The hypothalamic-pituitary-adrenal axis regulates the secretion of glucocorticoids in response to environmental challenges. In the brain, a nuclear receptor transcription factor, the glucocorticoid receptor, is an important component of the hypothalamic-pituitary-adrenal axis's negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity. The glucocorticoid receptor influences cognitive processes, including glutamate neurotransmission, calcium signaling, and the activation of brain-derived neurotrophic factor-mediated pathways, through a combination of genomic and non-genomic mechanisms. Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor, thereby affecting the hypothalamic-pituitary-adrenal axis and stress-related cognitive functions. An appropriate level of glucocorticoid receptor expression can improve cognitive function, while excessive glucocorticoid receptors or long-term exposure to glucocorticoids may lead to cognitive impairment. Patients with cognitive impairment-associated diseases, such as Alzheimer's disease, aging, depression, Parkinson's disease, Huntington's disease, stroke, and addiction, often present with dysregulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor expression. This review provides a comprehensive overview of the functions of the glucocorticoid receptor in the hypothalamic-pituitary-adrenal axis and cognitive activities. It emphasizes that appropriate glucocorticoid receptor signaling facilitates learning and memory, while its dysregulation can lead to cognitive impairment. This provides clues about how glucocorticoid receptor signaling can be targeted to overcome cognitive disability-related disorders.

People who have lost their only child (PLOCs) in China exhibit chronic hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and a range of abnormal symptoms. The hippocampus may serve as a potential mediator between HPA axis dysregulation and the symptoms. However, the mechanisms underlying these developments remain unclear.

Functional magnetic resonance imaging data were collected from 51 PLOCs and 29 healthy individuals. A linear regression model was utilized to explore the interrelationships between blood cortisol levels, hippocampal structure and function, and abnormal symptoms. Additionally, a mediation effect model was employed to examine the influence of the hippocampus on the relationship between blood cortisol levels and abnormal symptoms.

Compared with the healthy controls, the PLOCs had significantly reduced gray matter volume in the hippocampus, and increased degree centrality (DC) values in the right hippocampus. Additionally, the PLOCs exhibited more severe cognitive impairment and poorer immediate memory ability, which were significantly negatively correlated with blood cortisol levels. The mediation effect model revealed specific effects of DC values in the right hippocampus on the association between blood cortisol levels and MMSE scores and immediate memory scores.

Cross-sectional design of this study could not demonstrate the causality.

The alterations in DC in the right hippocampus substantially mediated the relationship between HPA axis dysregulation and cognitive impairment in the sampled Chinese PLOCs. High blood cortisol levels led to cognitive impairment by causing changes in right hippocampal function.

Childhood adversity (CA) is the leading preventable risk factor for mental illness. While CA can exacerbate affective symptoms across various psychiatric disorders, its impact on brain morphology, particularly the rostral anterior cingulate cortex (rACC), has mainly been studied in specific stress-related psychiatric disorders, such as depression and anxiety disorders. Therefore, we set out to disentangle the relationships between CA, psychopathology and brain structure across a broader range of psychiatric disorders. We studied 227 patients with stress-related and/or neurodevelopmental disorders and 95 healthy controls. We focused on the rACC, as this region is highly impacted by CA and has a pivotal role in affective functions across psychiatric disorders. The presence of CA was associated with decreased left rACC thickness across the whole sample, independent of psychopathology. Additionally, the contralateral right rACC was associated with psychopathology, with psychiatric patients having a thinner rACC compared to healthy controls, which was most pronounced in the stress-related disorders group. While left rACC thickness negatively correlated with social anxiety-related concerns, right rACC thickness negatively correlated with various core symptoms of stress-related and neurodevelopmental disorders. Finally, our exploratory analyses across cortical regions did not reveal any robust effects that survived multiple comparison correction. Taken together, our results suggest that within the stress-related disorders group, the CA-related thinning of the left rACC may compound the effects of the affected right rACC. This 'double hit' in stress-related disorders may contribute to the well-established phenomenon that CA leads to a worse illness trajectory in these disorders.

Depression is a prevalent and debilitating condition that has a severe negative impact on a person's life. Chronic stress exposure plays a substantial role in the development of depression. In the present study, rats were exposed to chronic unpredictable mild stress (CUMS) for four weeks. Empagliflozin (EMPA), a Sodium-Glucose Cotransporter-2 (SGLT-2) inhibitor, is an oral antidiabetic agent exhibiting antioxidant, anti-inflammatory, and antiapoptotic effects. This study aimed to examine the antidepressant effect of EMPA in an experimental animal model of depression induced by CUMS in rats and explore the probable underlying mechanisms. Rats were treated with EMPA, per-orally, at a dose of 10 mg/kg/day for four weeks. EMPA treatment counteracted CUMS-induced histopathological, biochemical and behavioral alterations. EMPA suppressed the CUMS-induced increase in the oxidative stress, inflammatory, and apoptotic markers, where levels of MDA, IL-1β, TNF-α, NF-κB, NLRP3 and active caspase 3 were reduced by 29.6 %, 24.8 %, 17.9 %, 36.6 %, 24.5 % and 41.5 %, respectively, compared to the disease group. Furthermore, EMPA decreased the level of the microglial activation marker, iba-1 by 24 % in comparison to the disease group. In addition, EMPA treatment decreased blood glucose levels by 39 %, decreased serum insulin levels by 60.6 %, decreased HOMA-IR by 76.5 % and increased GLUT 4 expression, compared to the CUMS group, all which proves that EMPA has an effect insulin signaling and alleviates insulin resistance. Our results conclude that modulating key factors involved in depression, such as inflammation, oxidative stress, and NLRP3 inflammasome pathway, accounts for the anti-depressant effect of EMPA.

Natural disasters are an increasing global health issue. Psychological outcomes from traumatic experiences appear linked to the glucocorticoid hormone cortisol. Here we analyze relations among salivary cortisol, traumatic events, and mental health from a 37-year study of a rural community in Dominica. The community has experienced multiple natural disasters. Our investigations of physiological responses to these traumatic experiences and downstream mental health outcomes are exploratory in nature because this research area is in early stages of methodological and theoretical development, and we are applying current biomedical and psychiatric concepts in a non-western culture. Our analyses suggest that temporal profiles of cortisol response are linked to mental health conditions associated with natural disasters including grief, depression, and post-traumatic stress disorders.

Mitochondria play a crucial role in brain homeostasis and changes in mitochondrial bioenergetics are linked to age-related neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. We investigated changes in the activities of the electron transport chain (ETC) complexes in normally aging baboon brains and determined how these changes relate to donor sex, morning cortisol levels, and walking speed. We assessed mitochondrial bioenergetics from archived prefrontal cortex (PFC) tissues from a large cohort (60 individuals) of well-characterized aging baboons (6.6-22.8 years, approximately equivalent to 26.4-91.2 human years). Aging was associated with a decline in mitochondrial ETC complexes in the PFC, which was more pronounced when normalized for citrate synthase activity, suggesting that the decline is predominantly driven by changes in the specific activity of individual complexes rather than global changes in mitochondrial content. When donor sex was used as a covariate, we found that ETC activity was preserved with age in females and declined in males. Males had higher activities of each individual ETC complex and greater lactate dehydrogenase activity at a given age relative to females. Circulating cortisol negatively correlated with walking speed when male and female data were combined. We also observed a robust positive predictive relationship between walking speed and respiration linked to complexes I, III, and IV in males but not in females. This data reveals a link between frailty and PFC bioenergetic function and highlights a potential molecular mechanism for sexual dimorphism in brain resilience.

Psychological resilience plays a crucial role in protecting individuals from mental health issues in the face of adverse life events. However, the neurobiological mechanisms through which resilience functions as a protective factor against mental disorders remain poorly understood. This study aims to investigate the neuroendocrinological mechanisms underlying psychological resilience by examining the relationship between endogenous cortisol and resilience in Chinese adolescents. Additionally, the study explores whether this relationship is moderated by parenting style, family cohesion and adaptability, school climate, and life events. A total of 270 adolescent students (mean age: 12.83 ± 0.60 years; 112 boys, 158 girls) were randomly recruited from a middle school in Jiangsu Province, China. Hair cortisol, a biomarker of chronic endogenous cortisol, was measured using liquid chromatography-tandem mass spectrometry. Resilience was assessed using a scale validated for Chinese adolescent populations, while family and school environmental factors were evaluated using questionnaires. The results showed significant negative correlations between hair cortisol levels and resilience, individual power, goal planning, family support, and positive thinking. However, no significant correlations were found between hair cortisol levels and parenting style, family cohesion and adaptability, school climate, or life events. Importantly, the associations between hair cortisol levels and resilience were stable and not significantly influenced by family or school environmental factors. In conclusion, adolescents with higher psychological resilience, greater individual power, better goal planning, stronger family support, and more positive thinking exhibited lower chronic hypothalamic-pituitary-adrenal (HPA) axis activity. These associations remained stable and were not significantly affected by family or school environments.

Migraine is a neurological disorder with recurrent attacks characterized by headaches and sensitivity to stimuli. Stress is a significant trigger for attacks; however, molecular mechanisms of the connection are poorly understood.

To better characterize such mechanisms, we performed a placebo-controlled, double-blind crossover study with 51 participants (21 patients with migraine without aura and 30 healthy controls).

Participants received a low-dose citalopram- or placebo challenge on 2 separate days. Prechallenge and postchallenge assessment of cortisol concentrations and transcriptomic changes using RNA-seq was performed from whole blood samples. Analysis of an accidental attack following the citalopram challenge was also conducted.

Neuroendocrine challenge elicited elevated cortisol concentrations at 30 (P-value = 0.1355) and 70 minutes (P-value = 0.07292) postchallenge in patients with migraine compared with controls. Gene expression analysis showed 10 differentially expressed genes (2 down- and 8 upregulated, P-value ≤ 0.005) and 10 dysregulated gene sets (P-value ≤ 0.005). Among them, dysregulated IKBKGP1 and NKRF genes and upregulated protein synthesis and translation, carbohydrate metabolism, and, attack-related, glycosylation can be highlighted.

Patients with migraine without aura showed an enhanced cortisol response to a neuroendocrine challenge. This was accompanied by a probable suppression of NFκB activity through dysregulation of NKRF and an altered immune function. Upregulated carbohydrate metabolism may reflect the elevated cortisol concentrations' stimulating effects on endothelial glycocalyx, playing a role in NO-induced vasodilation, a trigger for migraine attacks. The results suggest the elevated cortisol response may trigger migraine attacks through altered glycocalyx and immune functions.

Conductive nanofibers can exhibit excellent mechanical properties such as flexibility, elasticity, porosity, large surface area-to-volume ratio, etc making them suitable for a wide range of applications including biosensor development. Their large surface area provides more active sites for immobilization of large amount of bioreceptors enabling more interaction sites with the target analytes, enhancing sensitivity and detection capabilities. However, engineering conductive nanofibers with such excellent properties is challenging limiting their effective deployment for intended applications. In this research, we propose a novel approach for easy fabrication of highly conductive and flexible nanofiber leveraging the electrospinning, electroless deposition and have applied it to cortisol monitoring; a common biomarker for stress which is often quantified through enzyme-linked immunoassays using blood or saliva samples. By adopting the nanofiber sheet as a transducer for aptamer immobilization and cortisol sensing our developed biosensor was able to detect cortisol in buffer, artificial saliva, and artificial sweat within five minutes, from 10 pg/mL to 10 µg/mL (27.59 pM to 27.59 µM) with a low detection limit of 1 pg/ml (2.76 pM). The Au-coated PLA nanofiber-based electrochemical biosensor's flexibility allows for compact manufacturing, rendering it an optimal choice for integration into point-of-care testing and wearable systems.

Because early-life stress is common and constitutes a strong risk factor for cognitive and mental health disorders, it has been the focus of a multitude of studies in humans and experimental models. Yet, we have an incomplete understanding of what is perceived as stressful by the developing brain, what aspects of stress influence brain maturation, what developmental ages are particularly vulnerable to stress, which molecules mediate the effects of stress on brain operations, and how transient stressful experiences can lead to enduring emotional and cognitive dysfunctions. Here, we discuss these themes, highlight the challenges and progress in resolving them, and propose new concepts and avenues for future research.

Major depressive disorder (MDD) has been consistently associated with hypothalamic-pituitary-adrenal (HPA)-axis and autonomic nervous system (ANS) (re-)activity abnormalities, however, often with conflicting results.

This study offers a concurrent multi-measure assessment of both HPA-axis and ANS activity and reactivity over 3 days to better characterize baseline and dynamic neuroendocrine alterations in MDD accounting for multiple individual factors. We therefore investigated group differences between 20 unmedicated MDD patients and 20 carefully-matched healthy controls (HC) by simultaneously assessing morning plasma (CORT, ACTH, copeptin) and awakening response saliva (CORT, DHEA, DHEA-s) endocrine measures, as well as multiple linear and non-linear measures of resting heart rate (HR) and its variability (HRV), before (baseline, day 1) and after a successive overnight metyrapone (HPA-axis stimulation, day 2) and dexamethasone (HPA-axis suppression, day 3) pharmaco-endocrine challenge, controlling for childhood trauma (CT) history.

Statistically significant group differences emerged only for baseline plasma CORT and ACTH levels (MDD > HC) and resting HR in all 3 days. No differences were found in dynamic plasma levels and all saliva endocrine measures, as well as all HRV measures. Baseline HR was the only significant predictor for MDD diagnosis.

Our detailed baseline and dynamic neuroendocrine comparison using closely matched HC indicates fewer neuroendocrine alterations in MDD than expected. These results challenge prior findings and support the importance of exact matching when investigating neuroendocrine biomarkers, as previously reported findings may rely on unaccounted individual but not group differences.

The cortisol awakening response (CAR) has been linked to a variety of emotion-related psychiatric conditions and is proposed to prepare the brain for upcoming stress and challenges. Yet, the underlying neurobiological mechanisms of such proactive effects on emotional processing remain elusive. In the current double-blinded, pharmacologically-manipulated study, 36 male adults (DXM group) received cortisol-repressive dexamethasone on the previous night, then performed the Emotional Face Matching Task (EFMT) during fMRI scanning the next afternoon. Relative to the placebo group (31 males), the DXM group exhibited lower accuracy in the emotion matching condition (p < 0.01), but not in the sensorimotor control shape matching condition. ROI-to-voxel psychophysiological interaction (PPI) analyses revealed significant task-by-group interaction involving the right and left amygdala, but not the medial orbitofrontal cortex (MOFC) or hippocampus. Specifically, the DXM group exhibited stronger functional connectivity between the right amygdala and left dorsolateral prefrontal cortex (lDLPFC) during emotion matching (p < 0.001) but reduced connectivity in the same network during shape matching, as compared to the placebo group (p = 0.023). Meanwhile, the DXM group exhibited weaker left amygdala-right posterior middle temporal gyrus (rMTG) connectivity than the placebo group during shape matching (p < 0.001), but there was no group effect in the connectivity during emotion matching (p = 0.392). These results indicate that the CAR proactively prepares fronto-limbic functional organization for emotion processing in male adults. The findings support a causal link between CAR and its proactive effects on emotional processing, and suggest a model of CAR-mediated brain preparedness where CAR sets a tonic tone for the upcoming day to actively regulate neuroendocrinological responses to emotionally charged stimuli on a moment-to-moment basis.

To investigate the relationship between depression and AD, water avoidance stress (WAS) was induced for 10 days in both Tg2576 mice and wild-type (WT) mice. After WAS, memory function and depressive-like behavior were investigated in Tg2576 mice. Tg2576 WAS mice exhibited more depressive-like behaviors than WT WAS and Tg2576 control (CON) mice. Strikingly, Tg2576 CON mice showed more depressive-like behaviors than WT mice. Moreover, corticosterone and phospho-glucocorticoid receptor (p-GR) levels were also higher in Tg2576 WAS mice in comparison to Tg2576 CON mice. Spinster homologue 2 (SPNS2) is a member of non-ATP-dependent transporter. The role of SPNS2 was widely known as a sphingosine-1-phosphate (S1P) transporter, which export intracellular S1P from cells. Using GEO database to analyze SPNS2 gene expression changes in patients with AD and depression, we show that SPNS2 gene expression correlates with AD and depression. Interestingly, Tg2576 WAS mice displayed significantly increased levels of SPNS2 w1hen compared to Tg2576 CON counterparts. SPNS2 levels were also higher in Tg2576 CON mice in comparison with WT CON mice. Remarkably, we found a decrease in S1P brain levels and an increase in S1P serum levels of Tg2576 WAS mice in comparison with Tg2576 CON mice. Accordingly, WAS induced group further decreased S1P levels in the brains. However, the level in the serum further increased in comparison with non-induced group. Therefore, these results suggest that AD and depression could be associated, and that Tg2576 transgenic mice are more susceptible to stress-induced depression through the release of S1P by SPNS2 up-regulation.

N6-methyladenosine (m6A) is one of the most common post-transcriptional RNA modifications, which plays a critical role in various bioprocesses such as immunological processes, stress response, cell self-renewal, and proliferation. The abnormal expression of m6A-related proteins may occur in the central nervous system, affecting neurogenesis, synapse formation, brain development, learning and memory, etc. Accumulating evidence is emerging that dysregulation of m6A contributes to the initiation and progression of psychiatric disorders including depression. Until now, the specific pathogenesis of depression has not been comprehensively clarified, and further investigations are warranted. Stress, inflammation, neurogenesis, and synaptic plasticity have been implicated as possible pathophysiological mechanisms underlying depression, in which m6A is extensively involved. Considering the extensive connections between depression and neurofunction and the critical role of m6A in regulating neurological function, it has been increasingly proposed that m6A may have an important role in the pathogenesis of depression; however, the results and the specific molecular mechanisms of how m6A methylation is involved in major depressive disorder (MDD) were varied and not fully understood. In this review, we describe the underlying molecular mechanisms between m6A and depression from several aspects including inflammation, stress, neuroplasticity including neurogenesis, and brain structure, which contain the interactions of m6A with cytokines, the HPA axis, BDNF, and other biological molecules or mechanisms in detail. Finally, we summarized the perspectives for the improved understanding of the pathogenesis of depression and the development of more effective treatment approaches for this disorder.

Maternal premating stress (mPMS) has been linked to adverse outcomes in the next generation. In this systematic review, we examined the impact of mPMS on offspring's neurodevelopmental milestones, behavioral outcomes, and physiological alterations before and after adulthood in rodent studies. We conducted a systematic literature review using PubMed, Scopus, ProQuest, and APA PsycNet, using the terms "premating stress", "pregestational stress", "prepregnancy stress, and "preconception stress". Thirty studies that met exclusion and inclusion criteria and contained relevant data were included. The reviewed literature suggests that mPMS can delay progeny's neurobehavioral development during the first week of life and increase their stress\anxiety- and depression-like behaviors, especially before postnatal day 60. Furthermore, male offspring's memory abilities may be impaired, although learning ability remained intact in both sexes. Finally, mPMS appear to have a negative impact mainly on male offsprings' social behaviors. Some physiological alterations are discussed in relation to these behavioral outcomes, but cautiously, as studies' foci were highly diverse and prevented identifying consistent patterns of results. We also note that dams' recovery period, stress intensity and severity, type, duration, and offspring's weaning age should be considered in future studies.

Anxiety, a future-oriented negative emotional state, is characterized by heightened arousal and vigilance. The elevated plus maze (EPM) test is a widely used assay of anxiety-related behaviors in rodents and shows a phenomenon where animals with prior test experience tend to avoid open arms in retest sessions. While this one-trial tolerance (OTT) phenomenon limits the reuse of the EPM test, the potential mechanisms remain unsolved. Here, we found that neither anxiogenic factors like acute restraint stress nor anxiolytic factors like diazepam (2 mg/kg) influenced the emergence of the OTT phenomenon in mice in the EPM test. In contrast, OTT was markedly attenuated by MK-801 (0.1 mg/kg), a non-competitive N-methyl-D-aspartate receptor antagonist. Through the use of c-fos mapping, MK-801 was found to increase neuronal activation in the thalamic nucleus reuniens (Re). Moreover, chemogenetic inactivation of Re neurons could prevent the effects of MK-801. Our findings suggest the Re as a crucial brain region in emotional adaptation in the EPM and shed light on the experimental design optimization and mechanistic investigation of anxiety-related behaviors.

A subgroup of patients with acute depression show an impaired regulation of the hypothalamic-pituitary-adrenocortical axis, which can be sensitively diagnosed with the combined dexamethasone (dex)/corticotropin releasing hormone (CRH)-test. This neuropathological alteration is assumed to be a result of hyperactive AVP/V1b signalling. Given the complicated procedure of the dex/CRH-test, this study aimed to develop a genetic variants-based alternative approach to predict the outcome of the dex/CRH-test in acute depression.Using data of a representative cohort of 352 patients with severe depression participating in the dex/CRH-test, a genome-wide interaction analysis was performed starting with an anchor single nucleotide polymorphism located in the upstream transcriptional region of the human V1b-receptor gene to predict the adrenocorticotropic hormone (ACTH) response to this test. A probabilistic neural-network-algorithm was used to develop the optimal prediction model.Overall prediction accuracy for correctly identifying high ACTH responders in the dex/CRH-test was 93.5% (sensitivity 90%; specificity 95%). Analysis of pituitary RNAseq expression data confirmed that the identified genetic interactions of the gene test translate into an interactive network of corresponding transcripts in the pituitary gland, which is the biologically relevant target tissue, with the aggregated strength of the transcript interactions significantly stronger than expected from chance.The findings suggest the suitability of the presented gene test as a proxy for hyperactive AVP/V1b signalling during an acute depressive episode, highlighting its potential as companion test for identifying patients with acute depression whose pathology can be optimally treated by specific drugs targeting the AVP/V1b-signaling cascade.

Chronic low-grade inflammation and exposure to stress are key contributing factors in the etiology and progression of many neuropsychiatric disorders. Dietary emulsifiers, such as carboxymethylcellulose (CMC) and polysorbate-80 (P80), are commonly added to processed foods and drinks and are classified by the Food and Drug Administration (FDA) as generally recognized as safe (GRAS). Recently, however, we and others have reported that these additives at translationally relevant doses cause low-grade intestinal inflammation, microbiota dysbiosis, and alterations in gene expression in brain areas that mediate behavioral and neuroendocrine responses to stress-provoking stimuli.

To test whether emulsifier exposure sensitizes behavioral, hormonal, and neuronal responses to stress, C57BL/6 J male mice were given water +1 % emulsifier (CMC or P80) or water alone for 12 weeks after which they were exposed to social defeat stress. We previously found increased PTGS2 (COX-2) gene expression in the amygdala following emulsifier consumption. To determine whether inflammation, potentially through the COX pathway, is a potential mechanism driving emulsifier-induced increases in stress sensitivity, we administered the COX inhibitor aspirin (25 mg/kg/day) in conjunction with emulsifiers for the last six weeks of treatment.

In defeated mice, CMC increased circulating corticosterone, while both emulsifiers increased social avoidance behavior and altered defeat-induced c-Fos immunofluorescence in various brain regions. Moreover, behavioral and hormonal alterations were attenuated by aspirin.

These data demonstrate that ingestion of at least some dietary emulsifiers at concentrations analogous to those ingested by humans increases sensitivity to social stress in mice and that the COX pathway may be a mechanistic candidate by which emulsifier-induced increases in sensitivity to social stress occur.

Although evolutionary medicine has produced several novel insights for explaining prevalent health issues, it has yet to sufficiently address possible adverse mental health effects of humans during long-term space missions While evolutionary applications to medicine have increased over the past 20 years, there is scope for the integration of evolutionary applications in the new branch of space medicine called bioastronautics, which analyses the effects on human bodies when in outer space. Evolutionary principles may explain what kinds of space environments increase mental health risks to astronauts, both in the short and long term; secondly, evolutionary principles may provide a more informed understanding of the evolutionary mismatch between terrestrial and space environments in which astronauts exist. This information may assist in developing frameworks for improving mental health of astronauts and future space colonists. Consequently, this paper will focus on some of the major evolutionary mismatches currently confronting astronauts' mental health, with an aim to improve medical knowledge. It will also provide possible therapeutic countermeasures based on evolutionary principles for reducing adverse mental effects on astronauts.

The neural substrates of anxiety are poorly understood, which hinders treatment of anxiety disorders. Here we found, αCaMKII+ neurons in the ventral medial hypothalamic nucleus (VMH) responded to stressors with increased activity in male mice, both under physiological conditions and after repeated restraint stress. Activation of VMH αCaMKII+ neurons were necessary and sufficient to ameliorate stress-induced anxiety. The peripheral metabolic hormone ghrelin and receptor GHS-R1a play a complex role in emotion regulation; however, the mechanism is uncertain. A delayed increase in GHS-R1a expression in VMH αCaMKII+ neurons coincided with the development of stress-induced enhancement of anxiety-related behavior. GHS-R1a expression in VMH αCaMKII+ neurons promoted anxiety-related behavior, whereas GHS-R1a knockdown had the opposite effect. GHS-R1a upregulation inhibited the excitability of VMH αCaMKII+ neurons. We conclude that GHSR1a signaling drives stress-induced anxiety by shaping the activity of VMH αCaMKII+ neurons. GHS-R1a may be a therapeutic target for treating anxiety disorders such as post-traumatic stress disorder.

Stress activates the hypothalamic-pituitary-adrenal (HPA) axis of which cortisol is an end product. 'Allostatic load' is where systems including the HPA axis are exposed to high, cumulative, physiologic burdens (such as chronic breathlessness) leading to flatter diurnal cortisol slopes and poorer health outcomes. The aim of this hypothesis-generating study explored longitudinal changes in cortisol secretion and any associated changes in breathlessness after introducing regular, low dose morphine or placebo.

This was an optional, hypothesis-generating sub-study embedded in a multi-site, randomised, double-blind, placebo-controlled trial (RCT) of regular, low-dose morphine for chronic breathlessness and chronic obstructive pulmonary disease. In a blinded dose-increment algorithm by week three, doses were 0 mg-32 mg. Participants in the RCT could elect to continue in a six-month blinded extension. This sub-study excluded people who used non-inhaled corticosteroids in the previous month or were on subcutaneous insulin. Participants collected saliva for cortisol assays for two days at baseline, and ends of weeks 1, 3 and 12 at 3,6 and 12 h after waking, generating sufficient data to calculate diurnal cortisol slopes and areas under the curve (AUC). Samples were analysed using ELISA. Correlations between diurnal cortisol profiles (slope and AUC) and a range of measures were explored.

Twenty mostly female former smokers were in this sub-study. At baseline and the end of week 1, one-way ANOVA between-group analyses showed no significant differences in the log-transformed cortisol slope or ln-AUC. There was a strong correlation between the age-adjusted Charlson Comorbidity Index (CCI) and ln-AUC (r=-0.70, p < 0.001) and moderate correlation with age (r=-0.43, p = 0.06). In the blinded extension study, there was a self-selecting blinded group (n = 7) all on active medication. Global impression of change (GIC) was highly correlated with the diurnal cortisol slope (rs = 0.98, p = 0.01), and with decrease in average breathlessness (r = 0.89, p = 0.04).

This hypothesis-generating study did not show a relationship between the diurnal cortisol profile and morphine in people with chronic breathlessness and COPD. For the sub-group still on study at 12weeks, the cortisol curves became steeper as average breathlessness decreased and as global impression of change (GIC) improved, suggesting that reducing breathlessness may potentially positively impact the HPA axis in a sub-group of people.

Registration Number NCT02720822 date registered 28/03/2016.

Primary cilia are cellular antennae emanating from vertebrate cell surfaces to sense and transduce extracellular signals intracellularly to regulate cell behavior and function. However, their signal sensing and physiological functions in neocortical neurons remain largely unclear. Here, we show that, in response to various animal stressors, primary cilia in the mouse prefrontal cortex (PFC) exhibit consistent axonemal elongation. Selective removal of excitatory neuron primary cilia in the prefrontal but not sensory cortex leads to a reduction in animal stress sensing and response. Treatment with corticosterone, the major stress hormone, elicits an increase in primary ciliary cyclic adenosine 3',5'-monphosphate (cAMP) level in PFC excitatory neurons and a decrease in neuronal excitability dependent on primary cilia. Suppression of primary ciliary protein kinase A (PKA) activity in PFC excitatory neurons reduces animal stress. These results suggest that excitatory neurons in the PFC are involved in sensing and regulating animal stress via primary ciliary cAMP/PKA signaling.

Psychosocial stress, a pervasive factor in mental health disorders, is tightly linked to serotonin (5-HT) dysregulation. Real-time electrochemical monitoring of 5-HT in vivo is challenged by interference from vitamin C (Vc) and biofouling, requiring invasive pretreatments. We present a self-powered aptamer-engineered galvanic sensor (aptGRP5-HT) that integrates phosphorothioate aptamers with a redox potentiometric mechanism, achieving 21.5-fold higher selectivity and 98.3-fold enhanced sensitivity against Vc over conventional sensors while resisting electrochemical biofouling. The aptGRP5-HT operates in complex biological environments without pretreatment, enabling direct monitoring in a rodent psychosocial stress model. Using this tool, we uncover a neurochemical signature of social hierarchy: high-ranking mice exhibit elevated 5-HT release in the medial prefrontal cortex (mPFC) and dorsal raphe nucleus (DRN), with region-specific correlations to neuronal activity-reduced spontaneous firing in the mPFC and increased activity in the DRN. This work resolves long-standing challenges in neurochemical sensing and establishes aptGRP5-HT as a transformative platform for probing brain function and stress-related disorders.

Life stress modulates decision making, particularly in the face of risk, in some cases prompting vulnerable populations to make suboptimal, life-altering choices. In the brain, stress is known to alter the extracellular release of catecholamines in structures such as basolateral amygdala (BLA) and nucleus accumbens (NAc), but the relationship between catecholamines and decision-making behavior under stress has not been systemically explored. We developed an operant touchscreen decision-making task for rats comprising elements of loss aversion and risk seeking behavior. Rats were first injected systemically with an adrenergic α2A-receptor agonist (guanfacine) and antagonist (yohimbine), as well as a partial inverse GABAA agonist, FG 7142, known to induce anxiety and stress related physiological responses in a variety of species, including humans. We then used fiber photometry to monitor NE in the basolateral amygdala (BLA), and DA activity in the nucleus accumbens (NAc) while animals engaged in decision-making and following systemic injections of FG 7142 and yohimbine. We found that neither yohimbine nor guanfacine had any impact on decision making strategy but altered motivational state with yohimbine making the animal almost insensitive to the reward outcome. The pharmacological induction of stress with FG 7142 biased the rats' decisions towards safety, but this bias shifted towards risk when co-treated with yohimbine. In the BLA and NAc, FG 7142 altered catecholamine release with systemic yohimbine producing opposing effects on NE and DA release. These findings highlight the catecholamine basis of loss aversion and neuromodulation of critical brain structures during stress through α2A adrenoreceptors.

Previous studies suggest that early-life stress (ELS) induced by early maternal separation and isolation (MS) stress during the stress hyporesponsive period (SHRP) leads to increased curiosity-like and increased risky decision-making behaviour in adolescence. Evidence suggests that dietary interventions early in adolescence could play an important role in mitigating the detrimental effects of MS stress on risky decision-making behaviour. Hence, the present study hypothesized that nutritional supplements such as saturated fat (SFA) and/or polyunsaturated fat (PUFA) would be beneficial in ameliorating the impact of MS stress on risky decision-making behaviour when incorporated into the diet during early adolescence. NC and MS rats were subjected to the Risky Decision-Taking Task (RDTT) to assess the rats' ability to make decisions under risky conditions. The results showed that MS rats took less time to cross the risky zone to collect a large reward. However, when an SFA-rich and PUFA-rich diet was provided, the latency of the MS rats increased. Similarly, MS stress-induced reduction in risk assessment was restored to normal with the SFA and PUFA-rich diet. Risk-index (RI) values also showed a similar trend with reduced RI values in MS, but nutritional supplementation increased the RI values making it comparable to that NC. Correlation analysis has further revealed a direct correlation between the anxiety-like behaviour and the risk-taking tendency in MS rats and not in the NC group. SFA-rich diet led to a positive correlation between anxiety-like and risk-taking behaviour. These findings thus support the hypothesis that PUFA- and SFA-rich diet may be introduced at adolescence to mitigate MS-stress induced increased risky decision-making behaviour due to a deficit in risk assessment.

This study explores the impact of stress on working memory (WM) performance, and the potential mitigating effects of transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (dlPFC) and ventromedial prefrontal cortex (vmPFC). The study had a mixed, randomized, single-blind, sham-controlled design, with stress induction as within-subject and stimulation condition as between-subject factors. We assessed stress-induced WM deficits using aversive video clips to induce stress and a verbal n-back task to assess WM performance. We analyzed physiological (cortisol and heart rate), behavioral, and electroencephalographic (EEG) changes due to stress before, during, and after WM task performance and their modulation by tDCS. Stress impaired WM performance in the sham stimulation condition for the 3-back load, but not for 2-back or 4-back loads in the WM task and was associated with elevated physiological stress markers. tDCS over the vmPFC led to better WM task performance while stimulation over the dlPFC did not. Active tDCS with both dlPFC and vmPFC stimulation blunted cortisol release in stress conditions compared to sham. The EEG analysis revealed potential mechanisms explaining the behavioral effects of vmPFC stimulation. vmPFC stimulation led to a decreased P200 event-related potential (ERP) component compared to the sham stimulation condition and resulted in higher task-related alpha desynchronization, indicating reduced distractions and better focus during task performance. This study thus shows that the vmPFC might be a potential target for mitigating the effects of stress on WM performance and contributes to the development of targeted interventions for stress-related cognitive impairments.

To explore the effects of restraint stress and orthodontic tooth movement on the body weight and behavior of rats.

Twenty 8-week-old male Wistar rats were randomly divided into four groups: sham stress nonorthodontic (CC), sham stress orthodontic (CO), stress nonorthodontic (SC) and stress orthodontic (SO). Rats in the stress group were subjected to restraint stress for 21 days, and those in the orthodontic group received molar retraction on days 8 to 21 (D8-D21). The weights of the rats were measured, and behavioral tests were performed on D0, D10, and D20. Serum corticosterone levels in the rats were measured on D0, D4, D8, D12, D16, and D21.

The weights of rats in the CO, SC, and SO groups were significantly lower than those in the CC group. In the open-field test, the number of times the rats entered the central zone in the CC group was significantly higher than that in the other three groups. In the elevated plus maze test, at D10, the number of times the rats entered the open arms in the SO, SC, and CO groups was significantly lower than that in the CC group. From D12, the serum corticosterone levels in the CO, SC, and SO groups were significantly higher than those in the CC group.

Both restraint stress and orthodontic tooth movement interventions may have adverse effects on weight, behavior, and neuroendocrine responses. However, overlapping the two intervention methods did not increase the magnitude of the effect.

Mood disorders are often precipitated by chronic stress and can result in an inability to adapt to the environment and increased vulnerability to challenging experiences. While diagnoses of mood disorders are diagnosed twice as frequently in women than in men, most preclinical chronic social defeat stress mouse models exclude females due to decreased aggression toward female intruders.

We previously reported that the chronic non-discriminatory social defeat stress (CNSDS) paradigm is effective in both sexes, allowing for comparisons between male and female mice. We aimed to improve the screening protocol to identify CD-1 aggressors for use in CNSDS and the method for determining susceptibility to CNSDS. Finally, we aimed to determine whether susceptibility to CNSDS correlated with impaired performance in a satiety-based outcome devaluation task.

We analyzed CNSDS screening and social defeat sessions to determine appropriate parameters for selecting CD-1 aggressors and investigated aggressions toward male and female intruder mice. We also investigated CNSDS effects on a reward valuation task.

We observed that despite receiving fewer attacks, female mice are equally susceptible to CNSDS as males and that CNSDS abolished satiety-based outcome devaluation in susceptible male and female mice, but not in resilient male and female mice.

These data suggest that CNSDS-defined susceptible and resilient phenotypes extend to reward behaviors.

In the case of incomplete episodic memory retrieval, semantic knowledge may play a vital role compared to random memory errors in filling in memory gaps (semantic substitution). Stress impairs (episodic) memory retrieval via stress hormones (mainly cortisol) targeting the hippocampus. This preregistered neuroimaging study aimed to examine the neural mechanisms of the interplay between episodic memories and prior knowledge during the reconstruction of a past scenario under elevated cortisol levels in men. During encoding, sixty men prepared a virtual apartment for having guests over by using button presses to interact with household objects (e.g., toasting a slice of bread) that were placed congruently to semantic knowledge (e.g., a coffee machine in the kitchen) or incongruently (e.g., a toaster in the bathroom). One day later, participants received (order randomized, double-blind) either 20 mg of cortisol (n = 30) or a placebo (n = 30) before a recognition task. After identifying objects as old, we included a room recall using a forced-choice question in which room the objects were remembered. For incongruent objects this allowed us to differentiate the involvement of episodic, semantic, or random memory. Cortisol did not impair general recognition memory. The manipulation of stimuli during encoding, as being congruent and interactable (relevant to the goal) appears to be predictive of later accurate room recall. Semantic substitution in case of episodic memory failure was associated with anterior parahippocampal and gyrus rectus activation. Cortisol administration increased hippocampal activation during semantic substitution, suggesting a compensatory effect. The results characterized the neural correlates of semantic substitution and speak for an intertwined view of episodic memory and semantic knowledge, which is further shaped by the stress hormone cortisol.

Background: Orthostatic hypotension (OH) is a chronic, debilitating condition common in older adults. This study examined the effects of daily lifestyle habits on non-neurogenic OH in older adults in South Korea. We further compared the effects of daily lifestyle habits on OH to those of the autonomic nervous system (ANS) function. Methods: In a cross-sectional study, 217 community-dwelling older adults aged ≥65 years were recruited using the convenience sampling method. Data were collected using two questionnaires to assess OH and daily lifestyle habits: OH was measured by Orthostatic Grading Scale (OGS) and lifestyle habits included nutrition, sleep, physical activity, and psychological status (stress and depression levels). Plasma catecholamines (epinephrine and norepinephrine) were measured to indicate the ANS function. The data were analyzed using t-tests, Pearson's correlation coefficients, and multiple linear regression analysis. Results: Significant factors related to OGA score included nutritional status (B = -0.20, p ≤ 0.040), poorer sleep quality (B = 0.15, p = 0.005), physical activity (B = -0.01, p = 0.032), stress (B = 0.04, p = 0.001), and depression (B = 0.23, p = 0.001). These together explained 40.5% of the variance in OH. However, no significant association was found between catecholamines and OGS score. Conclusions: These results suggest that lifestyle habits are important factors, while ANS function may be less associated with non-neurogenic OH. Thus, preventive and non-pharmacological interventions for decreasing OH symptoms should focus on maintaining healthy lifestyle habits in older adults.

Post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) are debilitating stress-related psychiatric disorders that can develop following exposure to traumatic events or chronic stress in some individuals. The neurobiological processes leading to disease remain largely unknown. Among others, these disorders are characterized by a dysregulated hypothalamic-pituitary-adrenal axis, which is regulated by the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). This leads to altered downstream corticosteroid-induced gene expression. In vitro models are promising tools to investigate specific neurobiological underpinnings of the stress response in the brain. Here, we investigated the suitability of SH-SY5Y-derived neurons as a cost-efficient system to study the role of GR and MR in the neuronal stress response. SH-SY5Y-derived neurons were characterized, exposed to corticosteroids, and analyzed on transcriptomic and proteomic levels. We show that (i) these neurons express sufficient and seemingly functional GR and MR to allow the study of corticosteroid-induced transcription, (ii) three corticosteroids cortisol, dexamethasone, and aldosterone, induced similar transcriptomic effects, (iii) the antagonist spironolactone mildly attenuated the effects of dexamethasone in FKBP5, DUSP1, and SUPV3L1. Mifepristone did not significantly alter the effect of aldosterone. (iv) Integrating transcriptomic alterations of these corticosteroid-exposed neurons with those of iPSC-derived neurons exposed to dexamethasone showed concordant corticosteroid-induced effects in the two in vitro systems. To determine translational validity, we compared the gene expression in these neurons with the transcriptome of postmortem brain samples from individuals with PTSD and MDD, yielding stronger negative correlations of corticosteroid effects in SH-SY5Y-derived neurons with PTSD signatures than with MDD signatures. Upon further refinement and validation, SH-SY5Y-derived neurons may serve as a simplistic tool to study neuronal corticosteroid-induced gene expression and the implicated molecular networks around GR and MR. Strengthening our insight into these receptors' functions improves our understanding of the hypothalamic-pituitary-adrenal axis, which is commonly altered in stress-related psychiatric disorders such as PTSD and MDD.

Subclinical depressive symptoms and the associated risk of cognitive deficits have been overlooked. We aimed to investigate depressive symptom trajectories and the effect of depressive symptoms on cognitive performance among Chinese adolescents. The research population of our study was 1314 adolescents aged 10-15 years old from the China Family Panel Studies. The Center for Epidemiologic Studies Depression Scale was used to assess the depressive symptoms of adolescents. Vocabulary and mathematics tests were used to test fluid intelligence. Memory and number series tests were used to test crystal intelligence. The 6-year depressive symptom trajectories of adolescents were identified by the latent class mixed model. Linear regression models and Generalized Estimating Equation models were applied to test the associations between depressive symptom trajectories and cognitive performance. We identified three distinct trajectories of depressive symptoms: (a) low depressive symptom trajectory (88.51%), (b) remitting depressive symptom trajectory (5.86%), (c) decreasing depressive symptom trajectory (5.63%). We found that decreasing depressive symptom trajectory predicted worse fluid intelligence (β: -0.51, 95% CI: -0.88, -0.13) and crystal intelligence (β: -2.09, 95% CI: -3.78, -0.41) compared with low depressive symptom trajectory. Gender-stratified analysis showed that the negative association between depressive symptoms trajectory and crystal intelligence was only found in males. Depressive symptom episodes in early adolescence were associated with worse cognitive performance later. Performing mental health screenings, especially during the sensitive windows of cognitive development, is critical to reducing the negative impact of depressive symptoms.

Responses to acute stress function to restore homeostasis. Hence, the study of neurophysiological responses to acute stress helps to understand mechanisms underlying adaptive coping in the face of environmental demands. The infralimbic medial prefrontal cortex (IL-mPFC) modulates the switch between behavioral coping styles, and acute stress enhances glutamatergic neurotransmission on mPFC projection neurons. However, the role of acute stress responses and stress hormones on the physiology of IL-mPFC projection neurons during adulthood remains underexplored. Here, we studied rapid and slow effects of acute corticosterone exposure on synaptic transmission and intrinsic membrane excitability in layer 5 pyramidal neurons of the IL (L5-IL PNs) in adult male rats using ex vivo whole-cell patch-clamp of mPFC slices. We report that corticosterone dynamically modulates the physiology of L5-IL PNs in a time-dependent manner. Specifically, corticosterone elicits a strong rapid shift of the excitatory-inhibitory balance towards enhanced excitation with mineralocorticoid (MR) and glucocorticoid receptors (GR) playing complementarily roles. Also, corticosterone rapidly and transently decreases the firing rate of L5-IL PNs via GR. Moreover, acute stress or corticosterone slowly enhance glutamatergic neurotransmission via MR and GR without modulating inhibitory neurotransmission or intrinsic excitability of adult L5-IL PNs. Our findings highlight the potential relevance of corticosterone effects on L5-IL PNs to promote a homeostatic response in adult male rats. First, corticosterone rapidly attenuates IL intrinsic excitability during the rapid initial phase of the acute stress response. Later on, corticosterone slowly restores IL output function over time to promote adaptive executive responses when context changes.Significance statement Corticosterone modulates physiological processes during stress to support adaptation. However, acute effects of corticosterone on stress control networks remains underexplored. Here, we explored mechanisms underlying corticosterone regulation of the activity of stress regulatory neurons of the infralimbic cortex (IL). Stress levels of corticosterone rapidly shift the excitatory-inhibitory balance of synaptic transmission towards enhanced excitation while diminishing firing of IL excitatory long-range neurons (IL PNs). Slow, lasting effects of corticosterone primarily target excitatory synaptic activity. Synaptic actions of glucocorticoids are cooperatively mediated by the mineralocorticoid (MRs) and glucocorticoid receptors (GRs), whereas the transient reduction in firing relies on GR in IL PNs. Thus, corticosterone provides an adaptive signal that controls IL output over time, promoting adaptive responses to environmental context.

Early life stress (ELS) can increase vulnerability to psychiatric disorders, but also trigger resilience. FKBP51 has been associated with an increased risk for developing psychiatric disorders, specifically in interaction with ELS exposure. Here, the contribution of FKBP51 in glutamatergic forebrain neurons to the long-term consequences of ELS was investigated in both sexes. In female wild-type Fkbp5lox/lox mice, ELS exposure led to an anxiolytic phenotype and improved memory performance in a stressful context, however this ELS effect was absent in Fkbp5Nex mice. These interactive FKBP51 x ELS effects in female mice were also reflected in reduced brain region volumes, and on structural and electrophysiological properties of CA1 pyramidal neurons of the dorsal hippocampus. In contrast, the behavioral, structural and functional effects in male ELS mice were less pronounced and independent of FKBP51. RNA sequencing of the hippocampus revealed the transcription factor 4 (TCF4) as a potential regulator of the female interactive effects. Cre-dependent viral overexpression of TCF4 in female Nex-Cre mice led to similar beneficial effects on behavior as the ELS exposure. This study demonstrates a sex-specific role for FKBP51 in mediating the adaptive effects of ELS on emotional regulation, cognition, and neuronal function, implicating TCF4 as a downstream effector.

Chronic stress impacts the brain through complex physiological, neurological, and immunological responses. The stress response involves the activation of the sympathetic-adrenal-medullary (SAM) system and the hypothalamic-pituitary-adrenal (HPA) axis, releasing stress hormones like norepinephrine and cortisol. While these responses are adaptive short-term, chronic stress disrupts homeostasis, increasing the risk of cardiovascular diseases, neurodegenerative disorders, and psychiatric conditions such as depression. This dysregulation is linked to persistent neuroinflammation, oxidative stress, and neurotransmitter imbalances involving dopamine and serotonin, impairing neuroplasticity and leading to structural changes in critical brain areas, such as the hippocampus and prefrontal cortex. Moreover, stress affects gene expression, particularly neuroinflammatory pathways, contributing to long-term cognitive function and emotional regulation alterations. Advancements in neuroimaging and molecular techniques, including MRI, PET, and SPECT, hold promise for identifying biomarkers and better understanding stress-induced brain changes. These insights are critical for developing targeted interventions to mitigate the adverse effects of chronic stress on brain health.

Emotional exhaustion, a central component of burnout syndrome, affects social workers due to adverse work factors such as excessive workload, work-family conflict, and a lack of social support. The job demands-resources and conservation of resources models explain how chronic stress influences these professionals.

A systematic review was carried out using the recommendations of the PRISMA guidelines as a reference for the selection and identification of studies and the Joanna Briggs Institute guidelines, registering the protocol in PROSPERO. Cross-sectional studies published from 1 January 2019 to 30 September 2024 were included and five main databases-Web of Science, Scopus, PubMed, Medline, and PsycInfo-were used to search for specific studies written in English, Spanish, French, and Portuguese.

Of 361 initial records, 21 studies involving more than 24,000 social workers from diverse global settings were analyzed. The main risk factors identified were workload, work-family conflict, and work victimization. Resilience, self-care, and social support were highlighted as protective factors. Emotional exhaustion was associated with low job satisfaction, turnover intention, and mental health problems such as anxiety and depression.

Emotional burnout requires specific strategies, such as work flexibility, wellness programs, and organizational support. These measures can mitigate its impact, improving work-life balance and fostering resilience.

Acute stress response has been linked to body condition and associated with the allocation of finite energy resources in wild, free-living birds. However, the relationship between the body condition of individuals and the acute stress response is less clear for birds kept in captive settings, where energy resources are abundant and readily available. We evaluated how individual variation in body condition, reflected as body mass, relates to the acute stress response in adult captive Wood Ducks (Aix sponsa) hatched from eggs collected in the wild and reared in captivity while birds were fed ad libitum, in and out of the breeding season. We determined plasma corticosterone (CORT) levels from blood collected within 3 min of capture and at 10, 30, and 60 min post-capture from 28 ducks during spring and fall, in and out of breeding season. Body condition measurements were recorded once for each bird in early spring. The effects of body mass, age, and time of year (in vs. out of breeding season) on total and maximum CORT secreted were analyzed in Generalized Linear Mixed Models (GLMM). No relationships between age, body mass, and total or maximum CORT were found. There was a significant difference in response in and out of the breeding season for total CORT (p < 0.01) and maximum CORT (p < 0.001), with a higher response during the breeding season. Measures of individual responses for total (p = 0.001) and maximum CORT (p < 0.01) were consistent across seasons. Baseline CORT levels were consistently low, with 53.6 % and 78.6 % of the samples below the detection limit during and outside of breeding season, respectively. These results highlight differences in baseline CORT maintenance compared to studies on wild Wood Ducks, potentially relating to environmental differences such as unlimited food supply and protection from predators in captivity. Additionally, we found that captive birds maintain seasonal variation in acute stress response, which reflects some trends found in wild birds, although more research across multiple seasons is warranted. We also found that some captive Wood Ducks continue to increase CORT secretion at the end of the 60 min handling period, indicating that longer handling times may reveal differences in total CORT secreted. Further investigation should be done to assess the costs and benefits of variation in body condition in terms of coping ability across life stages.

While benzodiazepines have been a mainstay of the pharmacotherapy of anxiety disorders, their short-term efficacy and risk of abuse have driven the exploration of alternative treatment approaches. The endocannabinoid (eCB) system has emerged as a key modulator of anxiety-related processes, with evidence suggesting dynamic interactions between the eCB system and the GABAergic system, the primary target of benzodiazepines. According to the existing literature, the activation of the cannabinoid receptors has been shown to exert anxiolytic effects, while their blockade or genetic deletion results in heightened anxiety-like responses. Moreover, studies have provided evidence of interactions between the eCB system and benzodiazepines in anxiety modulation. For instance, the attenuation of benzodiazepine-induced anxiolysis by cannabinoid receptor antagonism or genetic variations in the eCB system components in animal studies, have been associated with variations in benzodiazepine response and susceptibility to anxiety disorders. The combined use of cannabinoid-based medications, such as cannabinoid receptor agonists and benzodiazepine co-administration, has shown promise in augmenting anxiolytic effects and reducing benzodiazepine dosage requirements. This article aims to comprehensively review and discuss the current evidence on the involvement of the eCB system as a key modulator of benzodiazepine-related anxiolytic effects, and further, the possible mechanisms by which the region-specific eCB system-GABAergic connectivity modulates the neuro-endocrine/behavioral stress response, providing an inclusive understanding of the complex interplay between the eCB system and benzodiazepines in the context of anxiety regulation, to inform future research and clinical practice.

The experience of stress and the need to regulate emotions are pervasive in everyday life. Emotion regulation (ER) is particularly required under stress to facilitate successful adaptation and recovery. Importantly, a growing body of work has identified stress and ER deficits as transdiagnostic risk factors for psychopathology. This highlights the relevance of understanding how stress impacts ER to elucidate individual vulnerability to mental disorders. Stress alters cognitive and emotional functioning via stress hormones secreted by the two major stress systems: sympathetic nervous system and hypothalamus-pituitary adrenocortical axis. This review aims to compile and synthesize empirical studies in humans investigating the effects of acute stress and stress hormones on ER. A systematic literature search yielded 14 relevant studies, 11 investigating acute stress effects and 3 examining the influence of pharmacological cortisol elevations on ER. The results of the stress studies are mixed revealing either impairing, beneficial or no effects at all. Cortisol administration mostly facilitated ER attempts. Notably, we detected timing differences in measuring ER performance relative to stress exposure that potentially reconcile divergent findings. Here, we propose the PRESSURE model (Predominant Stress System Underpins Regulation of Emotions) postulating that the direction and magnitude of stress effects on ER depends on the relative predominance of one stress system over the other. Additionally, sex-stress hormone interactions, stimulus intensity and ER strategy are discussed as possible moderators. Finally, we highlight limitations in current research and provide recommendations for future studies that will further advance our understanding of the intricate relationship between stress and ER.

Modern habits are becoming more and more disruptive to health. As our days are often filled with circadian disruption and stress exposures, we need to understand how our responses to these external stimuli are shaped and how their mediators can be targeted to promote health. A growing body of research demonstrates the role of the gut microbiota in influencing brain function and behavior. The stress response and circadian rhythms, which are essential to maintaining appropriate responses to the environment, are known to be impacted by the gut microbiota. Gut microbes have been shown to alter the host's response to stress and modulate circadian rhythmicity. Although studies demonstrated strong links between the gut microbiota, circadian rhythms and the stress response, such studies were conducted in an independent manner not conducive to understanding the interface between these factors. Due to the interconnected nature of the stress response and circadian rhythms, in this review we explore how the gut microbiota may play a role in regulating the integration of stress and circadian signals in mammals and the consequences for brain health and disease.

Iron is a trace metal that takes part in the maintenance of body homeostasis by, for instance, aiding in energy production and immunity. A body of evidence now demonstrates that dysfunction in iron metabolism can have detrimental effects and is intricately associated with the development of neuropsychiatric disorders, including Major Depressive Disorder (MDD), anxiety, and schizophrenia. For instance, changes in serum and central nervous system (CNS) levels of iron and in proteins mediating iron metabolism have been documented in patients grappling with the aforementioned diseases. By contrast, targeting iron metabolism by using iron chelators, for instance, has proven to be effective in alleviating disease burden. Therefore, here we review the state-of-the-art regarding the role of iron metabolism and its dysfunction in the context of neuropsychiatric disorders. Furthermore, we discuss how targeting iron metabolism can be an effective therapeutic option to tackle this class of diseases. Finally, we discuss the mechanisms linking this dysfunction to behavioral changes in these disorders. Harnessing the knowledge of iron metabolism is not only key to the characterization of novel molecular targets and disease biomarkers but also crucial to drug repurposing and drug design.

Cortisol is a pivotal hormone regulating stress responses and is linked to various health conditions, making precise and continuous monitoring essential. Despite their non-invasive nature, conventional cortisol detection methods often suffer from inadequate sensitivity and reliability at low concentrations, limiting their diagnostic utility. To address these limitations, this study introduces a novel paradigm for high sensitivity cortisol detection using field-effect transistor (FET) sensors with dual-gate (DG) structures. The proposed sensor platform enhances sensitivity through capacitive coupling without requiring external circuits. Cortisol detection performance was evaluated by immobilizing monoclonal antibodies activated via 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide onto a SnO2 thin film-based extended-gate. The results revealed a sensitivity of 14.3 mV/dec in single-gate mode, which significantly increased to 243.8 mV/dec in DG mode, achieving a detection limit of 276 pM. Additionally, the reliability and stability of the sensor were validated by evaluating drift effects, confirming its ability to provide accurate detection even in artificial saliva environments containing interfering substances. In conclusion, the DG-FET-based cortisol detection approach developed in this study significantly outperforms conventional FET-based methods, enabling precise monitoring at ultra-low concentrations. This approach holds significant potential for diverse bioassays requiring high sensitivity and reliability in complex environments.