Allopregnanolone and intrusive memories: A potential therapeutic target for PTSD treatment?

Significant amounts of research have been devoted to treatment of post-traumatic stress disorder (PTSD) and the understanding of its fear and stress-related symptoms. However, current interventions are only effective in 60 % of the patient population. Allopregnanolone has become a topic of interest for PTSD due to its influences on inhibitory neurotransmission and the physiological stress response. This review explores available literature that suggests that allopregnanolone has an influence on (a) chronic stress and anxiety-like symptoms, (b) fear conditioning and contextual fear, and (c) intrusive and emotional memories. A relationship between allopregnanolone and PTSD is suggested, postulating that allopregnanolone is a potential target for the treatment of PTSD. This very exciting prospect calls for the expansion of research investigating a direct relationship between allopregnanolone and PTSD.

Chronic stimulation desensitizes ß2-adrenergic receptor responses in natural killer cells.

Adrenergic receptors (ARs) are preferentially expressed by innate lymphocytes such as natural killer (NK) cells. Here, we study the effect of epinephrine-mediated stimulation of the ß2-adrenergic receptor (ß2AR) on the function of human NK cells. Epinephrine stimulation inhibited early NK cell signaling events and blocked the function of the integrin LFA-1. This reduced the adhesion of NK cells to ICAM-1, explaining how NK cells are mobilized into the peripheral blood upon epinephrine release during acute stress or exercise. Additionally, epinephrine stimulation transiently reduced NK cell degranulation, serial killing, and cytokine production and affected metabolic changes upon NK cell activation via the cAMP-protein kinase A (PKA) pathway. Repeated exposure to ß2AR agonists resulted in the desensitization of the ß2AR via a PKA feedback loop-initiated G-protein switch. Therefore, acute epinephrine stimulation of chronically ß2AR stimulated NK cells no longer resulted in inhibited signaling and reduced LFA-1 activity. Sustained stimulation by long-acting ß2-agonists (LABA) not only inhibited NK cell functions but also resulted in desensitization of the ß2AR. However, peripheral NK cells from LABA-treated asthma patients still reacted unchanged to epinephrine stimulation, demonstrating that local LABA administration does not result in detectable systemic effects on NK cells.

Neuroimmune Interactions in Stress and Depression: Exploring the Molecular and Cellular Mechanisms within the Neuroinflammation-depression Nexus.

BACKGROUND: The escalating global burden of stress and depression underscores an urgent need to unravel their complex interrelationships and underlying mechanisms. This investigation delves into the intricate dynamics between stress and depression, spotlighting the Neuroimmunoinflammatory Stress Model (NIIS), which elucidates the pivotal role of cellular and molecular pathways in mediating these conditions. METHODS: Through an exhaustive review of literature spanning epidemiology, neurobiology, and psychoneuroimmunology, this study synthesizes the current understanding of stress and depression. It accentuates the definitional scopes, interplay, and intricacies of the NIIS model, which integrates neuroimmune-inflammatory responses into the conceptual framework of the stress-depression interaction. RESULTS: By identifying stress as a multifactorial reaction to perceived adversities and depression as a manifestation of prolonged stress exposure, our analysis foregrounds the NIIS model. This paradigmatic model reveals the transition from normal stress responses to pathological neuroinflammatory pathways, highlighting neurotransmitter imbalances, disruptions in neuronal and glial homeostasis, and ensuing low-grade neuroinflammation as key factors in the pathogenesis of depression under chronic stress conditions. The NIIS model identifies prolonged cellular pro-inflammatory stress of neurons and microglia as a fundamental pathological subsystem of many neuropsychiatric disorders. In turn, neuroinflammation and associated neurodegenerative processes are complications of chronic psychoemotional stress, which can clinically manifest as depression. CONCLUSIONS: The NIIS model views depression as the terminal stage of chronic stress, pathogenetically linked to latent neuroinflammation. This insight not only advances our understanding of their etiopathogenesis but also paves the way for developing precise therapeutic interventions.

Chronic stress induces insulin resistance and enhances cognitive impairment in AD.

BACKGROUND: Chronic stress can induce the cognitive impairment, and even promote the occurrence and development of Alzheimer's disease (AD). Evidence has suggested that chronic stress impacts on glucose metabolism, and both of these have been implicated in AD. Here we focused on the effect of insulin resistance in glucose metabolism, and further evaluated the changes in cognition and pathology. METHODS: Male 9-month-old wild-type and APP/PS1 mice were randomly divided into 4 groups. Mice in the chronic unpredictable mild stress (CUMS) groups were exposed for 4 weeks. Homeostatic Model Assessment (HOMA) was utilized to evaluate insulin sensitivity. A total of eighty-four genes related to the insulin signaling pathway were examined for rapid screening. Additionally, the phosphorylated protein expressions of insulin receptors (IR), IR substrate 1 (IRS1), c-Jun N-terminal kinase (JNK), and amyloid were detected in the hippocampus. Cognitive function was assessed through ethological methods. Cognitive function was assessed using both the Morris water maze (MWM) and the Passive avoidance test (PAT). RESULTS: Four weeks of CUMS exposure significantly increased the HOMA value, indicating reduced insulin sensitivity. The gene expressions of Insr and Lipe were downregulated. Additionally, the analysis revealed a significant interaction between the genotype (wild-type vs. APP/PS1) and CUMS treatment on the phosphorylated protein expressions of insulin receptor substrate 1 (IRS1). Specifically, CUMS exposure increased the inhibitory phosphorylation site (IRS1-pSer636) and decreased the excitatory phosphorylation site (IRS1-pTyr465) in the post-insulin receptor signaling pathway within the hippocampus of both wild-type and APP/PS1 mice. Moreover, CUMS exposure induced and exacerbated cognitive impairments in both wild-type and APP/PS1 mice, as assessed by the Morris water maze (MWM) and Passive avoidance test (PAT). However, there was no significant effect of CUMS on senile plaque deposition or levels of Aß42 and Aß40 in wild-type mice. CONCLUSIONS: Chronic stress significantly affects hippocampal cognitive function through insulin resistance and exacerbates AD pathology. This study reveals the complex relationship between chronic stress, insulin resistance, and AD, providing new insights for developing interventions targeting chronic stress and insulin resistance.

Chronic stress and functional health in older adults with concerns about falling: a study protocol of a randomized controlled trial with multicomponent exercise intervention (FEARFALL).

BACKGROUND: Maintenance of physical function, mobility, and independent living are important goals for older adults. However, concerns about falling (CaF) play a central role in the vicious cycle of CaF, inflammation, loss of muscle mass, and decreasing physical function ultimately resulting in negative health outcomes. CaF, like other states of chronic stress and anxiety, can be considered as enduring adverse stimuli affecting the stress systems and the inflammatory system. Therefore, the aim of this study is to investigate whether a reduction of CaF leads to a reduction of stress and therefore possibly reduces chronic low-grade inflammation. Understanding the role and directionality of the effects of inflammation on CaF increases our understanding of age-related loss of mobility and physical function. METHODS: In this study, community-dwelling older adults, aged 70 years and older, will be randomly assigned to either a 4-month, multi-component intervention with exercise training and cognitive-behavioral components or to a sham control group with light stretching exercises, cognitive training, and educational health lectures. For the operationalization of specific CaF, the Falls Efficacy Scale-International will be used. Stress and related psychological symptoms will be monitored using established self-reports and by measuring salivary cortisol. Concentrations of C-reactive protein, interleukin 6, interleukin 10, and tumor-necrosis-factor-alpha, as well as gene expression of selected inflammatory transcripts, will be used as surrogate parameters of the inflammatory status at baseline, after the 4-month intervention and 8-month follow-up. DISCUSSION: This study will be the first to test whether CaF are related with stress system activity or reactivity or with markers of inflammation in the context of a multi-component intervention with exercise training and cognitive-behavioral components addressing CaF. The reduction of specific CaF or general psychological symptoms should reverse alterations in stress systems, and / or slow down low-grade inflammation. Changes in activity, as well as psychological and biological pathways leading from CaF to muscle loss will be measured, to disentangle the individual contribution to sarcopenia, and to provide an additional pathway to break or slow-down the vicious cycle of CaF and sarcopenia. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00029171 . Registered 22 July 2022.

Occlusal disharmony promotes anxiety-like behaviours by suppressing Sirt1.

BACKGROUND: Previous studies have indicated that occlusal disharmony (OD) can promote anxiety-like behaviours. However, the specific molecules involved in the development of anxiety-like behaviours and their underlying mechanisms remain unknown. METHODS: OD was produced by anterior crossbite of female mice. We measured the anxiety levels of mice in each group and screened the hippocampal mRNA expression profiles of mice in the control group and OD group. The role of target mRNA in OD-induced anxiety-like behaviours was evaluated and we preliminarily explored the possible downstream pathways. RESULTS: The results suggested that OD can induce and promote anxiety-like behaviours with/without chronic unpredictable mild stress. We found that Sirt1 was significantly downregulated within the hippocampus in OD mice. In addition, the downregulation of Sirt1 within the hippocampus in OD and control mice promoted anxiety-like behaviours, increased acetylated histone H3 expression and decreased Dnah12 transcription levels. In contrast, in OD mice subjected to an injection of resveratrol, there was a remission of anxiety-like behaviours and an upregulation of Sirt1 in the hippocampus, the effects of which were accompanied by decreased acetylated histone H3 expression and increased Dnah12 transcription levels. CONCLUSIONS: OD leads to increased sensitivity to chronic stress in mice, resulting in anxiety-like behaviours. During this process, Sirt1 acts as an effective factor in the regulation of OD-induced anxiety-like behaviours. CLINICAL RELEVANCE: OD, as a stressor, could induce anxiety-like behaviours. It investigates the impact of OD (a stressor) on the molecular genetic of the pathophysiology of major neuropsychiatric disorders.

Neurobiological Implications of Chronic Stress and Metabolic Dysregulation in Inflammatory Bowel Diseases.

Chronic stress is a significant factor affecting modern society, with profound implications for both physical and mental health. Central to the stress response is cortisol, a glucocorticoid hormone produced by the adrenal glands. While cortisol release is adaptive in acute stress, prolonged exposure to elevated levels can result in adverse effects. This manuscript explores the neurobiological implications of chronic stress and its impact on metabolic dysregulation, particularly in the context of inflammatory bowel diseases (IBDs). The hypothalamic-pituitary-adrenal (HPA) axis regulates cortisol production, which influences metabolism, immune response, and neurobiology. Elevated cortisol levels are associated with the development and exacerbation of metabolic disorders like IBD and contribute to neurodegenerative processes, including cognitive impairments and increased susceptibility to psychiatric conditions. The interaction between cortisol and its receptors, particularly glucocorticoid receptors, underscores the complexity of these effects. This review aims to elucidate the mechanisms through which chronic stress and cortisol dysregulation impact metabolic health and neurobiological function, providing insights into potential therapeutic strategies for mitigating these effects.

A single intravenous reelin injection restores corticosterone-induced neurochemical and behavioral alterations in dams during the post-partum period.

Introduction: Treatment with the synaptic plasticity protein reelin has rapid antidepressant-like effects in adult corticosterone (CORT)-induced depressed rats, whether administered repeatedly or acutely. However, these effects remain unexplored in the context of post-partum depression (PPD). Methods: This study investigated the antidepressant-like effect of a single injection of reelin in a CORT-induced model of PPD. Long-Evans female dams received either daily subcutaneous CORT (40 mg/kg) or saline injections (controls) from the post-partum day (PD) 2 to 22, and on PD22 were treated with a single intravenous reelin (3 µg) or vehicle injection. Results: Reelin treatment fully normalized to control levels the CORT-induced increase in Forced Swim Test (FST) immobility and the decrease in reelin-positive cells in the subgranular zone of the intermediate hippocampus. It also increased the number of oxytocin-positive cells in the paraventricular nucleus (PVN), the number of reelin-positive cells in the dorsal and ventral hippocampus, and the dendritic complexity of newborn neurons in the intermediate hippocampus, causing a partial recovery compared to controls. None of these changes were associated with fluctuations in estrogen levels measured peripherally. Discussion: This study brings new insights into the putative antidepressant-like effect of peripherally administered reelin in an animal model of PPD. Future studies should be conducted to investigate these effects on a dose-response paradigm and to further elucidate the mechanisms underlying the antidepressant-like effects of reelin.

The association of perceived ethnic discrimination and institutional verbal violence with chronic stress in an immigrant sample: The role of protective factors - results from the VIOLIN study.

Immigrants are exposed to a variety of stressors, such as ethnic discrimination, and therefore experience a higher risk of developing adverse health outcomes. However, the role of potentially protective psychological factors is not well-studied. The present study addresses the question how discrimination and institutional verbal violence (IVV) are associated with chronic stress in an immigrant sample. In addition, this study highlights moderating effects of migration-specific variables (first or second migration generation and citizenship status). Participants (n = 232; 69.4 % female) completed an online-survey, which included demographics, questionnaires (Everyday Discrimination Scale, EDS; Perceived Stress Scale, PSS-4; Resilience Scale, RS-11; Self-Compassion Scale, SCS-SF) as well as a self-developed questionnaire on institutional verbal violence. Only participants living in Germany with migration background (self or one parent migrated to Germany) were included. Results showed that perceived discrimination and institutional verbal violence were highly associated with chronic stress. Further, self-compassion buffered the connection between discrimination and stress, whereas resilience was no protective factor. The inclusion of migration-specific variables showed that the second-generation sub-group experienced less discrimination-related stress and self-compassion was shown to be particularly protective within this sub-group. Citizenship status did not appear to be a moderator, but especially persons with temporary or permanent residence status, compared to German/EU-citizens, reported higher values of verbal violence and discrimination-related stress. These findings highlight the importance of considering not only psychological but also structural and societal protective and risk factors, as they may be differentially associated with immigrants' stress perceptions. Implications for future research and practical implementations are presented.

Chronic Stress-induced Serotonin Impairs Intestinal Epithelial Cell Mitochondrial Biogenesis via the AMPK-PGC-1α Axis.

Chronic stress is closely associated with gastrointestinal disorders. However, the impact of stress-related neurotransmitters such as serotonin (5-hydroxytryptamine, 5-HT) on the intestines under chronic stress conditions remains poorly understood. This study aims to elucidate the mechanisms by which 5-HT affects mitochondrial biogenesis and intestinal barrier integrity during chronic stress. Employing a chronic restraint stress (CRS) mouse model, we observed elevated intestinal 5-HT levels, altered colonic mucosal structure, and disrupted tight junctions. The increase in 5-HT was associated with up-regulated serotonin synthesis enzymes and downregulated serotonin reuptake transporters, indicating an imbalance in serotonin homeostasis imbalance caused by chronic stress. Furthermore, serotonin exacerbated oxidative stress and impaired tight junction protein expression, highlighting its role in promoting intestinal barrier dysfunction. Experiments with cells in vitro demonstrated that 5-HT impairs mitochondrial biogenesis by inhibiting the AMPK-PGC-1α axis via 5-HT7 receptors and the cAMP-PKA pathway. Pharmacological inhibition of serotonin synthesis or 5-HT7 receptors alleviated the intestinal barrier damage caused by 5-HT and chronic stress, restoring mitochondrial biogenesis. These findings provide compelling evidence that serotonin exacerbates chronic stress-induced intestinal barrier disruption by inhibiting the AMPK-PGC-1α axis, paving the way for novel therapeutic interventions targeting the detrimental effects of serotonin on the intestine, particularly under chronic stress conditions.

Effects of arketamine on depression-like behaviors and demyelination in mice exposed to chronic restrain stress: A role of transforming growth factor-ß1.

BACKGROUND: Chronic restrain stress (CRS) induces depression-like behaviors and demyelination in the brain; however, the relationship between these depression-like behaviors and demyelination remains unclear. Arketamine, the (R)-enantiomer of ketamine, has shown rapid antidepressant-like effects in CRS-exposed mice. METHODS: We examined whether arketamine can improve both depression-like behaviors and demyelination in the brains of CRS-exposed mice. Additionally, we investigated the role of transforming growth factor ß1 (TGF-ß1) in the beneficial effects of arketamine. RESULTS: A single dose of arketamine (10 mg/kg) improved both depression-like behavior and demyelination in the corpus callosum of CRS-exposed mice. Correlations were found between depression-like behaviors and demyelination in this region. Furthermore, pretreatment with RepSox, an inhibitor of TGF-ß1 receptor, significantly blocked the beneficial effects of arketamine on depression-like behaviors and demyelination in CRS-exposed mice. Finally, a single intranasal administration of TGF-ß1 ameliorated both depression-like behaviors and demyelination in CRS-exposed mice. LIMITATIONS: The precise mechanisms by which TGF-ß1 contributes to the effects of arketamine remain unclear. CONCLUSIONS: These data suggest that CRS-induced demyelination in the corpus callosum may contribute to depression-like behaviors, and that arketamine can mitigate these changes through a TGF-ß1-dependent mechanism.

The interplay of serotonin 5-HT1A and 5-HT7 receptors in chronic stress.

Serotonin regulates multiple physiological and pathological processes in the brain, including mood and cognition. Serotonin receptors 5-HT1AR and 5-HT7R have emerged as key players in stress-related disorders, particularly depression. These receptors can form heterodimers, which influence their functions. Here we explored the developmental dynamics of 5-HT1AR and 5-HT7R expression and validated heterodimerization levels in the brain of control and stressed mice. In control animals, we obtained increase in 5-HT1AR expression over 5-HT7R in the prefrontal cortex (PFC) and hippocampus during development. Using a chronic unpredictable stress as a depression model, we found increase in 5-HT7R expression exclusively in the PFC of resilient animals, while no changes in 5-HT1AR expression between control and anhedonic mice were obtained. Quantitative in situ analysis of heterodimerization revealed the PFC as region exhibiting the highest abundance of 5-HT1AR/5-HT7R heterodimers. More importantly, upon chronic stress amount of heterodimers was significantly reduced only in PFC of anhedonic mice, while it was not affected in resilient animals. These results suggest an important role of brain-region specific 5-HT1AR/5-HT7R heterodimerization for establishing depressive-like behavior and for development of resiliency.

Increased forebrain EAAT3 expression confers resilience to chronic stress.

Depression is a disabling and highly prevalent psychiatric illness. Multiple studies have linked glutamatergic dysfunction with the pathophysiology of depression, but the exact alterations in the glutamatergic system that contribute to depressive-like behaviors are not fully understood. Recent evidence suggests that a decreased level in neuronal glutamate transporter (EAAT3), known to control glutamate levels and limit the activation of glutamate receptors at synaptic sites, may contribute to the manifestation of a depressive phenotype. Here, we tested the possibility that increased EAAT3 expression at excitatory synapses could reduce the susceptibility of mice to develop depressive-like behaviors when challenged to a 5-week unpredictable chronic mild stress (UCMS) protocol. Mice overexpressing EAAT3 in the forebrain (EAAT3glo/CMKII) and control littermates (EAAT3glo) were assessed for depressive-like behaviors and long-term memory performance after being subjected to UCMS conditions. We found that, after UCMS, EAAT3glo/CMKII mice did not exhibit depressive-like behaviors or memory alterations observed in control mice. Moreover, we found that EAAT3glo/CMKII mice did not show alterations in phasic dopamine release in the nucleus accumbens neither in long-term synaptic plasticity in the CA1 region of the hippocampus after UCMS, as observed in control littermates. Altogether these results suggest that forebrain EAAT3 overexpression may be related to a resilient phenotype, both at behavioral and functional level, to the deleterious effect of chronic stress, highlighting the importance of neuronal EAAT3 in the pathophysiology of depressive-like behaviors.

Unraveling the Liver-Brain Axis: Resveratrol's Modulation of Key Enzymes in Stress-Related Anxiety.

Stress-related anxiety disorders and anxiety-like behavior in post-traumatic stress disorder (PTSD) are associated with altered neurocircuitry pathways, neurotransmitter systems, and the activities of monoamine and glucocorticoid-metabolizing enzymes. Resveratrol, a natural polyphenol, is recognized for its antioxidant, anti-inflammatory, and antipsychiatric properties. Previous studies suggest that resveratrol reduces anxiety-like behavior in animal PTSD models by downregulating key enzymes such as 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1) and monoamine oxidases (MAOs). However, the underlying mechanisms remain unclear. In this study, we explored the efficacy of resveratrol in treating stress-induced anxiety using a chronic predator stress model in rats. Resveratrol was administered intraperitoneally at 100 mg/kg following a 10-day stress exposure, and anxiety behavior was assessed with an elevated plus maze. Our results indicated that stress-related anxiety correlated with increased activities of brain MAO-A, MAO-B, and hepatic 11ß-HSD-1, alongside elevated oxidative stress markers in the brain and liver. Resveratrol treatment improved anxiety behavior and decreased enzyme activities, oxidative stress, and hepatic damage. We demonstrate that resveratrol exerts antianxiogenic effects by modulating glucocorticoid and monoamine metabolism in the brain and liver. These findings suggest resveratrol's potential as a therapeutic agent for anxiety disorders, warranting further clinical investigation.

PRKCB methylation: a potential biomarker of MDD with childhood chronic stress, a cross-sectional study in drug-naive, first-episode adolescent MDD.

The purpose of this study was to investigate the relationship between childhood chronic stress(CCS), Protein kinase C beta (PRKCB) methylation and adolescent major depressive disorder (MDD). After recruiting 100 adolescents with MDD and 50 healthy controls (HCs), we evaluated the severity of CCS. PRKCB methylation was assessed by pyrosequencing using whole blood-derived DNA. To explore the relationship between CCS, PRKCB and adolescent MDD, we conducted correlation analysis and regression analysis, and constructed multiplicative interaction models and generalized linear models. PRKCB methylation and CCS were both found to be associated with MDD, and CCS was associated with PRKCB methylation. No significant CCS-PRKCB methylation interactions were observed. However, we found the interaction of CCS and MDD on PRKCB methylation. Our results found that PRKCB methylation was influenced by CCS and the disease itself, and PRKCB methylation was significantly positively associated with MDD severity, suggesting that PRKCB methylation may be a potential biomarker for adolescent MDD. This study is a cross-sectional observational study, which cannot draw the conclusion of causality. Prospective cohort studies are needed to further examine the relationship between CCS, adolescent MDD, and PRKCB methylation.

Chronic stress increases adaptive immune response over six weeks in the house sparrow, Passer domesticus.

The vertebrate stress response enables an organism to shift energy towards activities that promote immediate survival when facing a threat to homeostasis, but it can also have detrimental effects on organismal health. Acute and chronic stressors generally have contrasting effects on immune responses, but the timeline of this transition between acute and chronic stressors and their effects on immune responses remains unclear. In this study, we investigate changes in immune markers in captive house sparrows (Passer domesticus) after exposure to normal laboratory conditions, an acute stressor, and chronic stressors for 42 days. Specifically, we examined changes in baseline and stress-induced corticosterone concentrations, body condition, heterophil/lymphocyte (H:L) ratio, hemolysis-hemagglutination, and wound healing. We found that individuals exposed to a single acute stressor had significantly higher stress-induced corticosterone concentrations 24 h after stressor exposure, however this effect was reversed after 48 h. Chronic stressor exposure resulted in generally stronger adaptive immune responses, demonstrated by higher baseline and stress-induced lysis, higher baseline hemagglutination, and slower wound healing. Within-trait correlations also increased with chronic stressor exposure, suggesting limitations on phenotypic plasticity. Most of the effects of chronic stressor exposure on immune markers strengthened over the 42 days of the experiment and differences between captivity-only and treatment groups were not apparent until approximately 20 days of chronic stressor exposure. These results highlight the importance of stressor duration in understanding the effects of chronic stressor exposure on immune responses.

miR-124 mediates the effects of gut microbial dysbiosis on brain function in chronic stressed mice.

The gut microbiota plays a key role in the brain function impairment caused by chronic stress, yet its exact mechanism remains unclear. Many studies have revealed the important role of miR-124 in the central nervous system. Meanwhile, previous studies have indicated that miR-124 may be regulated by chronic stress and gut microbiota. Here, we aimed to explore whether miR-124 serves as a mediator for the impacts of gut microbial dysbiosis on brain function in mice subjected to chronic stress. Repeated daily restraint stress for 4 weeks was used to induce chronic stress in mice. Chronic stress resulted in gut microbial dysbiosis, abnormal behaviors, and a decrease in hippocampal miR-124 levels. Treatment with different probiotic mixtures significantly alleviated the effects of chronic stress on hippocampal miR-124 levels and mouse behaviors. Suppression of hippocampal miR-124 expression reversed the beneficial effects of probiotics on cognitive function, neurogenesis, and related molecular markers in chronically stressed mice. Bioinformatics analysis and qPCR suggested that Ptpn11 might be a target gene for miR-124 in mediating the effects of gut microbial dysbiosis on brain function in these mice. These findings suggest that miR-124 is a pivotal regulator that mediates the detrimental effects of gut microbial dysbiosis on brain function and the subsequent cognitive impairment during chronic stress.

Chronic Stress Exacerbates Cerebral Amyloid Angiopathy Through Promoting Neutrophil Extracellular Traps Formation.

Cerebral amyloid angiopathy (CAA) is the leading cause of vascular dementia among the elderly. Neuropsychiatric symptoms are commonly manifested in cerebral amyloid angiopathy patients but are usually considered as consequences of cerebral amyloid angiopathy pathology. Here, it is reported that chronic stress promotes cerebral amyloid angiopathy progression, which enhances deposition of amyloid protein beta (Aß) in brain blood vessels and exacerbates subsequent brain injury. Mechanistically, neutrophil is implicated in cerebral amyloid angiopathy development. Aß that accumulates in brain vasculature induces neutrophil extracellular traps (NETs) by activating STAT6 signaling, which inhibits neutrophil apoptosis and switches the programmed cell death toward NETosis. During chronic stress, circulatory Norepinephrine (NE) strengthens STAT6 activation in neutrophil and promotes NET formation, thus exacerbates the NET-dependent angiopathy. It is demonstrated that inhibiting neutrophil chemotaxis towards brain or suppressing NET formation both ameliorate cerebral amyloid angiopathy severity in the context of chronic stress. Therefore, it is proposed that stress-associated psychological disorders and NETs are promising therapeutic targets in cerebral amyloid angiopathy.

Effects of multisession prefrontal cortex tDCS or taVNS on stress, perceived stress and sleep quality: a double-blind, randomized controlled study.

Introduction: Chronic stress is a condition characterized by prolonged stimulation, leading to mental and physical weakness. It can have detrimental effects on individuals' mental health and cognitive function, potentially causing various health issues. This article explores the potential of non-invasive neuromodulation techniques, specifically transcranial direct current stimulation (tDCS) and transcutaneous auricular vagus nerve stimulation (taVNS), in managing chronic stress and improving sleep quality. Methods: The study conducted a randomized, double-blinded, controlled trial with participants experiencing chronic stress. In total, 100 participants were randomly assigned to one of four conditions: the anodal tDCS group (n = 50), the sham tDCS group (n = 50), the taVNS group (n = 50), or the sham taVNS group (n = 50). Within each condition, participants received five sessions of either active treatment or sham treatment, with 20 min of tDCS over the dorsolateral prefrontal cortex (2 mA) for the tDCS groups, or taVNS on the left ear (20 Hz) for the taVNS groups. At baseline, post-intervention, and 4 weeks thereafter, we evaluated stress using the Lipp's Inventory of Stress Symptoms for Adults (LSSI), perceived stress through the Perceived Stress Scale (PSS-10), and sleep quality via the Pittsburgh Sleep Quality Index (PSQI). Results: The tDCS and taVNS interventions resulted in reduced stress levels, improved sleep quality, and enhanced perception of stress. Discussion: These findings suggest that tDCS and taVNS hold promise as effective treatments for chronic stress, offering a safe and accessible approach to improving individuals' wellbeing and overall quality of life. Clinical trial registration: https://ensaiosclinicos.gov.br/rg/RBR-2ww2ts8, identifier UTN: U1111-1296-1810; Brazilian Registry of Clinical Trials (REBEC) RBR-2ww2ts8.

Age and Hair Cortisol Levels as Predictors of SARS-CoV-2 Infection.

Chronic psychosocial stress is known to adversely impact immune function. During the SARS-CoV-2 pandemic, occupational stress among workers in healthcare was at an unprecedented level due to risks of infection and work demands. We performed a nested case-control study to investigate the associations between chronic stress and the risks of contracting SARS-CoV-2. We collected 3 cm of hair from employees at an academic medical center who tested positive for SARS-CoV-2 (N = 49) and controls who tested negative (N = 49), matched for age, race, and sex. The diagnosis of SARS-CoV-2 was based on polymerase chain reaction or antibody tests. As a proxy for chronic stress, we segmented hair into 1 cm sections each representing one month and measured cortisol levels using a cortisol enzyme-linked immunosorbent assay. For cases, we used cortisol concentrations measured in hair segments from the month prior to a positive SARS-CoV-2 test, and for controls, we used time-matched hair segments. We fitted conditional logistic regression models adjusted for sex, age, race, body mass index, and healthcare worker status, and stratified models by older vs. younger age (cutoff = 41 years). African Americans had higher hair cortisol levels relative to participants of other races and ethnicities. In adjusted models, higher hair cortisol concentrations were associated with an increased odds of infection with SARS-CoV-2 (OR = 1.84; CI: 1.10-3.07) among older, but not younger, participants. The results suggest that psychosocial stress may be a risk factor for SARS-CoV-2 infection; stress management may be an important part of a comprehensive approach to protect against SARS-CoV-2 infection.