Exaggerated Stress Response Research Articles

LPS-induced whole-blood cytokine production and depressive symptoms in dementia spousal caregivers: The moderating effect of childhood trauma

Dementia spousal caregivers are at risk for adverse mental and physical health outcomes. Caregiver burden, anticipatory grief, and proinflammatory cytokine production may contribute to depressive symptoms among caregivers. People who report childhood trauma are more likely to have exaggerated stress responses that may also contribute to depressive symptoms in adulthood. This study aimed to test whether the relationship between whole-blood cytokine production and depressive symptoms is strongest in caregivers who report high levels of childhood trauma. MethodsA sample of 103 dementia spousal caregivers provided self-report data on demographics, health information, caregiver burden, anticipatory grief, and depressive symptoms. We also determined lipopolysaccharide-induced whole-blood cytokine production as the primary measure of immune cell reactivity. We measured interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-10 (IL-10) and converted z-scores of each cytokine into a composite panel. We regressed depressive symptoms on proinflammatory cytokine production, caregiver burden, and anticipatory grief, adjusting for demographic and health-related covariates. ResultsWhole-blood cytokine production and childhood trauma were associated with depressive symptoms. Childhood trauma moderated the relationship between whole-blood cytokine production and depressive symptoms. Whole-blood cytokine production was only associated with depressive symptoms at mean and high levels of childhood trauma, but not at low levels of childhood trauma. The main effects of burden and anticipatory grief on depressive symptoms were strongest for caregivers reporting high levels of childhood trauma. DiscussionChildhood trauma has lasting impacts on psychosocial experiences later in life and has effects that may confer susceptibility to inflammation-related depression. Our findings contribute to ongoing efforts to identify risk factors for adverse mental health in dementia spousal caregivers.

Retention of stress susceptibility in the mdx mouse model of Duchenne muscular dystrophy after PGC-1α overexpression or ablation of IDO1 or CD38.

Duchenne muscular dystrophy (DMD) is a lethal degenerative muscle wasting disease caused by the loss of the structural protein dystrophin with secondary pathological manifestations including metabolic dysfunction, mood and behavioral disorders. In the mildly affected mdx mouse model of DMD, brief scruff stress causes inactivity, while more severe subordination stress results in lethality. Here, we investigated the kynurenine pathway of tryptophan degradation and the nicotinamide adenine dinucleotide (NAD+) metabolic pathway in mdx mice and their involvement as possible mediators of mdx stress-related pathology. We identified downregulation of the kynurenic acid shunt, a neuroprotective branch of the kynurenine pathway, in mdx skeletal muscle associated with attenuated peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) transcriptional regulatory activity. Restoring the kynurenic acid shunt by skeletal muscle-specific PGC-1α overexpression in mdx mice did not prevent scruff -induced inactivity, nor did abrogating extrahepatic kynurenine pathway activity by genetic deletion of the pathway rate-limiting enzyme, indoleamine oxygenase 1. We further show that reduced NAD+ production in mdx skeletal muscle after subordination stress exposure corresponded with elevated levels of NAD+ catabolites produced by ectoenzyme cluster of differentiation 38 (CD38) that have been implicated in lethal mdx response to pharmacological β-adrenergic receptor agonism. However, genetic CD38 ablation did not prevent mdx scruff-induced inactivity. Our data do not support a direct contribution by the kynurenine pathway or CD38 metabolic dysfunction to the exaggerated stress response of mdx mice.

Surgical Stress and Cancer Progression: New Findings and Future Perspectives.

The stress response to surgery is essential for maintaining homeostasis and exhibits anti-tumor effects; however, an ongoing and exaggerated stress response may have adverse clinical consequences and even promote cancer progression. This review will discuss the complex relationship between surgical stress and cancer progression. Surgical stress exhibits both anti-tumor and cancer-promoting effects by causing changes in the neuroendocrine, circulatory, and immune systems. Many studies have found that many mechanisms are involved in the process, and the corresponding targets could be applied for cancer therapy. Although surgical stress may have anti-tumor effects, it is necessary to inhibit an excessive stress response, mostly showing cancer-promoting effects.

Case Report - An Unusual Case of Vanishing White Matter Disease with Cataract and Exaggerated Stress Response

Case Report - An Unusual Case of Vanishing White Matter Disease with Cataract and Exaggerated Stress Response

Voluntary wheel running behaviour as a tool to assess the severity in a mouse pancreatic cancer model.

Laboratory animals frequently undergo routine experimental procedures such as handling, restraining and injections. However, as a known source of stress, these procedures potentially impact study outcome and data quality. In the present study, we, therefore, performed an evidence-based severity assessment of experimental procedures used in a pancreatic cancer model including surgical tumour induction and subsequent chemotherapeutic treatment via repeated intraperitoneal injections. Cancer cell injection into the pancreas was performed during a laparotomy under general anaesthesia. After a four-day recovery phase, mice received either drug treatment (galloflavin and metformin) or the respective vehicle substances via daily intraperitoneal injections. In addition to clinical scoring, an automated home-cage monitoring system was used to assess voluntary wheel running (VWR) behaviour as an indicator of impaired well-being. After surgery, slightly elevated clinical scores and minimal body weight reductions, but significantly decreased VWR behaviour were observed. During therapy, body weight declined in response to chemotherapy, but not after vehicle substance injection, while VWR activity was decreased in both cases. VWR behaviour differed between treatment groups and revealed altered nightly activity patterns. In summary, by monitoring VWR a high impact of repeated injections on the well-being of mice was revealed and substance effects on well-being were distinguishable. However, no differences in tumour growth between treatment groups were observed. This might be due to the severity of the procedures uncovered in this study, as exaggerated stress responses are potentially confounding factors in preclinical studies. Finally, VWR was a more sensitive indicator of impairment than clinical scoring in this model.

Single paternal dexamethasone challenge programs offspring metabolism and reveals multiple candidates in RNA-mediated inheritance

SummarySingle traumatic events that elicit an exaggerated stress response can lead to the development of neuropsychiatric conditions. Rodent studies suggested germline RNA as a mediator of effects of chronic environmental exposures to the progeny. The effects of an acute paternal stress exposure on the germline and their potential consequences on offspring remain to be seen. We find that acute administration of an agonist for the stress-sensitive Glucocorticoid receptor, using the common corticosteroid dexamethasone, affects the RNA payload of mature sperm as soon as 3 hr after exposure. It further impacts early embryonic transcriptional trajectories, as determined by single-embryo sequencing, and metabolism in the offspring.We show persistent regulation of tRNA fragments in sperm and descendant 2-cell embryos, suggesting transmission from sperm to embryo. Lastly, we unravel environmentally induced alterations in sperm circRNAs and their targets in the early embryo, highlighting this class as an additional candidate in RNA-mediated inheritance of disease risk.

The dysregulation of the hypothalamic\u2013pituitary\u2013adrenal axis in diet-induced prediabetic male Sprague Dawley rats

BackgroundAltered function of the hypothalamic–pituitary–adrenal (HPA) axis in type 2 diabetic patients, a condition preceded by pre-diabetes, has been shown to increase the risk of depression as well as cause downstream effects resulting in upregulation of gluconeogenesis and dyslipidemia. In addition, stress, either psychological from managing diabetes or lifestyle related, further activates the HPA axis causing an exaggerated stress response. This study investigated the activity of the HPA axis in selected markers of glucose handling, and the stress response relative to components of the HPA axis in a diet-induced pre-diabetic rat model.MethodsSprague Dawley Rats were randomly divided into non-pre-diabetic group (NPD) and pre-diabetic group (PD) (n = 6, per group) over a 20-week induction period and a further 12-week experimental period to get 32 weeks. At the end of the 20 and 32-week periods, glucose handling using the Homeostasis Model Assessment indices, adrenocorticotropic (ACTH) and corticosterone (CORT) concentrations were measured. Stress was induced and the forced swim test were performed in the 12-week experimental week. At the end of 32 weeks glucocorticoid and mineralocorticoid hippocampal receptors were also measured.ResultsImpaired glucose handling in the PD group as well as increase in corticosterone was observed at the end of both 20 and 32-week periods by comparison to NPD groups. No changes were observed in ACTH concentration at week 20 while, at week 32, a decrease in plasma ACTH concentration was observed in the PD group by comparison to the NPD group. The stressed-induced animals were stressed using the forced swim test: the behaviour observed showed an increase in immobility time in the PD stressed group by comparison to the NPD group. This was followed by the observation of a decrease in ACTH and CORT concentration in the PD stressed group by comparison to the NPD stressed group. Mineralocorticoid and glucocorticoid receptors gene expression were elevated in the stressed PD group relative to the stressed NPD group.ConclusionThese observations, together, suggest that diet-induced pre-diabetes is associated with impaired HPA axis activity and deteriorating response to stress.

Firing activity of locus coeruleus noradrenergic neurons decreases in necdin-deficient mice, an animal model of Prader\u2013Willi syndrome

BackgroundPrader–Willi syndrome (PWS) is a neurodevelopmental disorder characterized by multiple respiratory, cognitive, endocrine, and behavioral symptoms, such as central apnea, intellectual disabilities, exaggerated stress responses, and temper tantrums. The locus coeruleus noradrenergic system (LC-NE) modulates a diverse range of behaviors, including arousal, learning, pain modulation, and stress-induced negative affective states, which are possibly correlated with the pathogenesis of PWS phenotypes. Therefore, we evaluated the LC-NE neuronal activity of necdin-deficient mice, an animal model of PWS.MethodsHeterozygous necdin-deficient mice (B6.Cg-Ndntm1ky) were bred from wild-type (WT) females to generate WT (+m/+p) and heterozygotes (+m/−p) animals, which were examined of LC-NE neuronal activity, developmental reflexes, and plethysmography.ResultsOn slice electrophysiology, LC-NE neurons of Ndntm1ky mice with necdin deficiency showed significantly decreased spontaneous activities and impaired excitability, which was mediated by enhanced A-type voltage-dependent potassium currents. Ndntm1ky mice also exhibited the neonatal phenotypes of PWS, such as hypotonia and blunt respiratory responses to hypercapnia.ConclusionsLC-NE neuronal firing activity decreased in necdin-deficient mice, suggesting that LC, the primary source of norepinephrine in the central nervous system, is possibly involved in PWS pathogenesis.

Abstract # 3143 Inflammatory markers in postpartum depression – a sign of an exaggerated stress response?

Compared with major depressive disorder, postpartum depression and its relation to immune activation and inflammation is less studied. Postpartum, after vast adaptations of the immune system during pregnancy, the immune system needs to return to a non-pregnant state, during a period of immune challenging events, such as wound healing, sleep loss, and a fall in levels of proteins and hormones. The study aim was to investigate potential differences in peripheral levels of immune related biomarkers in women with and without postpartum depression (n = 62 and 107 respectively). Among the 71 markers analyzed with multiplex proximity extension assay, five were significantly elevated in women with postpartum depressive symptoms in the adjusted LASSO logistic regression analysis, including TRANCE (OR = 1.20), HGF (OR = 1.17), IL-18 (OR = 1.06), FGF-23 (OR = 1.25), and CXCL1 (OR 1.11). Previously, HGF, IL-18 as well as FGF-23 have been reported lower in severe forms of depression while high levels of IL-18 and CXCL1 have been associated to stress responses. The delivery triggers stress-induced immune responses. Our results might be due to an elevated response to stress as immune reactions previously has been associated with exaggerated inflammation in women with depressive symptoms. Future research should evaluate the relevance of the identified markers, in combination with other known risk factors for postpartum depression. .

Improved glucose homeostasis in male obese Zucker rats coincides with enhanced baroreflexes and activation of the nucleus tractus solitarius.

Young adult male obese Zucker rats (OZR) develop insulin resistance and hypertension with impaired baroreflex-mediated bradycardia and activation of nucleus tractus solitarius (NTS). Because type 1 diabetic rats also develop impaired baroreflex-mediated NTS activation, we hypothesized that improving glycemic control in OZR would enhance compromised baroreflexes and NTS activation. Fasting blood glucose measured by telemetry was comparable in OZR and lean Zucker rats (LZR) at 12-17 wk. However, with access to food, OZR were chronically hyperglycemic throughout this age range. By 15-17 wk of age, tail samples yielded higher glucose values than those measured by telemetry in OZR but not LZR, consistent with reports of exaggerated stress responses in OZR. Injection of glucose (1g/kg ip) produced larger rises in glucose and areas under the curve in OZR than LZR. Treatment with metformin (300 mg·kg-1·day-1) or pioglitazone (5 mg·kg-1·day-1) in drinking water for 2-3 wk normalized fed glucose levels in OZR with no effect in LZR. After metformin treatment, area under the curve for blood glucose after glucose injection was reduced in OZR and comparable to LZR. Hyperinsulinemia was slightly reduced by each treatment in OZR, but insulin was still greatly elevated compared with LZR. Neither treatment reduced hypertension in OZR, but both treatments significantly improved the blunted phenylephrine-induced bradycardia and NTS c-Fos expression in OZR with no effect in LZR. These data suggest that restoring glycemic control in OZR enhances baroreflex control of heart rate by improving the response of the NTS to raising arterial pressure, even in the presence of hyperinsulinemia and hypertension.

The Impact of Tobacco Cigarette Smoking on Spinal Cord Stimulation Effectiveness in Chronic Spine-Related Pain Patients.

Despite the observation that select nicotine receptor agonists have analgesic effects, smokers report higher pain scores and more functional impairments than lifelong nonsmokers, attributable to exaggerated stress responses, receptor desensitization, and altered pharmacokinetics compounded by accelerated structural damage resulting from impaired bone healing, osteoporosis, and advancement of disk disease. We hypothesized that smoking diminishes the analgesic response to spinal cord stimulation (SCS) in patients with chronic spine-related pain conditions. A retrospective cohort study was performed at Cleveland Clinic by collecting and assessing data of 213 patients who had been implanted with SCS for spine-pain indications. History of tobacco smoking was subcategorized into 3 categories: past (former smoker), present (current smoker), or those who had never previously smoked (lifelong nonsmokers), and a multivariable linear regression was run to measure the correlation, if any, between smoking status and numerical rating scale pain score. In addition, opioid consumption at baseline and 12-month follow-up, expressed in milligram oral morphine equivalents, was collected and compared. Adjusted for differences, at 1-year follow-up, current smokers (n = 62) reported numerical rating scale pain score of 7.0, which is 1.93 (P < 0.001) and 1.32 (P = 0.001) points higher than those of lifelong nonsmokers (n = 77) and former smokers (n = 74), respectively. Opioid intake was 2.4 times higher (P = 0.004) in smokers than in lifelong nonsmokers. Among our SCS-implanted sample, a positive correlation was observed between tobacco use and degree of pain reduction as early as 12 months postimplant; this was evident by the reported higher pain scores and opioid use in current smokers in comparison with former smokers and lifelong nonsmokers.

Mild prenatal hypoxia-ischemia leads to social deficits and central and peripheral inflammation in exposed offspring

Hypoxic-ischemic encephalopathy (HIE) resulting from intrauterine or perinatal hypoxic-ischemia (HI) is a leading cause of long-term neonatal neurodisability. While most studies of long-term outcome have focused on moderate and severe HIE in term infants, recent work has shown that those with mild HIE may have subtle neurological impairments. However, the impact of mild HI on pre-term infants is much less clear given that pre-term birth is itself a risk factor for neurodisability. Here we show that mild HI insult alters behaviour, inflammation and the corticosterone stress response in a rat model of pre-term HIE. Mild HI exposure led to social deficits in exposed offspring at postnatal day 30, without impairments in the novel object recognition test nor in the open field test. This was also accompanied by elevations in circulating adrenocorticotropic hormone and corticosterone indicating an exaggerated stress response. There were also elevations in il-1β and il-6 but not tnf-α mRNA and protein in the brain and blood samples. In summary we find that a mild HI exposure leads to social deficits, central and peripheral inflammation, and an abnormal corticosterone response which are three core features of autism spectrum disorder. This shows that mild HI exposure may be a risk factor for an abnormal neurodevelopmental outcome in pre-term offspring.

Assessment of adrenocortical reserve capacity and inflammatory parameters in critically ill dogs.

Inflammatory markers and adrenocorticotropic hormone (ACTH) stimulation test results may help us recognise critically ill dogs with poor disease outcome. Systemic inflammatory response syndrome (SIRS) criteria, the fast version of the Acute Patient Physiologic and Laboratory Evaluation Score (APPLEfast), complete blood count, albumin and C-reactive protein (CRP) levels, baseline and stimulated cortisol levels and Δcortisol value were recorded in 50 client-owned dogs admitted to the Small Animal Hospital of the University of Veterinary Medicine Budapest with various inflammatory or neoplastic conditions. Increasing APPLEfast score was associated with a decreasing chance of survival (P = 0.0420). The Δcortisol value was significantly higher in SIRS dogs than in non-SIRS dogs (mean ± SD ΔcortisolSIRS: 342.5 ± 273.96; mean ± SD Δcortisolnon-SIRS: 175.3 ± 150.35; P = 0.0443). Elevated baseline or stimulated cortisol levels were associated with a higher chance of non-survival (P = 0.0135 and P = 0.0311, respectively). These data indicate that pathologically higher baseline and stimulated cortisol levels represent an exaggerated stress response in critically ill dogs, which is negatively associated with survival.

Interview with Dr H.R. Nagendra, Chancellor, Swami Vivekananda Yoga Anusandhana Samsthana (S-VYASA)

Health and wellness have become key considerations in human resource management in the context of stressful world of work in a highly globalized, technology-intensive and 24/7 work environment. Holistic development through Yoga, a ‘science of body, mind, consciousness and soul’, has been a part of the Indian culture for thousands of years, and the popularity of yoga as a means of physical and psychological well-being has been recently globally recognized with the United Nations (UN) declaring International Day of Yoga on 21 June 2015. According to Harvard Medical School, “available reviews of a wide range of yoga practices suggest they can reduce the impact of exaggerated stress responses and may be helpful for both anxiety and depression” (HMS ( 2015 ). Yoga for anxiety and depression. Boston: Harvard Health Publications, Harvard Medical School).

Oxytocin Regulates Stress-Induced Crf Gene Transcription through CREB-Regulated Transcription Coactivator 3.

The neuropeptide oxytocin has been proposed to reduce hypothalamic-pituitary-adrenal (HPA) axis activation during stress. The underlying mechanisms are, however, elusive. In this study we show that activation of the oxytocin receptor in the paraventricular nucleus delays transcription of the gene encoding corticotropin releasing factor (Crf), the main regulator of the stress response. It does so by sequestering the coactivator of the transcription factor CREB, CRTC3, in the cytosol, resulting in reduced binding of CRTC3 to the Crf gene promoter and subsequent Crf gene expression. This novel oxytocin receptor-mediated intracellular mechanism might provide a basis for the treatment of exaggerated stress responses in the future.

Exertional vs. Passive Heat Stroke: Altered Time Course of Cytokine Expression in Plasma and Skeletal Muscle

Exertional heat stroke (EHS) is a unique model where hyperthermia, exhaustive exercise, and other signals place simultaneous demands on the innate immune system. We hypothesized that when heat was superimposed on exercise there would be an exaggerated stress response due to the cumulative effect of these factors. To explore this, we determined cytokine protein expression in plasma and changes in skeletal muscle gene expression post EHS, passive heat stroke (PHS), exercise sham controls (EXC), and exhaustive exercise (EE) and compared these to naïve controls (NC). Gene expression was evaluated using qRT‐PCR in the diaphragm (DIA), soleus (SOL), and gastrocnemius (GASTROC) at 0.5, 3, 24, and 96 hrs after treatment. Plasma cytokine proteins were determined using Luminex. In EHS and in EXC, peak plasma IL‐6 was observed at 0.5 hr recovery; by 3 hrs it was not different from NC. Contrastingly, following PHS, IL‐6 reached a peak at 3 hrs. IL‐10 was also significantly elevated at 3 hrs in PHS, whereas in EXC and EHS there were no elevations. In EHS, IL‐6 mRNA in the SOL and DIA was increased 0.5 hr post treatment while IL‐10 was only increased in the DIA. In PHS, 30 min post, IL‐6 and IL‐10 mRNA were greatly elevated. Importantly, 30 min after EE or EXC, IL‐6 and IL‐10 mRNA in SOL and GASTROC were significantly suppressed relative to NC. SOCS3 (a downstream response to IL‐6 and IL‐10 receptor activation via JAK/STAT3) was measured as a possible mechanism for suppression of IL‐6 and IL‐10. In EHS SOCS3 was elevated at 30 min in SOL, implying cytokine signaling events began early during exercise or heat exposure. In conclusion, exercise superimposed on heat blunts overall cytokine production and shifts expression to earlier points in time.

Chronic stress, cortisol dysfunction, and pain: a psychoneuroendocrine rationale for stress management in pain rehabilitation.

Pain is a primary symptom driving patients to seek physical therapy, and its attenuation commonly defines a successful outcome. A large body of evidence is dedicated to elucidating the relationship between chronic stress and pain; however, stress is rarely addressed in pain rehabilitation. A physiologic stress response may be evoked by fear or perceived threat to safety, status, or well-being and elicits the secretion of sympathetic catecholamines (epinephrine and norepinepherine) and neuroendocrine hormones (cortisol) to promote survival and motivate success. Cortisol is a potent anti-inflammatory that functions to mobilize glucose reserves for energy and modulate inflammation. Cortisol also may facilitate the consolidation of fear-based memories for future survival and avoidance of danger. Although short-term stress may be adaptive, maladaptive responses (eg, magnification, rumination, helplessness) to pain or non-pain-related stressors may intensify cortisol secretion and condition a sensitized physiologic stress response that is readily recruited. Ultimately, a prolonged or exaggerated stress response may perpetuate cortisol dysfunction, widespread inflammation, and pain. Stress may be unavoidable in life, and challenges are inherent to success; however, humans have the capability to modify what they perceive as stressful and how they respond to it. Exaggerated psychological responses (eg, catastrophizing) following maladaptive cognitive appraisals of potential stressors as threatening may exacerbate cortisol secretion and facilitate the consolidation of fear-based memories of pain or non-pain-related stressors; however, coping, cognitive reappraisal, or confrontation of stressors may minimize cortisol secretion and prevent chronic, recurrent pain. Given the parallel mechanisms underlying the physiologic effects of a maladaptive response to pain and non-pain-related stressors, physical therapists should consider screening for non-pain-related stress to facilitate treatment, prevent chronic disability, and improve quality of life.

Stability of mental stress-induced hemodynamic and autonomic reaction despite successful treatment for psychosomatic disorder

Autonomic imbalance and exaggerated stress responses are associated with an increased risk of morbidity and mortality and have been associated with several psychosomatic disorders. Has in-patient psychotherapy any effect on autonomic regulation and mental stress reactivity? In 77 patients undergoing in-patient psychometric treatment psychometric examination and psychophysiological assessment of hemodynamic and autonomic parameters during rest and 2 mental stress tests was performed at the beginning and at the end of in-patient psychotherapy. Despite marked improvements in symptoms our short-term treatment for psychosomatic disorders did not affect autonomic and hemodynamic activation at rest or during stress testing. It remains to be investigated if increased physical activity and relaxation expected after improvement have beneficial physiological effects over longer time spans.

Should β-blockers be used in septic shock?

University of Pittsburgh Department of Critical Care Medicine: Evidence-Based Medicine Journal Club, edited by Sachin Yende

Differential visceral nociceptive, behavioural and neurochemical responses to an immune challenge in the stress-sensitive Wistar Kyoto rat strain

A highly regulated crosstalk exists between the immune and neuroendocrine systems with the altered immune responses in stress-related disorders being a valid example of this interaction. The Wister Kyoto (WKY) rat is an animal model with a genetic predisposition towards an exaggerated stress response and is used to study disorders such as depression and irritable bowel syndrome (IBS), where stress plays a substantial role. The impact of a lipopolysaccride (LPS) immune challenge has not yet been investigated in this animal model to date. Hence our aim was to assess if the stress susceptible genetic background of the WKY rat was associated with a differential response to an acute immune challenge. Central and peripheral parameters previously shown to be altered by LPS administration were assessed. Under baseline conditions, WKY rats displayed visceral hypersensitivity compared to Sprague Dawley (SD) control rats. However, only SD rats showed an increase in visceral sensitivity following endotoxin administration. The peripheral immune response to the LPS was similar in both strains whilst the central neurochemistry was blunted in the WKY rats. Sickness behaviour was also abrogated in the WKY rats. Taken together, these data indicate that the genetic background of the WKY rat mitigates the response to infection centrally, but not peripherally. This implies that heightened stress-susceptibility in vulnerable populations may compromise the coordinated CNS response to peripheral immune activation.