Role In Stress-related Disorders Research Articles

Understanding Work Ability in Employees with Pain and Stress-Related Ill-Health: An Explorative Network Analysis of Individual Characteristics and Psychosocial Work Environment.

There is a wide range of individual and work environment factors that influence work ability among workers with pain and stress-related ill-health. The multiple interactions and overlap between these factors are insufficiently understood, and a network approach could mitigate limitations of previous research. This pilot study aimed to explore interactions between individual characteristics and psychosocial work environment and potential links to long-term work ability. Prospective data from a prevention project was used. Individuals (N = 147) with pain and/or stress-related ill-health (95% women) at public sector workplaces filled out baseline questionnaires about a collection of individual and work environment factors, which were used for constructing undirected networks. The model was run in three subsamples of workplaces. Finally, a separate model was established with work ability at 6-month follow-up as outcome variable. A shortest pathway analysis was calculated to identify mediators of work ability. Symptom catastrophizing and perceived stress were the most influential factors in all network models. Symptom catastrophizing and pain-disability risk were found to mediate the relation between perceived stress and long-term work ability. Further, demand-control-support factors were interrelated, and patterns of interaction differed between different types of workplaces. The findings support the importance of individual factors, specifically symptom catastrophizing in an individual's coping with pain or stress-problems and its influence on long-term work ability. Catastrophizing might play a role in stress-related disorders which should be further investigated. Individual and work environment factors interact and vary across context, which needs to be taken into consideration to prevent pain and stress-related ill-health at work.

Altered regulation of oligodendrocytes associated with parvalbumin neurons in the ventral hippocampus underlies fear generalization in male mice.

Fear generalization is a neurobiological process by which an organism interprets a novel stimulus as threatening because of its similarity to previously learned fear-inducing stimuli. Because recent studies have suggested that the communication between oligodendrocyte precursor cells (OPCs) and parvalbumin (PV)-expressing GABAergic neurons (PV neurons) may play critical roles in stress-related disorders, we examined the involvement of these cells in fear generalization. We first tested the behavioral characteristics of mouse models for conventional fear conditioning (cFC) and modified FC (mFC) with severe electric foot shocks and found that fear generalization was observed in mice treated with mFC but not in mice treated with cFC. The expression levels of genes related to OPCs, oligodendrocytes (OLs), and myelin in the ventral hippocampus were lower in mFC mice than in cFC mice. The densities of OPCs and OLs were decreased in the ventral hippocampus of mFC mice compared to cFC mice. The myelination ratios of PV neurons in the ventral hippocampus were lower in mFC mice than in cFC mice. The chemogenetic activation of PV neurons in the ventral hippocampus of mFC mice reduced fear generalization. The expression levels of genes related to OPCs, OLs, and myelin were recovered following the activation of PV neurons. Finally, the myelination ratios of PV neurons were increased after the activation of PV neurons. Our results suggest that altered regulation of OLs specifically associated with axons of PV neurons in the ventral hippocampus may underlie the generalization of remote fear memory following severe stress exposure.

Increased Lactobacillus Abundance Contributes to Stress Resilience in Mice Exposed to Chronic Social Defeat Stress

Introduction: Accumulating evidence indicates that abnormalities in the composition of gastrointestinal (GI) microbiota play a vital role in stress-related disorders. Both human beings and animals perceive stressful events differently, i.e., resilience or susceptibility. However, the role of GI microbiota in stress resilience/susceptibility and the underlying mechanisms remain largely unknown. Methods and Results: Sixty male C57BL/6J mice were exposed to 10-day chronic social defeat stress (CSDS), and 28 were found to be resilient to CSDS. We next analyzed microbiota compositions in the cecum using 16S rDNA gene sequencing, which revealed a significant increase in the relative abundance of Lactobacillus at the genus level in the resilient mice. In subsequent experiments, we found that oral administration of a strain of Lactobacillus (Lactobacillus murinus) for 2 weeks attenuated the increased levels of stress-induced corticosterone and anxiety-like behavior in stress-susceptible mice. The mRNA expression of tryptophan hydroxylase 2 (a rate-limiting enzyme in serotonin [5-HT] synthesis) was also significantly increased in the dorsal raphe nucleus (DR) of stress-susceptible mice. Conclusions: Lactobacillus contributes to stress resilience, and the DR 5-HT system may play an important role during this process. The above results suggest that certain organisms in the GI tract may play an essential role in stress response and be useful in the prevention and treatment of some stress-related psychiatric disorders, such as depression.

Saliva metabolome alterations after acute stress

Major stress has systemic effects on the body that can have adverse consequences for physical and mental health. However, the molecular basis of these damaging effects remains incompletely understood. Here we use a longitudinal approach to characterise the acute systemic impact of major psychological stress in a pig model. We perform untargeted metabolomics on non-invasively obtained saliva samples from pigs before and 24 h after transfer to the novel physical and social environment of a slaughterhouse. The main molecular changes occurring include decreases in amino acids, B-vitamins, and amino acid-derived metabolites synthesized in B-vitamin-dependent reactions, as well as yet-unidentified metabolite features. Decreased levels of several of the identified metabolites are implicated in the pathology of human psychological disorders and neurodegenerative disease, suggesting a possible neuroprotective function. Our results provide a fingerprint of the acute effect of psychological stress on the metabolome and suggest candidate biomarkers with potential roles in stress-related disorders.

Role of locus coeruleus expressing angiotensin type 1 receptors (AT1R) neurons in fear learning and stress‐induced anxiety

BackgroundThe renin‐angiotensin system (RAS) has been implicated in stress‐related disorders, however the central mechanisms responsible for this remains unknown. The locus coeruleus (LC), a major noradrenergic nucleus of the brain, plays a critical role in modulating anxiety‐like behaviors. The LC has also been previously shown to express angiotensinogen (AGT), the pre‐cursor for angiotensin, as well as strong expression of angiotensin II receptors, but its role in stress‐related disorders has not been examined. Using angiotensin II type 1 receptor (AT1R)‐eGFP and Cre mice combined with neuroanatomical and behavioral approaches, we examined the role of LC expressing AT1R in fear‐ and anxiety‐related behavior.MethodsRNAscope® in situ hybridization assay was used to analyze cellular mRNA expression of AGT in the LC while in vivo chemogenetics combined with behavioral testing in AT1R‐Cre mice mouse was used to examine the role of LC‐AT1R cells in fear memory and stress‐induced anxiety. Further, dual immunohistochemistry plus retrograde tract tracing was used to characterize LC AT1R‐eGFP+ cells and limbic circuit connections.ResultsAGT mRNA and AT1R‐eGFP+ immunoactivity was found localized to the LC. The majority of AT1R‐eGFP+neurons (94%) in LC were co‐localized with tyrosine hydroxylase, a marker for norepinephrine‐containing neurons. Retrograde labeling revealed that some of these AT1R‐eGFP+ neurons send projections to the basolateral amygdala (BLA), an important brain structure for modulating stress induced fear related anxiety responses. Next, the AT1R+ neurons in LC were silenced using Cre‐dependent inhibitory designer receptor exclusively activated by designer drug (hM4Di DREADD) expression followed by Clozapine‐n‐oxide (CNO) administration. Silencing the LC AT1R‐expressing neurons prior to fear extinction training impaired the extinction of learned fear as shown by increased percent freezing during the training (time × drug interaction, F (7, 70) = 3.219, p<0.01, n=6) (Fig 1). Furthermore, restraint stress‐induced anxiety behavior was attenuated by LC AT1R+ neuron inhibition, as shown by increased center entries (22.7 ± 7.3 Saline v.s. 50.5 ± 8.8 CNO, p<0.05, n=6) and % time in center (2.97 ± 1.14 Saline v.s. 8.6 ± 1.4 CNO, p<0.05, n=6) in the open field test, and increased open arm entries (5 ± 1.3 Saline v.s. 12 ± 1.1 CNO, p<0.05, n=6) in the elevated plus maze test (Fig. 2).ConclusionThese findings provide evidence for a novel angiotensinergic LC cell type and position the LC AT1R as a potential mediator of noradrenergic regulation in learned fear and stress‐induced anxiety. Future studies are needed to fully characterize the underlying neurocircuits and neuropeptide modulators that likely interact with the LC AT1R expressing neurons during stress‐related behaviors.

Gut microbiota depletion from early adolescence alters anxiety and depression-related behaviours in male mice with Alzheimer-like disease

The gut-microbiota–brain axis plays an important role in stress-related disorders, and dysfunction of this complex bidirectional system is associated with Alzheimer’s disease. This study aimed to assess the idea that whether gut microbiota depletion from early adolescence can alter anxiety- and depression-related behaviours in adult mice with or without Alzheimer-like disease. Male C57BL/6 mice were treated with an antibiotic cocktail from weaning to adulthood. Adult mice received an intracerebroventricular injection of amyloid-beta (Aβ)1–42, and were subjected to anxiety and depression tests. We measured, brain malondialdehyde and glutathione following anxiety tests, and assessed brain oxytocin and the hypothalamic–pituitary–adrenal (HPA) axis function by measuring adrenocorticotrophic hormone (ACTH) and corticosterone following depression tests. Healthy antibiotic-treated mice displayed significant decreases in anxiety-like behaviours, whereas they did not show any alterations in depression-like behaviours and HPA axis function. Antibiotic treatment from early adolescence prevented the development of anxiety- and depression-related behaviours, oxidative stress and HPA axis dysregulation in Alzheimer-induced mice. Antibiotic treatment increased oxytocin in the brain of healthy but not Alzheimer-induced mice. Taken together, these findings suggest that gut microbiota depletion following antibiotic treatment from early adolescence might profoundly affect anxiety- and depression-related behaviours, and HPA axis function in adult mice with Alzheimer-like disease.

Histamine Neuroimaging in Stress-Related Disorders.

Although histamine plays a major role in animal models of stress-related disorders, human neuroimaging data are sparse. Histamine H1 receptors in the human brain were first imaged by Professor Kazuhiko Yanai in 1992 by using 11C-doxepin, a potent ligand of H1 receptors, and positron emission tomography (PET). Subsequent work revealed that H1 receptors are reduced in the prefrontal and anterior cingulate cortices in patients with major depressive disorders. A sex difference in H1 receptor binding in the brain has also been found, with women exhibiting more abundant H1 receptor binding than men. Moreover, female patients with anorexia nervosa show higher H1 receptor binding in the amygdala and lentiform nucleus. These studies also found an inverse correlation of depression scores with H1 receptor binding. Histamine is considered to play a major role in the pathophysiology of irritable bowel syndrome (IBS), a representative disorder of brain-gut interactions. Along these lines, hypnotic suggestion dramatically changes the waveforms of viscerosensory cerebral evoked potentials in response to electrical rectal stimulation and these changes are modified by the administration of H1 antagonist. The direction of the H1 antagonist-induced changes in the viscerosensory cerebral evoked potentials differs between IBS patients and healthy controls. Thus, histamine likely plays an important role in stress-related disorders. Further histamine brain imaging studies of humans are warranted.

Food-Derived Opioid Peptides in Human Health: A Review.

World Health Organization data suggest that stress, depression, and anxiety have a noticeable prevalence and are becoming some of the most common causes of disability in the Western world. Stress-related disorders are considered to be a challenge for the healthcare system with their great economic and social impact. The knowledge on these conditions is not very clear among many people, as a high proportion of patients do not respond to the currently available medications for targeting the monoaminergic system. In addition, the use of clinical drugs is also associated with various side effects such as vomiting, dizziness, sedation, nausea, constipation, and many more, which prevents their effective use. Therefore, opioid peptides derived from food sources are becoming one of the safe and natural alternatives because of their production from natural sources such as animals and plant proteins. The requirement for screening and considering dietary proteins as a source of bioactive peptides is highlighted to understand their potential roles in stress-related disorders as a part of a diet or as a drug complementing therapeutic prescription. In this review, we discussed current knowledge on opioid endogenous and exogenous peptides concentrating on their production, purification, and related studies. To fully understand their potential in stress-related conditions, either as a drug or as a therapeutic part of a diet prescription, the need to screen more dietary proteins as a source of novel opioid peptides is emphasized.

Multilevel Interactions of Stress and Circadian System: Implications for Traumatic Stress.

The dramatic fluctuations in energy demands by the rhythmic succession of night and day on our planet has prompted a geophysical evolutionary need for biological temporal organization across phylogeny. The intrinsic circadian timing system (CS) represents a highly conserved and sophisticated internal “clock,” adjusted to the 24-h rotation period of the earth, enabling a nyctohemeral coordination of numerous physiologic processes, from gene expression to behavior. The human CS is tightly and bidirectionally interconnected to the stress system (SS). Both systems are fundamental for survival and regulate each other’s activity in order to prepare the organism for the anticipated cyclic challenges. Thereby, the understanding of the temporal relationship between stressors and stress responses is critical for the comprehension of the molecular basis of physiology and pathogenesis of disease. A critical loss of the harmonious timed order at different organizational levels may affect the fundamental properties of neuroendocrine, immune, and autonomic systems, leading to a breakdown of biobehavioral adaptative mechanisms with increased stress sensitivity and vulnerability. In this review, following an overview of the functional components of the SS and CS, we present their multilevel interactions and discuss how traumatic stress can alter the interplay between the two systems. Circadian dysregulation after traumatic stress exposure may represent a core feature of trauma-related disorders mediating enduring neurobiological correlates of trauma through maladaptive stress regulation. Understanding the mechanisms susceptible to circadian dysregulation and their role in stress-related disorders could provide new insights into disease mechanisms, advancing psychochronobiological treatment possibilities and preventive strategies in stress-exposed populations.

Micronutrient and their role in stress related disorders

Micronutrient and their role in stress related disorders

Abnormal composition of gut microbiota is associated with resilience versus susceptibility to inescapable electric stress

Increasing evidence indicates that abnormalities in the composition of gut microbiota might play a role in stress-related disorders. In the learned helplessness (LH) paradigm, ~60–70% rats are susceptible to LH in the face of inescapable electric stress. The role of gut microbiota in susceptibility in the LH paradigm is unknown. In this study, male rats were exposed to inescapable electric stress under the LH paradigm. The compositions of gut microbiota and short-chain fatty acids were assessed in fecal samples from control rats, non-LH (resilient) rats, and LH (susceptible) rats. Members of the order Lactobacillales were present at significantly higher levels in the susceptible rats than in control and resilient rats. At the family level, the number of Lactobacillaceae in the susceptible rats was significantly higher than in control and resilient rats. At the genus level, the numbers of Lactobacillus, Clostridium cluster III, and Anaerofustis in susceptible rats were significantly higher than in control and resilient rats. Levels of acetic acid and propionic acid in the feces of susceptible rats were lower than in those of control and resilient rats; however, the levels of lactic acid in the susceptible rats were higher than those of control and resilient rats. There was a positive correlation between lactic acid and Lactobacillus levels among these three groups. These findings suggest that abnormal composition of the gut microbiota, including organisms such as Lactobacillus, contributes to susceptibility versus resilience to LH in rats subjected to inescapable electric foot shock. Therefore, it appears likely that brain–gut axis plays a role in stress susceptibility in the LH paradigm.

PGC-1α-FNDC5-BDNF signaling pathway in skeletal muscle confers resilience to stress in mice subjected to chronic social defeat.

Skeletal muscle consumes two thirds of the body's energy and may play a role in stress-related disorders. Evidence suggests that the peroxisome proliferator-activated receptor γ coactivator α (PGC-1α)-fibronectin type III domain-containing 5 (FNDC5)-brain-derived neurotrophic factor (BDNF) signaling pathway in skeletal muscle plays a key role in conferring the beneficial effects of exercise. In this study, we aimed to determine whether this pathway contributes to the resilience or susceptibility of mice subjected to chronic social defeat stress (CSDS). BDNF-tropomyosin receptor kinase B (TrkB) and proBDNF-p75NTR signaling in the medial prefrontal cortex and nucleus accumbens of susceptible but not resilient mice were significantly altered compared with the controls. Furthermore, the levels of PGC-1α, FNDC5, and BDNF, as well as the p-TrkB/TrkB ratio in the skeletal muscle of susceptible but not resilient mice, were significantly lower than those of the controls, but the levels of proBDNF and p75NTR in the skeletal muscle of susceptible mice were significantly higher than those of the controls. Moreover, there were significant positive associations between social interaction test data and the expression of PGC-1α, FNDC5, and BDNF or the p-TrkB/TrkB ratio in skeletal muscle. These results suggest that the downregulation of the PGC-1α-FNDC5-BDNF signaling pathway in skeletal muscle contributes to resilience vs. susceptibility to CSDS. Therefore, alterations in this pathway in skeletal muscle may play a crucial role in mediating stress-related disorders.

Translocator protein mediates the anxiolytic and antidepressant effects of midazolam

The translocator protein (18kDa) (TSPO) plays an important role in stress-related disorders, such as anxiety, depression and post-traumatic stress disorder (PTSD), caused by neurosteroids (e.g. allopregnanolone). The present study sought to evaluate the significance of TSPO in anxiolytic and antidepressant effects induced by midazolam. The animals were administrated midazolam (0.25, 0.5 and 1mg/kg, i.p.) and subjected to behavioral tests, including Vogel-type conflict test, elevated plus-maze test, forced swimming test. Midazolam produced anxiolytic- and antidepressant-like effects Vogel-type conflict test (1mg/kg, i.p.), elevated plus-maze test (0.5 and 1mg/kg, i.p.), and forced swimming test (0.5 and 1mg/kg, i.p.). These effects of Midazolam were totally blocked by the TSPO antagonist PK11195 (3mg/kg, i.p.). To evaluate the role of allopregnanolone in the anxiolytic- and antidepressant-like effects of midazolam, the animals were decapitated at the end of the behavioral tests. The allopregnanolone levels of the prefrontal cortex and hippocampus were measured by enzyme-linked immunosorbent assay (ELISA). The allopregnanolone level of the prefrontal cortex and hippocampus was increased by midazolam (0.5, 1mg/kg, i.p.) and the increase was reversed by PK11195 (3mg/kg, i.p.). Overall, the results indicated that the anxiolytic- and antidepressant-like effects of midazolam were mediated by TSPO, via stimulation of allopregnanolone biosynthesis.

Intraperitoneal injection of neuropeptide Y (NPY) alters neurotrophin rat hypothalamic levels: Implications for NPY potential role in stress-related disorders

Neuropeptide Y (NPY) is a 36-amino acid peptide which exerts several regulatory actions within peripheral and central nervous systems. Among NPY actions preclinical and clinical data have suggested that the anxiolytic and antidepressant actions of NPY may be related to its antagonist action on the hypothalamic–pituitary–adrenal (HPA) axis. The neurotrophins brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are proteins involved in the growth, survival and function of neurons. In addition to this, a possible role of neurotrophins, particularly BDNF, in HPA axis hyperactivation has been proposed. To characterize the effect of NPY on the production of neurotrophins in the hypothalamus we exposed young adult rats to NPY intraperitoneal administration for three consecutive days and then evaluated BDNF and NGF synthesis in this brain region. We found that NPY treatment decreased BDNF and increased NGF production in the hypothalamus. Given the role of neurotrophins in the hypothalamus, these findings, although preliminary, provide evidence for a role of NPY as inhibitor of HPA axis and support the idea that NPY might be involved in pathologies characterized by HPA axis dysfunctions.

On the role of corticotropin-releasing hormone receptors in anxiety and depression

On the basis of extensive basic and clinical studies, corticotropin-releasing hormone (CRH) and its related family members are considered to play a pivotal role in stress-related disorders, such as anxiety and depression. CRH is regarded as the principal mediator in the brain of the stress response, as it mediates neuroendocrine, autonomic, and behavioral responses to stressful challenges. Recently, this neuropeptide family has expanded due to the discovery of two new members, urocortin II (also termed stresscopin-related peptide) and urocortin III (also termed stresscopin), which are selective agonists for the CRH receptor type 2. They show a discrete neuroanatomical localization and are involved in stress-coping responses, such as anxiolysis. Here, on the basis of recent developments, we suggest that CRH, the urocortins, and their receptors form a complex system in the brain, which is recruited during both the acute and the recovery phases of the stress response.

Potent NK1 antagonism by SR-140333 reduces rat colonic secretory response to immunocyte activation.

The potent neurokinin receptor 1 (NK1) antagonist SR-140333 has previously been shown to reduce castor oil-induced secretion in animal models. The importance of tachykinins in neuroimmune control of secretion and the effect of SR-140333 on key points in this pathway were elucidated in the present study to determine the type of intestinal dysfunction best targeted by this antagonist. Rat colonic secretion and substance P (SP) release were determined in vitro with the use of Ussing chamber and enzyme immunoassay techniques. NK1 receptors played a secretory role as receptor agonists stimulated secretion and SR-140333 antagonized the response to SP response (pK(b) = 9.2). Sensory fiber stimulation released SP and evoked a large secretion that was reduced by 69% in the presence of SR-140333 (10 nM). Likewise, mastocytes also released SP. The subsequent secretory response was reduced by 43% in the presence of SR-140333 (50 nM). SP was also released from granulocytes; however, this did not cause secretion. Functional NK3 receptors were present in the colon as senktide stimulated secretion, an effect that was increased during stress. We conclude that NK3 receptors may play a role in stress-related disorders, whereas NK1 receptors are more important in mast cell/afferent-mediated secretion.