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.

Pavlovian fear conditioning is a widely used behavioural task for studying fear memory in rodents. During conditioning, rodents learn to associate a conditioned stimulus (e.g., context or tone; contextual or auditory fear conditioning, CFC or AFC, respectively) with an aversive one (e.g., footshock), resulting in a conditioned fear response. Fear memory retention is assessed thorough freezing behaviour, a species-specific defensive reaction, observed during exposure to the conditioned stimulus alone. Fear memory is influenced by sex and stress, with stress exposure prior to conditioning potentially inducing maladaptive fear responses. This meta-analysis examines how pre-conditioning stress exposure modulates memory retention in rodents. Across N = 94 studies included, we analyzed freezing behaviour based on several factors: type of paradigm (CFC vs AFC), species (rat vs mouse), sex (male vs female), stress type (physical vs pharmacological vs psychological vs combination of two or more stressors type), stress duration (acute or chronic), stress timing (prenatal vs early postnatal vs adolescence vs adulthood). The results indicate that stress significantly enhances contextual conditioned freezing behaviour. Stress-induced effects in CFC models vary across species but are not sex-specific. Additionally, these effects are influenced by stress-related factors. These findings highlight the importance of considering multiple variables when studying stress and fear memory processes, offering valuable insights for improving clinical approaches to fear memory-related diseases (e.g., post-traumatic stress disorder).

Many people with mild intellectual disabilities are at increased risk to experience stress. Reducing stress is important because experiencing prolonged and elevated stress can have detrimental effects on mental and physical health and it is associated with aggressive behaviour and self-harm.

This preliminary study investigated whether an intervention combining biofeedback with listening to music is effective and whether a personalized music playlist is more effective than self-selected music in reducing physiological and subjective stress in participants with mild intellectual disabilities.

We collected 103 music listening sessions over a period of 2-4 weeks for 11 participants throughout their daily routines. They listened to music when they received biofeedback on their increased stress level (as measured by wearable biosensor Nowatch) or when they themselves felt stressed. Participants listened either to self-selected music or to a personalised playlist compiled with X-system, music technology that predicts the effect of a song on levels of autonomic arousal. Pulse rate (PR) and skin conductance level (SCL) were measured with the EmbracePlus and subjective feelings of stress and mood were measured with two scale questions. After the intervention phase, participants and their caregivers completed a short questionnaire to evaluate their experiences with using the X-system playlist.

Mixed regression analyses showed reductions in PR and SCL during listening to music, and indications were found for reductions in subjective stress and improvement of mood after intervention. Listening to music compiled with X-system was not more effective than listening to self-selected music. However, lower combined arousal values (a feature of X-system) from self-selected and X-system music predicted lower PR and SCL, indicating that these indices can be used to select songs that have a relaxing or energizing effect.

The present study suggests that music listening is associated with both subjective and physiological stress reduction. Listening to music might be an accessible, inexpensive and empowering strategy for stress reduction and improving emotion regulation, which could also benefit mental and physical health. Several challenges were encountered while implementing the intervention and suggestions for future research are given.

The relationship between diet and human physical and mental health is highly interconnected and has been significantly correlated with the occurrence of various diseases, including neurological disorders, cancer, and chronic inflammatory diseases. Moreover, diet has been demonstrated to play a pivotal role in governing gut microbiota composition, making it one of the most influential factors. The diet is crucial in connecting humans and their gut microorganisms. The nutrients ingested supply energy to the body and serve as substrates for the metabolic processes of the gut microorganisms. Consequently, the gut flora and their metabolites reciprocally impact the host's metabolism, thereby influencing the physiological state of the human body. Extensive investigations on human and mouse models have revealed that diet potentially underlies various effects on human health and disease.

Long-term anxiety is a hallmark symptom following traumatic brain injury (TBI). Although the central noradrenergic system (CNAS) is known to play a critical role in anxiety by regulating the excitability of several intricately interconnected brain structures via its projections to them, critical questions remain regarding the nature and extent of TBI-induced neuroplastic alterations in the CNAS and how these alterations relate to anxiety disorders. Knowledge relative to these questions is pivotal to development and refinement of therapies for TBI-associated anxiety disorders, including post-traumatic stress disorder. To this end, this study was designed to determine the impacts of chronic TBI on neuroplasticity of the CNAS and their significance in anxiety disorders in a clinically relevant rodent model. A standardized weight-drop model was used to produce controlled impacts of mild-to-moderate TBI in rats. Following the elevated plus maze tests to longitudinally assess anxiety-like behavior at 2 and 18 weeks post-injury of TBI animals, brain tissues of naïve and TBI rats were coronally sectioned and immunostained for a noradrenergic (NA) marker (dopamine β-hydroxylase) and neuronal nuclei in the central NA production sites and critical anxiety-regulating brain structures. We discovered that TBI caused robust losses of NA cells in the locus coeruleus and NA innervation of the central nucleus of the amygdala, an emotional processing center. Conversely, TBI caused intense gains of NA cells in the A2/A1 cell groups and NA innervation of other major anxiety-regulating regions. These changes coincided with progressively elevated anxiety-like behavior. Possibly, NA properties of A2/A1 cells were upregulated to compensate for the TBI-induced severe cell losses in the locus coeruleus. We conclude that these bi-directional vast alterations in the CNAS following chronic TBI contribute to dysregulated anxiety and, in part, the pathophysiology of human post-traumatic stress disorder.

Although the brain is not the only source of circulating endocannabinoids and their levels can be affected by many factors, it is underlined that serum endocannabinoid levels can be used as a biomarker in psychiatric disorders. In this study, we aimed to examine whether serum endocannabinoid and N-acylethanolamine concentrations reflect their brain levels.

In the present study acute immobilisation (AIS) and post-traumatic stress (PTSD) models were applied to Wistar albino male rats. Rota rod performance, forced swim, open field and elevated plus maze tests were performed. Endocannabinoid and N-acylethanolamine levels in serum and hippocampus, amygdala and cortex were assessed using LC-MS/MS.

We observed significant increases in anandamide (AEA), palmitoylethanolamide (PEA) and oleoethylethanolamide (OEA) levels in the amygdala and hippocampus in both models except PEA in amygdala in the AIS group, while 2-AG levels decreased. There was no change in serum AEA and 2-AG levels in all groups; in the PTSD group serum PEA levels were higher whereas OEA levels were lower in both the AIS and the PTSD groups.

Our results show that there is no correlation in endocannabinoid and N-acylethanolamine levels between serum and specific brain regions in two stress models of rat.

Hypnotherapy is increasingly recognized as an effective treatment option for a wide range of psychological conditions and the psychological elements of physiologic health concerns. Despite its growing use, the mechanisms underlying hypnotherapy's therapeutic benefits remain unknown. Heart rate variability (HRV), a non-invasive biomarker of autonomic nervous system (ANS) activity and other processes relevant to the psychophysiological stress response, has been used to study the physiological effects of hypnosis. HRV is associated with adaptability to stress and overall mental and physical health. We review how HRV changes during hypnosis treatment and propose mechanisms by which hypnotherapy influences the stress response and psychological flexibility and improves wellbeing. Additionally, we highlight the use of HRV biofeedback as an adjunct to hypnotherapy and psychotherapy and illustrate its potential to enhance therapeutic outcomes. To showcase practical applications, we present a case study of hypnotherapy's impact on HRV in the treatment of hot flashes in post-menopausal women. We conclude by calling for further empirical research, particularly randomized controlled trials, to solidify the integration of HRV metrics in hypnotherapy practice. Understanding the interaction between hypnotherapy and HRV will support more targeted and effective interventions, benefiting both clinicians and patients.

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.

Cranial radiotherapy and environmental radiation exposure are associated with increased risk of cognitive dysfunction, including memory deficits and mood disorders, yet the underlying mechanisms remain poorly understood. In this study, we demonstrate that cranial irradiation induces hypoactivity in the medial prefrontal cortex (mPFC) of mice, leading to anxiety-like behaviors and memory impairments, which can be prevented by optogenetic activation of mPFC excitatory neurons. Radiaiton exposure also causes a significant reduction in microglial density within the mPFC, accompanied by morphological and transcriptional alterations in the remaining microglia. Notably, microglial repopulation, achieved through CSF1R antagonist-mediated depletion prior to irradiation and subsequent repopulation, restores mPFC neuronal acitivity and reverses cognitive and behavioral deficits. Integrated bulk RNA sequencing and microglial proteomic analysis of the mPFC reveal that microglial repopulation specifically modulates the leukotriene-C4 biosynthesis pathway, without significant changes in canonical pro-inflammatory cytokines or chemokines. Importantly, pharmacological inhibition of leukotriene-C4 synthase ameliorates radiation-induced anxiety and memory impairments. These findings identify leukotriene-C4 signaling as a critical mechanism underlying radiation-induced cognitive dysfunction and suggest that microglial repopulation and targted inhibition of leukotriene-C4 represent potential therapeutic strategies for mitigating radiation-associated cognitive disorders.

Cardiac reactivity is proposed to be a central indicator of autonomic functioning. While hyperglycemia plays a limited role in cardiac stress reactivity, it is unclear whether it may modulate cardiac reactivity in non-stressful situations. We investigated the effect of glucose on cardiac reactivity to a relaxing exercise, namely, slow-paced breathing (SPB). A total of 115 adults (age mean = 23.28 years, SD = 6.88; 76% female) either consumed a sweet & caloric, a sweet, a caloric drink, or pure water after baseline. Later, they performed a sustained attention test and SPB. Electrocardiography and impedance cardiography was obtained, and blood glucose and subjective relaxation were measured repeatedly. We analyzed changes in parasympathetic (root mean square of successive differences [RMSSD]) and sympathetic (pre-ejection period [PEP]) cardiac activity and subjective relaxation using growth curve models and performed correlational analyses. Hyperglycemia triggered cardiac PNS withdrawal and SNS activation. Despite this, SPB increased cardiac PNS activity and subjective relaxation and decreased cardiac SNS activity in all groups. Our results align with the autonomic space model and highlight the tight link between autonomic regulation and blood glucose homeostasis. Hyperglycemia might play a limited modulating role in cardiac reactivity to slow-paced breathing.

Empathic pain, defined as the emotional resonance with the suffering of others, is akin to the observer's own experience of pain and is vital for building and sustaining positive interpersonal relationships. Despite its importance, the neural mechanism of empathic pain remains poorly understood. In this review, we integrated and summarized the currently knowledge on the neural networks associated with empathic pain, focusing on key brain regions such as the insula, anterior cingulate cortex (ACC), ventral tegmental area (VTA), nucleus accumbens (NAc), and locus coeruleus (LC)/norepinephrine (NE)-sympatho-adrenomedullar (LC/NE-SAM) system. We also reviewed the factors that affect empathic pain, including gender, personal beliefs, the intimacy of relationships, and the nature of interpersonal relationships, and highlighted the central role of the insula and ACC in the neural circuitry of empathy, the importance of the IC-BLA and ACC-NAc/VTA connections in modulating empathic pain, and the involvement of the LC/NE-SAM system in mediating pain empathy. We further discussed how gender significantly influences empathic pain, with women showing more intense emotional reactions to social distress than men. It also summarized the roles of personal pain history and empathy levels in modulating empathic responses. Furthermore, the review emphasized the impact of social factors such as the nature of interpersonal relationships and experiences of social exclusion on empathic pain. By providing a detailed exploration of the neural mechanisms and influencing factors of empathic pain, this review aims to establish a robust foundation for developing targeted therapeutic strategies and improving pain management in clinical settings.

Chronic post-surgical pain (CPSP) poses significant socioeconomic and humanitarian challenges. This study investigated relationships between resting-state neural activation in the somatosensory cortex (SMC) and emotional functioning outcomes (depression, anxiety, perceived stress), and between prefrontal cortex (PFC) activation and chronic stress, measured by hair cortisol concentration (HCC); and whether pain intensity moderates these relationships in females with CPSP. Twenty-nine females with CPSP reported baseline pain, completed emotional functioning questionnaires, underwent functional Near-Infrared Spectroscopy, and provided hair samples for HCC analysis. Pearson's correlation examined associations between emotional functioning and SMC activation, and between HCC and PFC activation. Benjamini-Hochberg correction adjusted for multiple comparisons. Significant correlations were further tested using moderation analyses to assess whether pain intensity influenced these associations. Left SMC activation was positively correlated with depressive symptoms (r = 0.505, pFDR = 0.036) and anxiety(r = 0.705, pFDR = 0.039). Right lateral PFC activation showed a negative correlation with HCC (r = -0.475, pFDR = 0.048). Pain intensity did not significantly moderate these relationships. Findings suggest associations between brain activity and emotional functioning in females with CPSP, highlighting potential neural targets for future interventions. This study supports the utility of multimodal approaches to further phenotype CPSP and inform precision medicine strategies.

Memory consolidation is enhanced by post-encoding stress via cortisol, although the role of dehydroepiandrosterone (DHEA) remains uncertain. This study investigated the effect of the Maastricht Acute Stress Test (MAST) on psychological and hormonal (salivary cortisol and DHEA) responses and performance on a virtual reality object-location memory (OLM) task. The association between hormonal reactivity and OLM task performance was also investigated. Fifty-four participants aged 18-23 were randomly assigned to a stress group (n = 30) and a control group (n = 24). Participants completed an encoding trial of the OLM task and the MAST/control procedure in an acquisition session. A retrieval session 24 h later included verbal object and visual location recognition tests, as well as an object-context binding (OCB) trial. Results showed that the stress group reported significantly higher state anxiety and negative affect after the MAST, perceived as more stressful, painful, and unpleasant. This group also exhibited a significant increase in cortisol and DHEA levels in response to the MAST. Controlling for age, participants in the stress condition made fewer errors in recognising semantically unrelated objects and tended to complete the OCB trial in a shorter time. In addition, no associations were found between cortisol or DHEA reactivity and memory performance in either the stress group or the control group. Our data indicate that post-encoding stress enhances consolidation; however, no association was found between hormonal reactivity and this process, suggesting that these endocrine responses do not directly support the observed improvement in memory consolidation.

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 male adults), the DXM group exhibited lower accuracy in the emotion matching condition, but not in the sensorimotor control condition. 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 condition but reduced connectivity in the same network during control condition, as compared to the placebo group. Meanwhile, the DXM group exhibited weaker left amygdala-right posterior middle temporal gyrus (rMTG) connectivity than the placebo group during control condition, but there was no group effect in the connectivity during emotion condition. These results indicate that the CAR proactively modulates fronto-limbic functional organization for emotion processing in male adults. Our 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.

Brainstem white matter bundles are essential conduits for neural signaling involved in modulation of vital functions ranging from homeostasis to human consciousness. Their architecture forms the anatomic basis for brainstem connectomics, subcortical mesoscale circuit models, and deep brain navigation tools. However, their small size and complex morphology compared to cerebral white matter structures makes mapping and segmentation challenging in neuroimaging. This results in a near absence of automated brainstem white matter tracing methods. We leverage diffusion MRI tractography to create BrainStem Bundle Tool (BSBT), which segments eight key white matter bundles in the rostral brainstem. BSBT performs automated segmentation on a custom probabilistic fiber map generated from tractography with a convolutional neural network architecture tailored for detection of small structures. We demonstrate BSBTs robustness across diffusion MRI acquisition protocols through validation on healthy subject in vivo scans and ex vivo scans of brain specimens with corresponding histology. Using BSBT, we reveal distinct brainstem white matter bundle alterations in Alzheimer's disease, Parkinson's disease, and acute traumatic brain injury cohorts through tract-based analysis and classification tasks. Finally, we provide proof-of-principle evidence supporting the prognostic utility of BSBT in a longitudinal analysis of coma recovery. BSBT creates opportunities to automatically map brainstem white matter in large imaging cohorts and investigate its role in a broad spectrum of neurological disorders.

Feline healthcare phobia is a major challenge in veterinary practice, limiting medical care and increasing stress for cats, owners, and veterinarians. Traditional desensitization-counter-conditioning (DS-CC) protocols aim to reduce fear responses, but their success is limited in sensitized cats. This study evaluates whether gabapentin can improve the efficiency of DS-CC training in healthcare phobia in cats. Forty-two sensitized cats participated in a claw-trimming learning protocol. Using a double-blind, placebo-controlled crossover trial, the cats followed 10 training sessions: the first 5 under one product and the last 5 under the other one. Their progression through the learning steps was monitored. The results indicate that gabapentin significantly accelerated the cats' ability to complete DS-CC steps, suggesting a positive effect on the learning process. While some side effects, such as mild sedation and ataxia, were observed in 42% of the cats, they were transient and did not hinder participation. These findings suggest that gabapentin should be added when engaging patients in DS-CC protocols in order to lower the time needed to achieve therapy, which will improve the overall welfare of our patients. Further studies are needed to confirm these results in other types of therapies and in a clinical setting.

Increasing evidence suggests that mothers experience stress before or during pregnancy, which can significantly impact their GABAergic system and lead to amygdala hyperactivity. While animal models are expected to reflect the above findings in humans, the current knowledge on the effects of chronic unpredictable mild stress (CUMS) in rat dams remains insufficient. Therefore, the objective of this study was to investigate the structural and neurochemical alterations in the dorsal hippocampus, specifically gamma-aminobutyric acid (GABA) and glutamate (Glu) relative to total creatine (tCr), induced by the CUMS and the effects of antidepressant mirtazapine (MIR) treatment. Magnetic resonance imaging and proton localized magnetic resonance spectroscopy were used in rat dams at two time points to assess the reversibility of these alterations. Eight weeks post-CUMS, chronic stress induced significant alterations in hippocampal metabolism and structural changes, including lower GABA/tCr concentrations and an increased amygdala volume compared to controls. In stressed dams treated with MIR, no changes in GABA levels or amygdala volume were observed. Fourteen weeks post-CUMS, no significant changes in hippocampal neurochemistry were confirmed, while amygdala changes persisted in stressed dams. Moreover, significant time-dependent changes were observed in the amygdala and hypothalamus in the control group with MIR. Interestingly, high-resolution respirometry was performed to assess brain mitochondrial function, revealing only changes in this group. Based on these findings, we confirmed the reversibility of metabolite. Furthermore, MIR has demonstrated potential in regulating neurotransmitter levels and protecting amygdala volume after stress; however, further research is needed to fully understand its therapeutic effects.

The hypothalamic-pituitary-thyroid axis has been well-known. However, whether follicular thyroid adenoma (FTA) could affect brain glucose metabolism is still unknown. Therefore, we explored the brain glucose metabolic characteristics of FTA with Fluorodeoxyglucose F18 positron emission tomography/magnetic resonance imaging.

Totally 30 FTA patients without clinical symptoms (FTA group), and 60 age- and sex-matched healthy controls (HC group) were included and randomly divided into cohort A and B in 2:1 ratio. Cohort A was analyzed with scaled sub-profile model/principal component analysis (SSM/PCA) for pattern identification. Cohort B was calculated the individual scores to validate expression of the pattern. Then we calculated the metabolic connectivity based on characteristics of the pattern to investigate the underlying mechanism. Finally, we constructed metabolic brain networks and analyzed the topological properties to further explore the brain metabolic model.

In SSM/PCA, FTA group showed an almost global, left-right symmetrical pattern. In metabolic connectivity, FTA group showed increased metabolic connectivity in brain regions of the sensorimotor network, ventral default mode network (DMN), posterior salient network, right executive control network (ECN), visuospatial network and language network when compared to HC group, and showed decreased connectivity in dorsal DMN and left ECN. In topological properties of brain network, FTA group showed an increased betweenness centrality (BC) in left rolandic operculum, a decreased BC in superior temporal gyrus, increased BC and Degree in right precentral gyrus, increased D in right parahippocampal gyrus and left hippocampus, and decreased D and efficiency in right orbital part of middle frontal gyrus (FDR correction for multiple comparisons, P < 0.05).

Although FTA patients are not yet symptomatic, their brain metabolic characteristics include extensive brain alterations, disrupted internal connectivity, not only involving brain regions associated with endocrine activity, but also brain networks and regions associated with motor, emotion and cognition.

Postpartum depression (PPD) is an increasingly prevalent but still poorly characterized disorder. Causal and modulating factors include hormones fluctuations, such as estrogen, progesterone, and allopregnolone, pathways imbalances, such as oxytocin and kynurenine, chronobiological factors, and brain imaging alterations. Treatment may differ from the traditional major depression management, while selective serotonin reuptake inhibitors such as sertraline are commonly used and suggested by guidelines, neurosteroids such as brexanolone and the more convenient zuranolone have been recently approved. Newer neurosteroids such as ganaxolone, valaxanolone, and lysaxanolone are currently under development, but also esketamine and psychedelics are promising potential treatments. Other somatic treatments including brain stimulation techniques and light therapy also showed benefit. PPD is therefore increasingly understood as, at least partially, independent from major depressive disorder. Specific and individualized treatments including pharmacological and non-pharmacological therapies are progressively being introduced in the routine clinical practice.

Responses to external and internal dangers is essential for survival and homeostatic regulation. Hypothalamic corticotropin-releasing hormone neurons (CRHNs) play a pivotal role in regulating neuroendocrine responses to fear and stress. In recent years, the application of neurogenetic tools, such as fiber photometry, chemogenetics and optogenetics, have provided new insights into the dynamic neuronal responses of CRHNs during stressful events, offering new perspectives into their functional significance in mediating neurobehavioural responses to stress. Transsynaptic viral tracers have facilitated the comprehensive mapping of neuronal inputs to CRHNs. Furthermore, the development and application of innovative single-cell genomic tools combined with viral tracing have begun to pave the way for a deeper understanding of the transcriptional profiles of neural circuit components, enabling molecular-anatomical circuit mapping. Here, I will discuss how these systems neuroscience approaches and novel single-cell genomic methods are advancing the molecular and functional mapping of stress neurocircuits, their associated challenges and future directions.

Post-Traumatic Stress Disorder (PTSD) is a debilitating condition in which a traumatic experience triggers symptoms related to re-experiencing, avoidance, arousal, and mood dysregulation. PTSD negatively impacts 6 % of people during their lifetime, with women being disproportionally affected and exhibiting different, more severe symptoms than men. Despite this widespread impact, the molecular mechanisms underlying PTSD and its sex differences remain poorly understood. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is a neuropeptide which participates in fine-tuning circuitry throughout the brain and has been associated with PTSD in humans, especially in women. Here, we use Single Prolonged Stress (SPS), an animal model of PTSD, to explore the roles of PACAP and sex in PTSD-like behaviors. Specifically, a PACAP agonist or antagonist was infused into the infralimbic (IL) prefrontal cortex, a region key to regulating fear- and anxiety-related behaviors, prior to SPS in male and female rats. Rats were then tested in open field/novel object, elevated plus maze, and social interaction. Utilizing a behavioral indexing method, we were able to uncover SPS effects in PTSD-related behavioral domains that were differentially impacted by PACAP manipulations in males and females. While both sexes exhibited increased threat avoidance and decreased threat assessment following SPS, females increased sociability while males decreased sociability. Males also appeared to be protected by IL PACAP antagonism while female SPS phenotypes were exacerbated by IL PACAP agonism. Furthermore, RNAscope revealed that PACAP in the prefrontal cortex responds differently to SPS in males and females. Together, these findings suggest complex relationships between SPS, sex, and IL PACAP which may have important implications for treating PTSD in men and women.

Chronic stress adversely affects intestinal health, but the specific neural pathways linking the brain to intestinal tissue are not fully understood. Here, we show that chronic stress-induced activation of the central amygdala-dorsal motor nucleus of the vagus (CeA-DMV) pathway accelerates premature aging and impairs the stemness of intestinal stem cells (ISCs). This pathway influences ISC function independently of the microbiota, the hypothalamic-pituitary-adrenal (HPA) axis, the immune response, and the sympathetic nervous system (SNS). Under chronic stress, DMV-mediated vagal activation prompts cholinergic enteric neurons to release acetylcholine (ACh), which engages ISCs via the M3 muscarinic acetylcholine receptor (CHRM3). This interaction activates the p38 mitogen-activated protein kinase (MAPK) pathway, triggering growth arrest and mitochondrial fragmentation, thereby accelerating an aging-like decline in ISCs. Together, our findings provide insights into an alternative neural mechanism that links stress to intestinal dysfunction. Strategies targeting the DMV-associated vagal pathway represent potential therapeutic approaches for stress-induced intestinal diseases.

Psychological stress changes both behaviour and metabolism to protect organisms. Adrenaline is an important driver of this response. Anxiety correlates with circulating free fatty acid levels and can be alleviated by a peripherally restricted β-blocker, suggesting a peripheral signal linking metabolism with behaviour. Here we show that adrenaline, the β3 agonist CL316,243 and acute restraint stress induce growth differentiation factor 15 (GDF15) secretion in white adipose tissue of mice. Genetic inhibition of adipose triglyceride lipase or genetic deletion of β-adrenergic receptors blocks β-adrenergic-induced increases in GDF15. Increases in circulating GDF15 require lipolysis-induced free fatty acid stimulation of M2-like macrophages within white adipose tissue. Anxiety-like behaviour elicited by adrenaline or restraint stress is eliminated in mice lacking the GDF15 receptor GFRAL. These data provide molecular insights into the mechanisms linking metabolism and behaviour and suggest that inhibition of GDF15-GFRAL signalling might reduce acute anxiety.

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.

Insulin secretion and resistance are key pathophysiological factors in type 2 diabetes. However, only 55% of patients achieve long-term blood glucose treatment goals, highlighting the need to clarify the pathophysiology of type 2 diabetes. While cortisol and aldosterone levels have been linked to insulin secretion and resistance in participants without type 2 diabetes, their role in patients with type 2 diabetes remains unclear. In this study, we aimed to investigate the relationships among insulin secretion, insulin resistance, and cortisol or aldosterone levels in patients with untreated type 2 diabetes.

We retrospectively reviewed 121 patients with untreated type 2 diabetes mellitus. We analyzed the relationships between various clinical parameters, including adrenal hormones, and insulin secretion (homeostatic model assessment [HOMA2-%B]) or insulin resistance (HOMA2-IR). Multiple regression analysis was performed to identify parameters associated with HOMA2-%B or HOMA2-IR.

Spearman's rank correlation coefficient revealed that body weight (BW); body mass index (BMI); estimated glomerular filtration rate; and serum creatinine, uric acid, total cholesterol, high-density lipoprotein cholesterol (HDL-C), sodium, potassium, chloride, fasting blood glucose (FBG), glycated hemoglobin (HbA1c), serum C-peptide, and cortisol levels were significantly correlated with HOMA2-%B. Similarly, BW, BMI, aspartate transaminase levels, alanine transaminase (ALT) levels, triglyceride levels, HDL-C levels, FBG levels, serum C-peptide levels, renin activity, and plasma aldosterone concentration (PAC) were significantly correlated with HOMA2-IR. Multiple regression analysis revealed BMI, HbA1c levels, and cortisol levels as predictors of HOMA2-%B, whereas ALT levels and the PAC were predictors of HOMA2-IR.

Serum cortisol levels are associated with insulin secretion, and the PAC is associated with insulin resistance in patients with untreated type 2 diabetes. These findings suggest that aldosterone blockade may represent a potential therapeutic approach for reducing insulin resistance in patients with type 2 diabetes.

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.

Chronic stress leads to elevated stress hormones, which may be linked to bone breakdown. Puerto Rican adults living on the US mainland have higher prevalence of stress than the general population, and higher and/or similar prevalence of osteoporosis compared with non-Hispanic Whites. The role of stress on bone remains unclear and may be modified by diet. A Dietary Approaches to Stop Hypertension (DASH) pattern, as a measure of dietary quality, was most protective for bone outcomes among Puerto Ricans. In this cross-sectional study, 958 Boston Puerto Rican Health Study participants were included (aged: 59.9 ± 7.6 yr). Stress markers (epinephrine, norepinephrine, cortisol) were collected via 12-h urine samples and elevated concentrations were categorized using sex-specific cutoffs. BMD was assessed via DXA. Analysis of covariance models with least squares means were used to test differences in mean BMD between participants with elevated and non-elevated stress markers. Multivariable logistic regression examined associations between stress markers and osteoporosis in postmenopausal females and males. Models were adjusted for age, height, smoking, alcohol use, education, glucocorticoid use, and diabetes. Higher urinary epinephrine was associated with lower BMD at the LS (p = .012), FN (p = .005), trochanter (p < .001), and TH (p < .001) in Puerto Rican adults, and with higher odds of osteoporosis among males (odds ratio = 4.01 [95%CI: 1.11, 14.5], p = .03). An interaction between DASH and norepinephrine was noted for postmenopausal females at the LS. No associations were noted for norepinephrine or cortisol (p > .11), although higher urinary norepinephrine was associated with lower LS BMD in postmenopausal females not taking estrogen, with lower adherence to DASH (p = .03). Higher urinary epinephrine and norepinephrine were associated with poorer bone outcomes in Puerto Rican adults, in a sex-specific manner, warranting future longitudinal studies to clarify associations. Dietary quality may moderate these associations.

Schizophrenia is a multifactorial disorder with a range of risk factors. Dysregulation in the systems involved in the stress response is a key component of its pathophysiology. Individuals at risk of developing schizophrenia exhibit hyperreactivity to stress and altered cognitive performance, both known as vulnerability markers. This study aims to determine whether stimulation of the prefrontal cortex can reduce reactivity to stress in unaffected siblings of patients with schizophrenia.

In a randomized, sham-controlled trial, 27 participants were assigned to receive either active (n = 14) or sham (n = 13) transcranial direct current stimulation (tDCS) over the prefrontal cortex for 30 min during exposure to an acute stressor. The stress response was measured biologically, via salivary cortisol levels, and cognitively, through a reality monitoring task, which serves as an intermediate cognitive vulnerability marker.

In contrast to the sham condition, active stimulation significantly reduced cortisol release in response to stress (F(9,216) = 1.972; p = 0.04) and prevented stress-induced impairment in reality monitoring (F(1,23) = 9.954; p = 0.004).

These findings suggest that tDCS should be a promising tool for reducing stress-induced biological and cognitive reactivity in a population at risk of schizophrenia.

Discrimination is a social stressor that is associated with adverse health outcomes, but the underlying neural mechanisms remain unclear. The fusiform, including the fusiform face area (FFA) plays a critical role in face perception especially regarding hostile faces during discrimination exposure; and are key regions involved in social cognition. We compared resting-state spontaneous activity and connectivity of the fusiform and FFA, between 153 individuals (110 women) with high (N = 73) and low (N = 80) levels of discrimination (measured by the Everyday Discrimination Scale) and evaluated the relationships of these brain signatures with psychological outcomes and stress-related neurotransmitters. Discrimination-related group differences showed altered fusiform signal fluctuation dynamics (Hurst exponent) and connectivity. These alterations predicted discrimination experiences and correlated with anxiety, depression, and cognitive difficulties. A molecular architecture analysis using cross-modal spatial correlation of brain signatures and nuclear imaging derived estimates of stress-related neurotransmitters demonstrated overlap between discrimination-related connectivity and dopamine, serotonin, gamma-aminobutyric acid (GABA), and acetylcholine. Discrimination exposure associated with alterations in the fusiform and face processing area may reflect enhanced baseline preparedness and vigilance towards facial stimuli and decreased top-down regulation of potential threats. These brain alterations may contribute to increased vulnerability for the development of mental health symptoms, demonstrating clinical relevance of social cognition in stressful interpersonal relationships.

Alcohol use disorder (AUD) and binge drinking are highly prevalent public health issues. Both ghrelin and corticotrophin-releasing factor (CRF) drive stress responses and alcohol drinking. Despite evidence of a relationship between the ghrelin and CRF systems, their potential interaction in modulating alcohol drinking is unclear. We tested the effect of a brain-penetrant CRF1 receptor antagonist (R121919) and a peripherally restricted nonselective CRF receptor antagonist (astressin) on plasma ghrelin levels. We also tested effects of R121919 and astressin alone and combined with the growth hormone secretagogue receptor (GHSR; the ghrelin receptor) antagonist JMV2959 and GHSR antagonist/inverse agonist PF-5190457 in a model of binge-like alcohol drinking in male and female C57BL/6 J mice. The intraperitoneal administration of R121919 but not astressin increased plasma ghrelin levels. R121919 but not astressin reduced binge-like alcohol drinking. CRF receptor antagonism had no effect on the ability of GHSR blockers to reduce alcohol drinking. No sex × drug treatment interactions were observed. These findings suggest that while both CRF receptor antagonism and GHSR antagonism reduce alcohol drinking, these two pharmacological approaches may not interact to mediate binge-like alcohol drinking in mice. Additionally, these results provide evidence that GHSR but not peripheral endogenous ghrelin may be key in driving binge-like alcohol drinking.

Reporting the histological effects of chronic stress on certain oral tissues, as well as the capacity of Thymus vulgaris (thyme) to protect tissues from stress and link both serum cortisol and serotonin levels.

30 rats were randomly divided into a trio of groups: normal control (no treatment), stress group (chronic stress without treatment), and treatment group (chronic stress treated with thyme at a dose of 200 mg/kg BW orally via needle gavage daily for 21 days). At the end of the experiment, tongues and major sublingual glands (SLGs) were surgically removed and processed for histological and histochemical studies. Blood samples were taken shortly before scarification for the biochemical study of cortisol and serotonin serum levels.

Examination of tongue and SLG sections of the stress group indicated significant alterations in histology and changes in SLG secretion. An examination of tongue and SLG histological sections of the thyme-treated group are showed an improvement. Chronic stress raises cortisol serum levels and lowers serotonin serum levels.

Chronic stress causes alteration of the tongue and major SLG histology, as well as changes in SLG secretion. Thyme may protect tissues from stress, and there is a relation between cortisol and serotonin levels.

Differences in multitasking (MT) performance have been found across the lifespan. Little is known about physiological stress responses to MT demands in older people. In our study, 106 younger (22.8 ± 3.9 years, 75.5 % female) and 113 older adults (70.9 ± 5.1 years, 70.8 % female) participated and were assigned to either a single-tasking (ST) or an MT condition. Physiological stress responses of the Autonomic Nervous System (ANS), and the hypothalamic-pituitary adrenal (HPA) axis were assessed. Task 1 was a sentence verification task, which was interrupted by push notifications (task 2) in the MT condition. Participants answered questions that assessed their comprehension of the notification content afterwards. Performance was lower in the MT condition in the older participants in task 1. All participants perceived stress during both tasks. Autonomic responses (i.e., for heart rate) were found for the MT condition in the older participants. No differences in physiological stress responses were found for the further autonomic measures. Cortisol levels decreased throughout the session for all participants. Our results confirm that MT performance decreases in older age. This may be associated with stronger ANS responses during MT in older than in younger people. Our findings partially support the specificity hypothesis, i.e., that cognitive stressors specifically initiate responses of the ANS, but no responses of the HPA axis. More research with more demanding tasks and the inclusion of further factors such as experience with MT and educational level is needed.

Schizophrenia spectrum disorders (SSD) are characterized by alterations in cortisol levels across various parameters, including stress reactivity, hair cortisol, and baseline levels, which may be influenced by antipsychotic treatment. To provide a comprehensive overview of cortisol dysregulation in SSD, we conducted meta-analyses assessing (1) the effects of antipsychotic treatment in SSD patients, and additionally comparing cortisol in SSD patients versus healthy controls (HC) (2) following stress induction (metabolic, physiological, psychological stressors), (3) in hair and (4) baseline levels. Systematic literature searches in PubMed, Web of Science, and PsycINFO (November 2024) identified 121 studies (9049 SSD patients) for inclusion. Meta-analytic results revealed that antipsychotic treatment significantly reduced cortisol levels in SSD (k = 16, g = -0.480, 95 % CI [-0.818, -0.142], p = 0.005). Additionally, compared to HC, SSD was associated with reduced cortisol suppression following dexamethasone exposure (k = 9, g = 0.299, 95 % CI [0.091, 0.507], p = 0.005) and with elevated baseline cortisol levels in the morning (k = 71, g = 0.38, 95 % CI [0.210, 0.546], p < 0.001) and evening (k = 11, g = 0.368, 95 % CI [0.076, 0.661], p = 0.014). However, there were no significant group differences in afternoon baseline cortisol, hair cortisol or cortisol reactivity to stress (p > 0.05). These findings offer a detailed understanding of cortisol alterations in SSD and improve our understanding of HPA axis dysregulation in SSD.

Alterations in tryptophan-kynurenine (TRP-KYN) pathway are implicated in major depressive disorder (MDD). α7 nicotinic acetylcholine (α7nACh) receptor regulates the hypothalamic-pituitary-adrenal (HPA) axis. We have shown that deficiency of kynurenine 3-monooxygenase (KMO) induces depression-like behaviour via kynurenic acid (KYNA; α7nACh antagonist). In this study, we investigated the involvement of the TRP-KYN pathway in stress-induced behavioural changes and the regulation of the HPA axis.

Mice were exposed to chronic unpredictable mild stress (CUMS) and subjected to behavioural tests. We measured TRP-KYN metabolites and the expression of their enzymes in the hippocampus. KMO heterozygous mice were used to investigate stress vulnerability. We also evaluated the effect of nicotine (s.c.) on CUMS-induced behavioural changes and an increase in serum corticosterone (CORT) concentration.

CUMS decreased social interaction time but increased immobility time under tail suspension associated with increased serum corticosterone concentration. CUMS increased KYNA levels via KMO suppression with microglial decline in the hippocampus. Kmo+/- mice were vulnerable to stress: they exhibited social impairment and increased serum corticosterone concentration even after short-term CUMS. Nicotine attenuated CUMS-induced behavioural changes and increased serum corticosterone concentration by inhibiting the increase in corticotropin-releasing hormone. Methyllycaconitine (α7nACh antagonist) inhibited the attenuating effect of nicotine.

CUMS-induced behavioural changes and the HPA axis dysregulation could be induced by the increased levels of KYNA via KMO suppression. KYNA plays an important role in the pathophysiology of MDD as an α7nACh antagonist. Therefore, α7nACh receptor is an attractive therapeutic target for MDD.

Olfaction is crucial to our dietary choices and significantly influences our emotional and cognitive landscapes. Understanding the underlying neural mechanisms is pivotal, especially through the use of electroencephalography (EEG). This technology has strong temporal resolution, allowing it to capture the dynamics of neural responses to odors, bypassing the need for subjective interpretations. The application of EEG in food flavor research is still relatively new, but it has great potential. This review begins with an examination of general scent stimulation, charts the advances in using EEG to understand odor perception, and explores its future in food flavor science. By analyzing EEG's ability to detect distinct patterns and strengths in brain activity, we can elucidate the perceptual, affective, and cognitive frameworks associated with food odors. Event-related potentials and oscillatory activities, markers of central olfactory processing, provide insights into the neural architecture of olfaction. These markers are instrumental in assessing the influence of food odors on health, emotions, and decision-making processes. We argue that EEG's application in olfaction research holds considerable promise for the food industry to innovate products that are not only healthier but also more appealing, thereby promoting human well-being.

Nearly half of mild traumatic brain injury (mTBI) patients continue to experience residual neurological dysfunction, which may be attributed to exposure to stress. Ferroptosis, a newly discovered form of cell death, is increasingly recognized for its involvement in the pathophysiology of TBI. Understanding the mechanisms by which stress influences mTBI, particularly through ferroptosis, is crucial for the effective treatment and prevention of mTBI patients who are sensitive to stressful events. In our study, a mouse mTBI model was established. An acute restraint stress (RS) and a chronic unpredictable mild stress (CUMS) model then were applied to make acute and chronic stress, respectively. We found acute RS significantly delayed the recovery of reduced body weight and short-term motor dysfunctions and exacerbated cell insults and blood-brain barrier leakage caused by mTBI. Further studies revealed that acute RS exacerbates neuronal ferroptosis, pyroptosis, and apoptosis by promoting iron overloading in the neocortex following mTBI. Interestingly, the inhibition of ferroptosis with iron chelators, including deferoxamine and ciclopirox, reversed pyroptosis and apoptosis. Moreover, CUMS aggravated neurological dysfunctions (motor function, cognitive function, and anxiety-like behavior) and exacerbated brain lesion volume. CUMS also exacerbates ferroptosis, pyroptosis, and apoptosis by intensifying iron deposition, along with decreasing the expression of neuronal brain-derived neurotrophic factor and glucocorticoid receptor in the neocortex post mTBI. These effects were also mitigated by iron chelators. Our findings suggest that alleviating ferroptosis induced by iron deposition may represent a promising therapeutic approach for mTBI patients who have experienced stressful events.

Premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) are prevalent emotional disorders in females, characterized by cyclic variations in physiological stress responses and emotional symptoms that correspond with the menstrual cycle. Despite extensive research, the underlying causes of these disorders remain elusive. This review delves into the neurobiological mechanisms connecting stress-induced neuroinflammation with PMS/PMDD. Additionally, it traces the conceptual development and historical context of PMS/PMDD. The review further evaluates clinical evidence on the association between PMS/PMDD and stress, along with findings from both clinical and animal studies that link these disorders to inflammatory processes. Additionally, the neurobiological pathways by which inflammatory responses may play a role in the pathogenesis of PMS/PMDD were elucidated, including their interactions with the hypothalamic-pituitary-ovary (HPO) axis, serotonin-kynurenine (5-HT-KYN) system, GABAergic system, brain-derived neurotrophic factor (BDNF), hypothalamic-pituitary-adrena(HPA)axis and. Future research is encouraged to further investigate the pathogenesis of PMS/PMDD through the perspective of neuroinflammatory responses.