Increasing expression of duodenal DCYTB and FPN (P < 0.05) was observed in mice exposed to chronic psychological stress. Moreover, chronic psychological stress greatly enhanced hepatic TFR1, FTL, and FPN protein expression (P < 0.05) in mice. Additionally, chronic psychological stress enhanced the levels of hepatic NADH, NAD + , ATP, mtDNA content, mtDNA-encoded genes, and the activity of mitochondrial complex I and II (P < 0.05). Taken together, chronic psychological stress impairs growth, disrupts iron metabolism, and enhances hepatic mitochondrial function in mice. These results will provide new insights for understanding the mechanisms of iron metabolism and mitochondrial function during chronic psychological stress.

Family and Individual Quality of Life in Parents of Children with Developmental Disorders and Diabetes Type 1.

Background: This cross-sectional study assessed both family and individual quality of life (QOL), and their association with self-esteem, optimism, chronic psychological stress, anxiety, and depression in parents of children with chronic conditions. Methods: Parents of children with Down syndrome (DS), autistic spectrum disorder (ASD), cerebral palsy (CP), diabetes mellitus type 1 (DMT1), and parents of children without chronic diseases with typical development (TD) were included. Multivariate linear regression analysis was used to assess parental characteristics associated with the domains of individual and family QOL. Results: Compared to the parents of TD children, parents of children with ASD and DS were more likely to report reduced family QOL in all domains, while parents of children with DMT1 had lower parental perception. Self-esteem was positively associated with all domains of individual QOL, while optimism was associated with the overall individual QOL perception and health. Higher stress perception was negatively associated with most of the domains of individual and family QOL. Conclusions: This study confirmed that parents of children with chronic conditions are more likely to have lower perception of both individual and family QOL, which were associated with self-esteem, chronic stress, anxiety, and depression. Interventions should focus not only on the child with a chronic condition but on parents too.

Scream Sound-induced Chronic Psychological Stress Results in Diminished Ovarian Reserve in Adult Female Rat

It is well established that chronic psychological stress (PS) induces female reproductive dysfunction. However, the studies on the consequences of chronic PS exposure precisely targeting ovarian reserve are lacking. In the present study, we employed a chronic scream sound-induced PS model to investigate the potential effect of pure psychosocial stressors on ovary reserve. Female rats were subjected to scream sound stress, white noise, or background for 3 weeks. Animals were euthanized by cervical dislocation after stress for collection of blood or ovaries. Sex hormones were analyzed by enzyme-linked immunosorbent assay. The follicle number was examined by histopathology. Granulosa cell apoptosis of the ovaries was examined by in situ cell death detection kit. Finally, rats were mated with proven fertile male rats to study fertility parameters. Female rats exposed to scream sound were presented with reduced weight gain and sucrose preference, while immobility time in forced swim test and serum corticosterone concentration were significantly increased. Scream sound stress sequentially decreased plasma anti-Müllerian hormone and estradiol concentration, induced primordial and preantral follicles loss, augmented granulosa cell apoptosis in ovarian growing follicles, and eventually decreased litter sizes. Based on these results, we suggest that chronic PS induced loss of ovarian reserve by accelerated primordial follicle activation and destruction of growing follicles, which results in follicle depletion and decreased fertility.

Chronic Stress Induces Hippocampal Mitochondrial Damage in APPPS1 Model Mice and Wildtype Littermates.

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia worldwide. Despite decades of investigation, the etiology of AD is not fully understood, although emerging evidence suggest that chronic environmental and psychological stress plays a role in the mechanisms and contributes to the risk of developing AD. Thus, dissecting the impact of stress on the brain could improve our understanding of the pathological mechanisms. We aimed to study the effect of chronic stress on the hippocampal proteome in male APPPS1 transgenic mice and wildtype (WT) littermates. APPPS1 and WT mice were subjected to 4 weeks of chronic stress followed by 3 weeks of continued diurnal disruption. Hippocampal tissue was used for proteomics analysis using label-free quantitative DIA based LC-MS/MS analysis. We identified significantly up- and downregulated proteins in both APPPS1 and WT mice exposed to chronic stress compared to the control groups. Via interaction network mapping, significant proteins could be annotated to specific pathways of mitochondrial function (oxidative phosphorylation and TCA cycle), metabolic pathways, AD pathway and synaptic functions (long term potentiation). In WT mice, chronic stress showed the highest impact on complex I of the oxidative phosphorylation pathway, while in APPPS1 mice this pathway was compromised broadly by chronic stress. Our data shows that chronic stress and amyloidosis additively contribute to mitochondrial damage in hippocampus. Although these results do not explain all effects of chronic stress in AD, they add to the scientific knowledge on the topic.

Chronic psychological stress alters gene expression in rat colon epithelial cells promoting chromatin remodeling, barrier dysfunction and inflammation.

Chronic stress is commonly associated with enhanced abdominal pain (visceral hypersensitivity), but the cellular mechanisms underlying how chronic stress induces visceral hypersensitivity are poorly understood. In this study, we examined changes in gene expression in colon epithelial cells from a rat model using RNA-sequencing to examine stress-induced changes to the transcriptome. Following chronic stress, the most significantly up-regulated genes included Atg16l1, Coq10b, Dcaf13, Nat2, Ptbp2, Rras2, Spink4 and down-regulated genes including Abat, Cited2, Cnnm2, Dab2ip, Plekhm1, Scd2, and Tab2. The primary altered biological processes revealed by network enrichment analysis were inflammation/immune response, tissue morphogenesis and development, and nucleosome/chromatin assembly. The most significantly down-regulated process was the digestive system development/function, whereas the most significantly up-regulated processes were inflammatory response, organismal injury, and chromatin remodeling mediated by H3K9 methylation. Furthermore, a subpopulation of stressed rats demonstrated very significantly altered gene expression and transcript isoforms, enriched for the differential expression of genes involved in the inflammatory response, including upregulation of cytokine and chemokine receptor gene expression coupled with downregulation of epithelial adherens and tight junction mRNAs. In summary, these findings support that chronic stress is associated with increased levels of cytokines and chemokines, their downstream signaling pathways coupled to dysregulation of intestinal cell development and function. Epigenetic regulation of chromatin remodeling likely plays a prominent role in this process. Results also suggest that super enhancers play a primary role in chronic stress-associated intestinal barrier dysfunction.

Keratinocytes take part in the regulation of substance P in melanogenesis through the HPA axis

BackgroundClinical findings have shown that skin depigmentation disorder such as vitiligo may be closely associated with the release of central and peripheral substance P (SP) resulted from chronic psychological stress or sudden mental blow. But the regulatory role of SP and its receptor, tachykinin receptor in the pathogenesis of vitiligo is unclear. ObjectivesTo investigate the function and mechanism of SP in melanogenesis. MethodsThe chronic mental stress was used to explore the intrinsic association between psychological factors, SP and melanogenesis disorder. The effect of SP on melanogenesis through hypothalamic pituitary adrenocortical (HPA) axis was studied by skin culture in vitro. The conditioned medium experiment demonstrated the indirect effect of SP on melanogenesis of B16F10 cells through HaCaT cells. The ability to produce melanin was evaluated by detecting melanin and tyrosinase activity. qRT-PCR, western blotting and immunohistochemistry were used to detect the expression of related genes and proteins in melanogenesis and HPA axis. ResultsIncreased SP expression and reduction of melanogenesis in the skin of mice were observed under mental stress. Melanogenesis was suppressed in the cultured human skin treated with SP due to the down-regulation of melanin-related proteins and HPA axis genes. The melanogenesis of B16F10 cells was inhibited by the conditioned medium of HaCaT cells treated with SP. ConclusionsOverall, these results indicate that excess SP originated from mental stress interferes with melanogenesis through keratinocytes in the skin. The HPA axis is the key downstream to perceive the SP signaling and furtherly regulate the melanogenesis.

Effects of Concurrent Exposure to Chronic Restraint-Induced Stress and Total-Body Iron Ion Radiation on Induction of Kidney Injury in Mice.

Concurrent exposure to ionizing radiation (IR) and psychological stress (PS) may affect the development of adverse health consequences in scenarios such as space missions, radiotherapy and nuclear accidents. IR can induce DNA damage and cell apoptosis in the kidneys, thus potentially leading to renal fibrosis, which is the ultimate outcome of various chronic progressive nephropathies and the morphological manifestation of a continuous coordinated response after renal injury. However, little is known regarding the effects of concurrent IR exposure and PS on renal damage, particularly renal fibrosis. In this study, using a chronic restraint-induced PS (CRIPS) model, we exposed Trp53-heterozygous mice to total body irradiation with 0.1 or 2 Gy 56Fe ions on the eighth day of 28 consecutive days of a restraint regimen. At the end of the restraint period, the kidneys were collected. The histopathological changes and the degree of kidney fibrosis were assessed with H&E and Masson staining, respectively. Fibronectin (FN) and alpha smooth muscle actin (α-SMA), biomarkers of fibrosis, were detected by immunohistochemistry. Analysis of 8-hydroxy-2 deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, was performed with immunofluorescence, and terminal deoxynucleotidyl transferase-mediated nick end labeling assays were used to detect apoptotic cells. Histopathological observations did not indicate significant structural damage induced by IR or CRIPS + IR. Western blotting revealed that the expression of α-SMA was much higher in the CRIPS + IR groups than the CRIPS groups. However, no differences in the average optical density per area were observed for FN, α-SMA and 8-OHdG between the IR and CRIPS + IR groups. No difference in the induction of apoptosis was observed between the IR and CRIPS + IR groups. These results suggested that exposure to IR (0.1 and 2 Gy 56Fe ions), 28 consecutive days of CRIPS or both did not cause renal fibrosis. Thus, CRIPS did not alter the IR-induced effects on renal damage in Trp53-heterozygous mice in our experimental setup.