Stress-related Disorders Research Articles

Exploring the molecular and neuronal bases involved in central amygdala-dependent control of emotional behaviors

The central extended amygdala, including the central nucleus of the amygdala (CeA) and the lateral division of the bed nucleus of the stria terminalis (BNSTL), is a pivotal brain region involved in the threat processing responsible for emotional states such as fear and anxiety. These brain regions alter their circuit activities and exhibit necessary functions to adapt to environmental changes. When faced with excessive threats or stress, it is thought that these neural circuit functions are disrupted and cause various stress-related psychiatric disorders. The CeA and BNSTL were suggested to be the same nuclei separated during development because of their dense neural connections, and the similarities in cellular composition and connectivity patterns with other brain regions. On the other side, some recent studies suggested functional differences between these two regions in controlling emotional behaviors. However, functional segregation at the subnuclei level was insufficient since the two regions have complex circuit structures composed of multiple subnuclei. In this review, we introduce the similarities and differences between the CeA and BNSTL that have been clarified from our recent comparative studies of gene expression profiles and circuit functions at the subnuclei level. Additionally, we also discuss how it can contribute to understanding the molecular pathogenesis of neuropsychiatric disorders, including stress-related psychiatric disorders.

Effect of Motor Interference Therapy on Distress Related to Traumatic Memories: A Randomized, Double-Blind, Controlled Feasibility Trial.

Traumatic memories (TM) are a core feature of stress-related disorders, including posttraumatic stress disorder (PTSD). Treatment is often difficult, and specific pharmacological interventions are lacking. We present a novel non-pharmacological intervention called motor interference therapy (MIT) as a promising alternative for these symptoms. To determine the feasibility of MIT, a brief, audio-delivered, and non-pharmacological intervention that uses cognitive and motor tasks to treat TM. We designed a randomized, double-blind trial. Twenty-eight participants from an outpatient clinic with at least one TM were included to receive either MIT or progressive muscle relaxation (PMR). Spanish versions of the PTSD symptom severity scale (EGS), visual analog scale for TM (TM-VAS), and quality of life (EQ-VAS) were applied prior to intervention, 1 week, and 1 month following intervention. Mean scores on all measures improved from baseline to posttest for both groups. MIT participants showed significantly more positive scores at 1 week and 1 month (TM-VAS baseline: 9.8±0.4; immediate: 6.0±2.0; 1 week: 3.8±3.1 [d=1.57]; 1 month 2.9±2.8 [d=1.93]) than PMR participants on measures of distress due to TM, trauma re-experiencing, anxiety, and a composite measure of PTSD. MIT is a simple, effective, and easy-to-use tool for treating TM and other stress-related symptoms. It requires relatively few resources and could be adapted to many contexts. The results provide proof-of-principle support for conducting future research with larger cohorts and controls to improve clinical effectiveness and research on brief interventions. ClinicalTrials.gov Identifier: NCT03627078.

LP-21 Chemical-induced disruptions to behavioral stress responses investigated using the zebrafish model: Deciphering risk for stress-related disorders

LP-21 Chemical-induced disruptions to behavioral stress responses investigated using the zebrafish model: Deciphering risk for stress-related disorders

Feedforward inhibition of stress by brainstem neuropeptide Y neurons

Resistance to stress is a key determinant for mammalian functioning. While many studies have revealed neural circuits and substrates responsible for initiating and mediating stress responses, little is known about how the brain resists to stress and prevents overreactions. Here, we identified a previously uncharacterized neuropeptide Y (NPY) neuronal population in the dorsal raphe nucleus and ventrolateral periaqueductal gray region (DRN/vlPAG) with anxiolytic effects in male mice. NPYDRN/vlPAG neurons are rapidly activated by various stressful stimuli. Inhibiting these neurons exacerbated hypophagic and anxiety responses during stress, while activation significantly ameliorates acute stress-induced hypophagia and anxiety levels and transmits positive valence. Furthermore, NPYDRN/vlPAG neurons exert differential but synergic anxiolytic effects via inhibitory projections to the paraventricular thalamic nucleus (PVT) and the lateral hypothalamic area (LH). Together, our findings reveal a feedforward inhibition neural mechanism underlying stress resistance and suggest NPYDRN/vlPAG neurons as a potential therapeutic target for stress-related disorders.

Faecalibacterium prausnitzii, FOS and GOS loaded synbiotic reverses treatment-resistant depression in rats: Restoration of gut-brain crosstalk

Alterations in commensal gut microbiota, such as butyrate-producing bacteria and its metabolites, have been linked to stress-related brain disorders, including depression. Herein, we investigated the effect of Faecalibacterium prausnitzii (ATCC-27766) administered along with fructooligosaccharides (FOS) and galactooligosaccharides (GOS) in a rat model of treatment-resistant depression (TRD). The behavioral changes related to anxiety-, anhedonia- and despair-like phenotypes were recorded employing elevated plus maze, sucrose-preference test, and forced-swim test, respectively. Rats exposed to unpredictable chronic mild-stress (UCMS) and adrenocorticotropic hormone (ACTH) injections exhibited a TRD-like phenotype. Six-week administration of F. prausnitzii and FOS + GOS ameliorated TRD-like conditions in rats. This synbiotic treatment also restored the decreased levels of short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate in the fecal samples of TRD rats. Synbiotic-recipient TRD rats displayed an increased abundance of Lactobacillus helveticus, Lactobacillus hamsteri, and Ruminococcus flavefaciens. Moreover, more mucus-producing goblet cells were seen in the colon of synbiotic-treated rats, suggesting improved gut health. The synbiotic treatment effectively modulated neuroinflammation by reducing proinflammatory cytokines (IFN-γ, TNF-α, CRP, and IL-6). It normalized the altered levels of key neurotransmitters such as serotonin, gamma-aminobutyric acid, noradrenaline, and dopamine in the hippocampus and/or frontal cortex. The enhanced expression of brain-derived neurotrophic factor, tryptophan hydroxylase 1, and serotonin transporter-3 (SERT-3), and reduced levels of indoleamine 2,3-dioxygenase 1 (IDO-1) and kynurenine metabolite were observed in the synbiotic-treated group. We suggest that F. prausnitzii and FOS + GOS-loaded synbiotic may reverse the TRD-like symptoms in rats by positively impacting gut health, neuroinflammation, neurotransmitters, and gut microbial composition.

Comparative Efficacy of Animal Depression Models and Antidepressant Treatment: A Systematic Review and Meta-Analysis.

Animal models are critical tools in the study of psychiatric disorders; however, none of the current models fully reflect human stress-related disorders, even though most of the knowledge about the mechanisms of depression comes from animal studies. Animal studies are useful in pharmacological research, whereby we can obtain results that translate into patient treatment by controlling environmental factors, especially in behavioural research. The authors systematically reviewed this issue since medical databases provide access to many primary studies. A systematic review and meta-analysis were conducted based on 25 primary studies. The studies were identified in databases such as PubMed, Embase, and Web of Science (December 2022) according to the inclusion and exclusion criteria established at the beginning of the research and published in the form of a protocol, following the PRISMA and Cochrane Collaboration methodology for secondary studies and CAMARADES (CAMARADES Berlin, QUEST-BIH Charité) for secondary studies on animals. Forest plot analyses were performed (data presented as Mean Difference, Random Model, Inverse Variance), Risk of Bias assessment (Systematic Review Center for Laboratory animal Experimentation (SYRCLE) evaluation), quality assessment of included studies (Animal research: Reporting of In Vivo Experiments (ARRIVE)), and a range of data from source publications were compiled in tabular form. The study analysed the popularity of both animal depression models (ADM) and rat strains used in pharmacological research to test the efficacy of antidepressant drugs based on the immobility time (IT) factor (Forced Swimming Test). The study examined selective serotonin reuptake inhibitors, namely fluoxetine, sertraline, paroxetine, citalopram, and escitalopram. Additionally, the study addressed issues concerning the "data availability statement" because precise IT data analysis was impossible in the case of 212 papers. Our data confirm that the Chronic Unpredictable Mild Stress (CUMS) model is the most popular and versatile model used in preclinical depression research, while the two most popular rat strains were Wistar and Sprague-Dawley. The quality of included papers based on the ARRIVE assessment showed a ratio value equal to 0.63, meaning that studies were of intermediate overall quality. The Risk of Bias assessment based on the SYRCLE tool revealed a high risk related to the blinding and the random outcome assessment. In the meta-analysis, the results indicate that all analysed drugs demonstrated efficacy in reducing IT, and the most analysed drug was fluoxetine (confirmed based on 17 studies (19 models)). The analysis of the efficacy of ADMs showed that the most effective models were CUMS, Flinders Sensitive Line (genetic model), Social Isolation, Restraint Stress, and Low-dose Lipopolysaccharide (pharmacological model). Only 2.35% (5 out of 212) of corresponding authors responded to our data request. The study highlights the dominance of the CUMS model and the Wistar and Sprague-Dawley rat strains in preclinical depression research, affirming the efficacy of SSRIs, particularly fluoxetine, in reducing IT. The findings underscore the need for better data availability and methodological improvements despite intermediate overall study quality and notable bias risks. Enhanced transparency and rigorous assessment standards are essential for advancing the reliability of animal models in depression research.

In vitro and in vivo modulatory effects of fluoxetine on gene expression and antioxidant enzymes in CFA-induced chronic inflammatory model: drug repurposing for arthritis.

Fluoxetine, being a selective serotonin uptake inhibitor, has been broadly used to modulate the neurotransmission of serotonin in the central nervous system. Fluoxetine performs a number of crucial central nervous system-related tasks, including neuroprotective effects against microglial neurotoxicity and protecting oxidative cell damage produced by stress in a variety of stress-related unfavourable health disorders. Studies have shown that the drug (fluoxetine) also has analgesic and anti-inflammatory characteristics in addition to its other basic benefits. Furthermore, existing treatment approaches (NSAIDs, DMARDs, corticosteroids and other immunosuppressants) for RA have limited effects on chronic immunological models. These facts served as the basis for carrying out a study on fluoxetine to explore its therapeutics in a chronic inflammatory rat model called Freund's complete adjuvant (FCA)-induced arthritis. The therapeutic effect of the fluoxetine in FCA-induced arthritic rats was assessed by paw volume, paw diameter, arthritic index and body weight at specific days through the experiment of 28days. These findings were further co-investigated by haematological, biochemical parameters and radiographic imaging at the end of experiment. Furthermore, the modulatory effects on gene expression (NF-κB, PGE2, COX2, INF-γ, IL-4 and IL-10) and antioxidant properties were gritty using qRT-PCR and ELISA kits, respectively, in experimental arthritic rats. Fluoxetine at 10, 20 and 40mg/kg doses reduced (p < 0.001) the serum concentration of C-reactive protein and rheumatoid factor as well as suppressed the expression of PGE2, NF-kB, COX2 and INF-γ when compared to arthritic control. Moreover, fluoxetine (at higher doses) caused significant rise of IL-4 and IL-10. These findings supported the anti-inflammatory and antioxidant potential of fluoxetine in chronic inflammatory model and endorsed it for clinical trials.

Exploring the reality of seafarers' deaths and injuries and preventive measures from the cases of overwork-related disorders

Till date, only few studies have detailed the reality of overwork-related disorders among seafarers. Therefore, in this study, we aimed to evaluate the prevalence of overwork-related disorders among seafarers and assess factors such as patient attributes, diseases diagnosed at the time of determination, workload factors, and other aspects, thereby suggesting relevant preventative measures. Among all the patients identified with overwork-related disorders from April 2010 to March 2017, 2,280 cases of cerebrovascular and cardiovascular diseases and 3,517 cases of mental disorders were selected. To identify seafarer-related cases, keywords related to seafarers were extracted. Subsequently, 33 cases of cardiovascular disease and 19 cases of mental disorders were obtained. The average age of the patients with cerebrovascular and cardiovascular diseases was 56.7 years; for those with mental disorders, it was 45.2 years. The patients were most commonly engaged in fishing, transportation, and postal services. Most patients were employed in the deck department or were captains. The most common types of vessels were fishing and cargo ships. Among the diseases diagnosed at the time of determination, cerebrovascular diseases accounted for 20 cases (60.6%) and cardiovascular diseases accounted for 13 cases (39.4%), with cerebral and myocardial infarctions being the most frequent conditions. Among mental disorders, "mood disorders" accounted for 7 cases (36.8%), and "neurotic disorders, stress-related disorders, and somatoform disorders" accounted for 12 cases (63.2%), with major depressive episodes, post-traumatic stress disorder, and adjustment disorders being the most common. The most common workload factor for patients with cerebrovascular and cardiovascular diseases was "long-term excessive work," and among non-workload factors, "long working hours" and "irregular working hours" were prevalent. For mental disorders, 8 cases were attributed to "extreme psychological stress." Specific events leading to these diseases included "interpersonal relationships," "experiencing accidents or disasters," and "work quantity and quality." Both cerebrovascular and cardiovascular diseases, as well as mental disorders, showed a notable aging trend among seafarers. Thus, measures that consider the characteristics of elderly workers, such as their physical function, are important. Additionally, as seafarers are distributed across various industries and occupations, measures should be specifically tailored to their industry and job type. Our study confirmed that long working hours and irregular working hours were prevalent in both cases. Therefore, there is an urgent need for further efforts to prevent and mitigate overwork-related deaths among seafarers, including organizational support from onshore workplaces and enhancement of medical and operational support using information and communication technology.

Oral Supplementation of L-Carnosine Attenuates Acute-Stress-Induced Corticosterone Release and Mitigates Anxiety in CD157 Knockout Mice.

Corticosterone, an end product of the hypothalamic-pituitary-adrenal (HPA) axis, is a crucial stress hormone. A dysregulated HPA axis and corticosterone release play pivotal roles in the onset and persistence of symptoms of stress-related psychiatric disorders, such as anxiety. The intake of nutrients, probiotics, and prebiotic supplements decreases blood corticosterone levels. The dipeptide L-carnosine is composed of beta-alanine and L-histidine and is commercially available as a nutritional supplement for recovery from fatigue. L-carnosine is involved in stress-induced corticosterone responses and anxiety behaviors in rodents. Here, we assessed the effect of L-carnosine in CD157 knockout (KO) mice, a murine model of autism spectrum disorder (ASD). The uptake of L-carnosine suppressed the increase in plasma corticosterone levels in response to acute stress and attenuated anxiety-like behaviors in CD157 KO mice. These results suggest that L-carnosine supplementation may relieve anxiety by suppressing excessive stress responses in individuals with ASD.

Feeding gut microbes to nourish the brain: unravelling the diet-microbiota-gut-brain axis.

The prevalence of brain disorders, including stress-related neuropsychiatric disorders and conditions with cognitive dysfunction, is rising. Poor dietary habits contribute substantially to this accelerating trend. Conversely, healthy dietary intake supports mood and cognitive performance. Recently, the communication between the microorganisms within the gastrointestinal tract and the brain along the gut-brain axis has gained prominence as a potential tractable target to modulate brain health. The composition and function of the gut microbiota is robustly influenced by dietary factors to alter gut-brain signalling. To reflect this interconnection between diet, gut microbiota and brain functioning, we propose that a diet-microbiota-gut-brain axis exists that underpins health and well-being. In this Review, we provide a comprehensive overview of the interplay between diet and gut microbiota composition and function and the implications for cognition and emotional functioning. Important diet-induced effects on the gut microbiota for the development, prevention and maintenance of neuropsychiatric disorders are described. The diet-microbiota-gut-brain axis represents an uncharted frontier for brain health diagnostics and therapeutics across the lifespan.

The emerging role of fat-inducing transcript 2 in endoplasmic reticulum proteostasis and lipoprotein biogenesis.

This review examines the evolving role of the fat-inducing transcript 2 (FIT2) protein in lipid droplet (LD) biology and its broader implications in cellular physiology and disease. With recent advancements in understanding FIT2 function across various model systems, this review provides a timely synthesis of its mechanisms and physiological significance. FIT2, an endoplasmic reticulum (ER)-resident protein, has been established as a critical regulator of LD formation in diverse organisms, from yeast to mammals. It facilitates LD biogenesis by sequestering diacylglycerol (DAG) and potentially influencing ER membrane dynamics. Beyond its role in lipid metabolism, FIT2 intersects with the ER-associated degradation (ERAD), is critical for protein homeostasis, and is linked to the unfolded protein response (UPR). Dysregulation of FIT2 has also been linked to metabolic disorders such as insulin resistance and lipodystrophy, highlighting its clinical relevance. Insights into FIT2 function underscore its pivotal role in LD formation and lipid homeostasis. Understanding its involvement in ER proteostasis and very low density lipoprotein biogenesis has broad implications for metabolic diseases and cancer. Therapeutic strategies targeting FIT2 may offer novel approaches to modulate lipid metabolism and mitigate associated pathologies. Further research is needed to elucidate the full spectrum of FIT2's interactions within cellular lipid and protein networks, potentially uncovering new therapeutic avenues for metabolic and ER stress-related disorders.

Inflammatory Biomarkers and Risk of Psychiatric Disorders

Individuals with psychiatric disorders have been reported to have elevated levels of inflammatory biomarkers, and prospective evidence is limited regarding the association between inflammatory biomarkers and subsequent psychiatric disorders risk. To assess the associations between inflammation biomarkers and subsequent psychiatric disorders risk. This was a prospective cohort study including individuals from the Swedish Apolipoprotein Mortality Risk (AMORIS) cohort, with no prior psychiatric diagnoses and having a measurement of at least 1 inflammatory biomarker. Data from the UK Biobank were used for validation. Longitudinal trajectories of studied biomarkers were visualized before diagnosis of psychiatric disorders in the AMORIS cohort via a nested case-control study. In addition, genetic correlation and mendelian randomization (MR) analyses were conducted to determine the genetic overlap and causality of the studied associations using publicly available GWAS summary statistics. Inflammatory biomarkers, eg, leukocytes, haptoglobin, immunoglobulin G (IgG), C-reactive protein (CRP), platelets, or albumin. Any psychiatric disorder or specific psychiatric disorder (ie, depression, anxiety, and stress-related disorders) was identified through the International Statistical Classification of Diseases, Eighth, Ninth, and Tenth Revision codes. Among the 585 279 individuals (mean [SD] age, 45.5 [14.9] years; 306 784 male [52.4%]) in the AMORIS cohort, individuals with a higher than median level of leukocytes (hazard ratio [HR], 1.11; 95% CI, 1.09-1.14), haptoglobin (HR, 1.13; 95% CI, 1.12-1.14), or CRP (HR, 1.02; 95% CI, 1.00-1.04) had an elevated associated risk of any psychiatric disorders. In contrast, we found an inverse association for IgG level (HR, 0.92; 95% CI, 0.89-0.94). The estimates were comparable for depression, anxiety, and stress-related disorders, specifically, and these results were largely validated in the UK Biobank (n = 485 620). Analyses of trajectories revealed that individuals with psychiatric disorders had higher levels of leukocytes and haptoglobin and a lower level of IgG than their controls up to 30 years before the diagnosis. The MR analysis suggested a possible causal relationship between leukocytes and depression. In this cohort study, inflammatory biomarkers including leukocytes, haptoglobin, CRP, and IgG were associated with a subsequent risk of psychiatric disorders, and thus might be used for high-risk population identification. The possible causal link between leukocytes and depression supports the crucial role of inflammation in the development of psychiatric disorders.

Machine Learning, Deep Learning, and Data Preprocessing Techniques for Detecting, Predicting, and Monitoring Stress and Stress-Related Mental Disorders: Scoping Review.

Mental stress and its consequent mental health disorders (MDs) constitute a significant public health issue. With the advent of machine learning (ML), there is potential to harness computational techniques for better understanding and addressing mental stress and MDs. This comprehensive review seeks to elucidate the current ML methodologies used in this domain to pave the way for enhanced detection, prediction, and analysis of mental stress and its subsequent MDs. This review aims to investigate the scope of ML methodologies used in the detection, prediction, and analysis of mental stress and its consequent MDs. Using a rigorous scoping review process with PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines, this investigation delves into the latest ML algorithms, preprocessing techniques, and data types used in the context of stress and stress-related MDs. A total of 98 peer-reviewed publications were examined for this review. The findings highlight that support vector machine, neural network, and random forest models consistently exhibited superior accuracy and robustness among all ML algorithms examined. Physiological parameters such as heart rate measurements and skin response are prevalently used as stress predictors due to their rich explanatory information concerning stress and stress-related MDs, as well as the relative ease of data acquisition. The application of dimensionality reduction techniques, including mappings, feature selection, filtering, and noise reduction, is frequently observed as a crucial step preceding the training of ML algorithms. The synthesis of this review identified significant research gaps and outlines future directions for the field. These encompass areas such as model interpretability, model personalization, the incorporation of naturalistic settings, and real-time processing capabilities for the detection and prediction of stress and stress-related MDs.

Electroacupuncture negatively regulates the Nesfatin-1/ERK/CREB pathway to alleviate HPA axis hyperactivity and anxiety-like behaviors caused by surgical trauma

BackgroundHyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis constitutes a pivotal response by surgical trauma, manifesting as a critical aspect of the acute stress reaction. This hyperactivity resulted in adverse surgical outcomes and is often associated with increased postoperative anxiety. Increased evidence suggests that Nesfatin-1 plays a crucial role in stress responses and stress-related psychiatric disorders. Electroacupuncture (EA) is widely used to alleviate stress responses and anxiety, although its mechanism of action remains unclear. This study aimed to assess the mechanisms by which hypothalamic Nesfatin-1 contribute to the alleviation of HPA axis hyperactivity and anxiety by EA.MethodsPartial hepatectomy (HT) was performed to simulate surgical trauma, and EA was applied at Zusanli (ST36) and Sanyinjiao (SP6). The levels of hypothalamic Nesfatin-1, c-Fos, and corticotropin-releasing hormone (CRH) were detected, and serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were regarded as indicators of HPA axis activity. Anxiety levels were assessed through open field tests (OFT), elevated plus maze (EPM), and light–dark box tests (LDBT). To investigate the role of Nesfatin-1, its expression was modulated using stereotactic viral injections or plasmid transfections. Transcriptome sequencing was employed to explore the downstream signaling pathways of Nesfatin-1. Additionally, brain cannula implantation was performed to facilitate targeted drug administration.ResultsOur findings demonstrated that EA reduced the hypothalamic overexpression of CRH and Nesfatin-1, as well as serum levels of ACTH and CORT. Additionally, it alleviated anxiety-like behaviors resulting from surgical trauma. We observed that overexpression of Nesfatin-1 in the hypothalamic paraventricular nucleus (PVN) triggered hyperactivity of the HPA axis and anxiety. Conversely, knocking down Nesfatin-1 in the PVN reversed these effects caused by surgical trauma. Transcriptome sequencing identified the extracellular regulated protein kinases (ERK)/cAMP-response element binding protein (CREB) pathway as a key mediator in the impacts of surgical trauma and EA on the hypothalamus. Both in vivo and in vitro studies showed that overexpression of Nesfatin-1 activated the ERK/CREB pathway. Furthermore, administering ERK or CREB inhibitors into the PVN mitigated HPA axis hyperactivity and anxiety-like behaviors induced by surgical trauma. Finally, EA was observed to decrease the phosphorylation levels of ERK and CREB in the PVN.ConclusionEA alleviates HPA axis hyperactivity and anxiety-like behaviors caused by surgical trauma through inhibition of Nesfatin-1/ERK/CREB pathway in the hypothalamus.

The impact of pubertal stress and adult hormone exposure on the transcriptome of the developing hypothalamus.

Why individuals suffer negative consequences following stress is a complex phenomenon that is dictated by individual factors, the timing of stress within the lifespan, and when in the lifespan the consequences are measured. Women who undergo adverse childhood experiences are at risk for lasting biological consequences, including affective and stress dysregulation. We have shown that pubertal adversity is associated with a blunted hypothalamic-pituitary-adrenal axis glucocorticoid response in peripartum humans and mice. In mice, our prior examination of the paraventricular nucleus (PVN) of the hypothalamus showed that pubertal stress led to an upregulation of baseline mRNA expression of six immediate early genes (IEGs) in the PVN of adult, pregnant mice. Separately, we showed that the pregnancy-associated hormone allopregnanolone is necessary and sufficient to produce the blunted stress response phenotype in pubertally stressed mice. In the current study, we further examined a potential mechanistic role for the IEGs in the PVN. We found that in pubertally stressed adult female, but not male, mice, intra-PVN allopregnanolone was sufficient to recapitulate the baseline IEG mRNA expression profile previously observed in pubertally stressed, pregnant mice. We also examined baseline IEG mRNA expression during adolescence, where we found that IEGs have developmental trajectories that showed sex-specific disruption by pubertal stress. Altogether, these data establish that IEGs may act as a key molecular switch involved in increased vulnerability to negative outcomes in adult, pubertally stressed animals. How the factors that produce vulnerability combine throughout the lifespan is key to our understanding of the etiology of stress-related disorders.

Comprehensive assessment of Zingiber sianginensis: Phytometabolomic analysis and its impact on oxidative stress biomarkers

In India, ginger is highly valued for cultural and medicinal purposes. Besides traditional uses, ginger has been proven for its efficacy in cancer, chemotherapy-induced nausea, bacterial infections, neuroinflammation, and oxidative stress. This study focuses on Zingiber sianginensis, a rare ginger species in the Siang region of Arunachal Pradesh, India. This study studied pharmacognostical evaluation, phytometabolomics analysis, and its effect on oxidative stress biomarkers. Microscopic and chemical tests were employed for pharmacognostical evaluation, revealing distinctive characteristics of Zingiber sianginensis, such as non-close collateral vascular bundles and unique cork layers. Chemical tests, including the phloroglucinol and hydrochloric acid test, differentiated Zingiber sianginensis from Zingiber officinale Roscoe. Phytometabolomics analysis, using Gas Chromatography-Mass Spectrometry (GC/MS) and Liquid Chromatography-Electrospray Ionisation-Quadrupole Time of Flight-Mass Spectrometry (LC-ESI-QTOF-MS/MS) techniques, identified a diverse range of metabolites in Zingiber sianginensis, including polyphenols, monoterpenoids, diterpenoids, sesquiterpenoids, and organic compounds. The LC-ESI-QTOF-MS/MS analysis revealed 158 compounds, verified through cross-referencing with established databases. Heavy metal analysis by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) confirmed that Zingiber sianginensis complies with safety standards, showing concentrations of heavy metals within acceptable limits. The isolation and characterization of compounds from Zingiber sianginensis identified natural products such as (R)-(-)- alpha-Curcumene (1), 1-Dehydro-[10]-gingerdione (2), 6-Shogaol (3), and 6-Gingerol (4). Quantification of 6-gingerol revealed that Zingiber sianginensis contains approximately twice the amount compared to Zingiber officinale Roscoe's, suggesting its potential as a source for higher 6-gingerol content. The hydroalcoholic extract of Zingiber sianginensis exhibited antioxidant properties, reducing oxidative stress biomarkers in human dermal fibroblast cells treated with rotenone. Allantoin and 3-bromotyrosine levels significantly decreased, indicating the extract's potential in combating oxidative stress-related disorders. Overall, this comprehensive study provides valuable insights into the pharmacognostical, phytometabolomic, and safety aspects of Zingiber sianginensis, highlighting its potential as a source of bioactive compounds with health benefits.

Kappa opioid receptor mediated operant performance in male and female rats

Anhedonia and avolition are emotions frequently endorsed by individuals with stress related disorders. Kappa opioid receptor (KOR) activation can induce negative emotions and recent clinical evidence suggests that KOR antagonism can alleviate anhedonia in a transdiagnostic cohort of patients. However, the behavioral consequences of KOR activation and antagonism in modulating motivation, as assessed by schedule-controlled behavioral performance without preexisting conditions (stress or substance use), have not been formally assessed. To address this gap in the literature, this report utilized male and female Sprague Dawley rats to (1) evaluate the impact of the selective KOR agonist U50,488, on the performance of animals responding for sucrose pellets under a progressive ratio (PR) schedule and (2) determine the effects of the short-acting KOR antagonist LY2444296 alone and on U50,488 mediated reductions in PR performance. Overall, U50,488 5 mg/kg significantly reduced the breakpoint and number of rewards obtained by animals. This occurred in the absence of motor impairment and independent of evidence for satiation. LY2444296 did not alter PR performance when administered alone but effectively blocked the deficits induced by U50,488. To further delineate the behavioral alterations that underlie these reductions in responding, a more detailed analysis was conducted on PR performance in the first 15 min of the session, the period of time when animals obtained the most reinforcers. During this period, U50,488 increased the length of the post-reinforcement pause and reduced the running rate on PR schedules. These changes in behavior produced by acute activation of KORs are consistent with a reduction of effort-related motivation in rodents. These data contribute to the understanding of how KORs modulate motivation, which is critical to future efforts to evaluate performance in the context of stress and assess how KOR antagonists alleviate anhedonic behaviors associated with stress.

Effects of Repeated Administration of Rauwolfia Serpentina on Stress-Induced Anorexia and Leptin Levels: Relationship With Adaptation to Stress

Background: Stress is a major contributor to various health issues, including depression, anorexia nervosa, diabetes, and obesity. Rauwolfia serpentina, a traditional medicinal plant, has shown potential in alleviating stress-induced effects due to its influence on serotonin neurotransmission and its anxiolytic properties. Objective: This study aimed to investigate the effects of repeated administration of Rauwolfia serpentina on stress-induced anorexia and leptin levels, and its relationship with adaptation to stress in rats. Methods: Male albino Wistar rats were divided into four groups: DMSO unstressed, DMSO stressed, Rauwolfia serpentina unstressed, and Rauwolfia serpentina stressed. The stressed groups were subjected to two hours of immobilization daily for five days, followed by oral administration of Rauwolfia serpentina at 10 mg/kg. Behavioral assessments included the open field and light-dark transition tests. Body weight, food intake, and plasma levels of glucose, leptin, and corticosterone were measured. Data were analyzed using ANOVA with post-hoc Newman-Keuls test, and significance was set at p&lt;0.05. Results: Rauwolfia serpentina significantly improved body weight maintenance (98.9 ± 1.3% vs. 99.5 ± 1.7%) and increased food intake (16.3 ± 0.6 g vs. 16.5 ± 0.5 g) in stressed rats. It also reduced anxiety-like behaviors and lowered corticosterone levels (15.9 ± 1.6 ng/mL vs. 18.4 ± 1.7 ng/mL) in stressed groups (p&lt;0.05). Conclusion: Rauwolfia serpentina effectively alleviates stress-induced anorexigenic and anxiogenic effects, suggesting its potential as a therapeutic agent for managing stress-related disorders.

Chronic stress deficits in reward behaviour co-occur with low nucleus accumbens dopamine activity during reward anticipation specifically

Whilst reward pathologies are major and common in stress-related neuropsychiatric disorders, their neurobiology and treatment are poorly understood. Imaging studies in human reward pathology indicate attenuated BOLD activity in nucleus accumbens (NAc) coincident with reward anticipation but not reinforcement; potentially, this is dopamine (DA) related. In mice, chronic social stress (CSS) leads to reduced reward learning and motivation. Here, DA-sensor fibre photometry is used to investigate whether these behavioural deficits co-occur with altered NAc DA activity during reward anticipation and/or reinforcement. In CSS mice relative to controls: (1) Reduced discriminative learning of the sequence, tone-on + appetitive behaviour = tone-on + sucrose reinforcement, co-occurs with attenuated NAc DA activity throughout tone-on and sucrose reinforcement. (2) Reduced motivation during the sequence, operant behaviour = tone-on + sucrose delivery + sucrose reinforcement, co-occurs with attenuated NAc DA activity at tone-on and typical activity at sucrose reinforcement. (3) Reduced motivation during the sequence, operant behaviour = appetitive behaviour + sociosexual reinforcement, co-occurs with typical NAc DA activity at female reinforcement. Therefore, in CSS mice, low NAc DA activity co-occurs with low reward anticipation and could account for deficits in learning and motivation, with important implications for understanding human reward pathology.

Hypocretin in the nucleus accumbens shell modulates social approach in female but not male California mice

The hypocretin (Hcrt) system modulates arousal and anxiety-related behaviors and has been considered as a novel treatment target for stress-related affective disorders. We examined the effects of Hcrt acting in the nucleus accumbens shell (NAcSh) and anterodorsal bed nucleus of the stria terminalis (adBNST) on social behavior in male and female California mice (Peromyscus californicus). In female but not male California mice, infusion of Hcrt1 into NAcSh decreased social approach. Weak effects of Hcrt1 on social vigilance were observed in both females and males. No behavioral effects of Hcrt1 infused into the adBNST were observed. Analyses of sequencing data from California mice and Mus musculus NAc showed that Hcrtr2 was more abundant than Hcrtr1, so we infused the selective Hcrt receptor 2 antagonist into the NAcSh, which increased social approach in females previously exposed to social defeat. A calcium imaging study in the NAcSh of females before and after stress exposure showed that neural activity increased immediately following the expression of social avoidance but not during freezing behavior. This observation is consistent with previous studies that identified populations of neurons in the NAc that drive avoidance. Intriguingly, calcium transients were not affected by stress. These data suggest that hypocretin acting in the NAcSh plays a key role in modulating stress-induced social avoidance.