Fetal endocrine axes mRNA expression levels are related to sex and intrauterine position.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes are two major pathways that connect the neural and endocrine systems in vertebrates. Factors such as prenatal stress and maternal exposure to exogenous steroids have been shown to affect these pathways during fetal development. Another less studied factor is the transfer of hormones across fetuses in multifetal pregnancies. This form of transfer has been shown to influence the morphology, anatomy, physiology, and behavior of the offspring in litter-bearing mammals, an influence termed the intrauterine position (IUP) effect. In this study, we sought to delineate how the IUP effects HPA and HPG brain receptors, peptides, and enzymes (hereafter components) in utero and how these influences may differ between males and females. METHODS: We utilized the unconventional model of culled free-ranging nutria (Myocastor coypus), with its large natural variation. We collected brain tissues from nutria fetuses and quantified the expression of key HPA and HPG components in three brain regions: prefrontal cortex, hypothalamus, and striatum. RESULTS: We found an interaction between sex and IUP in the mineralocorticoid receptor (MR), gonadotropin-releasing hormone receptor (GNRHR), androgen receptor (AR), and estrogen receptor alpha (ESR1). IUP was significant in both gonadotropin-releasing hormone (GnRH) and its receptor GNRHR, but in different ways. In the hypothalamus, fetuses adjacent to same-sex neighbors had higher expression of GnRH than fetuses neighboring the opposite sex. Conversely, in the cortex, GNRHR exhibited the inverse pattern, and fetuses that were neighboring the opposite sex had higher expression levels than those neighboring the same sex. Regardless of IUP, in most components that showed significant sex differences, female fetuses had higher mRNA expression levels than male fetuses. We also found that HPA and HPG components were highly related in the early stages of gestation, and that there was an interaction between sex and developmental stage. In the early stages of pregnancy, female component expression levels were more correlated than males', but in the last trimester of pregnancy, male components were more related to each other than female's. CONCLUSIONS: This study suggests that there are sexually different mechanisms to regulate the HPA and HPG axes during fetal development. Higher mRNA expression levels of endocrine axes components may be a mechanism to help females cope with prolonged androgen exposure over a long gestational period. Additionally, these findings suggest different coordination requirements of male and female endocrine axes during stages of fetal development.

PTSD biomarkers: Neuroendocrine signaling to epigenetic variants.

Posttraumatic stress disorder (PTSD) is characterized by exposure to traumatic events and involves symptom domains such as intrusive thoughts, avoidant behaviors, negative mood, and cognitive dysfunction. The disorder can be chronic and debilitating, and the heterogenous nature and varied presentation of PTSD has afforded difficulty in determining efficacious treatment. The ability to identify biomarkers for PTSD risk, prognosis, or for the purposes of treatment, would be highly valuable. There is evidence for peripheral biomarkers related to the hypothalamic-pituitary-adrenal axis, the immune system, neurotransmitters and neurohormones, while genome and epigenome wide association studies have identified genes of interest relating to neurocircuitry, monoaminergic function, and the immune system. Importantly, however, reproducibility is a persistent issue. Considerations for future research include the need for well-powered and well-designed studies to determine directionality, in addition to considering biomarkers as they relate to symptom domains and the spectrum of symptom severity rather than dichotomous diagnostic outcomes. We conclude by recommending the staging of biological processes and PTSD symptoms, from subsyndromal to chronic, which could eventually facilitate selection of personalized treatment interventions for individuals with PTSD, in addition to serving as a future framework for biomarker data.

Effect of circadian clock disruption on type 2 diabetes.

Introduction: Type 2 diabetes (T2D) is the predominant form of diabetes mellitus and is among the leading causes of death with an increasing prevalence worldwide. However, the pathological mechanism underlying T2D remains complex and unclear. An increasing number of studies have suggested an association between circadian clock disruption and high T2D prevalence. Method: This review explores the physiological and genetic evidence underlying T2D symptoms associated with circadian clock disturbances, including insulin secretion and glucose metabolism. Results and Discussion: Notably, circadian clock disruption reduces insulin secretion and insulin sensitivity and negatively affects glucose homeostasis. The circadian clock regulates the hypothalamic-pituitary-adrenal axis, an important factor that regulates glucose metabolism and influences T2D progression. Therefore, circadian clock regulation is an attractive, novel therapeutic approach for T2D, and various circadian clock stabilizers play therapeutic roles in T2D. Lastly, this review suggests novel therapeutic and preventive approaches using circadian clock regulators for T2D.

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

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

More allogrooming is followed by higher physiological stress in wild female baboons.

Social bonds increase fitness in a range of mammals. One pathway by which social bonds may increase fitness is by reducing the exposure to physiological stress, i.e. glucocorticoid (GC) hormones, that can be detrimental to health and survival. This is achieved through downregulating hypothalamic-pituitary-adrenal (HPA)-axis activity. Indeed, long-term measures of social (grooming) bonds are often negatively correlated with HPA-axis activity. However, the proximate role of physical touch through allogrooming remains an open question in the sociality-health-fitness debate. Demonstrating the potential anxiolytic benefits of grooming in the wild is hindered by methodological limitations. Here, we match accelerometer-identified grooming in wild female chacma baboons (Papio ursinus) to non-invasive faecal GC metabolite concentrations (fGCs). Consistent with previous work, we found a negative (but statistically non-significant) overall relationship between individual averaged fGCs and grooming rates. However, when time-matching grooming to fGCs, we found that both more giving and receiving grooming were followed by higher fGCs. This upregulation of HPA-axis activity suggests that maintaining social bonds (and its ultimate fitness benefits) may come at a shorter-term physiological cost. This finding sheds new light on a ubiquitous social behaviour typically considered 'relaxing' and suggests that sociopositive contact can trigger physiological stress.

Turn off that night light! Light-at-night as a stressor for adolescents.

Light-at-night is known to produce a wide variety of behavioral outcomes including promoting anxiety, depression, hyperactivity, abnormal sociability, and learning and memory deficits. Unfortunately, we all live in a 24-h society where people are exposed to light-at-night or light pollution through night-shift work - the need for all-hours emergency services - as well as building and street-lights, making light-at-night exposure practically unavoidable. Additionally, the increase in screentime (tvs and smart devices) during the night also contributes to poorer sleep and behavioral impairments. Compounding these factors is the fact that adolescents tend to be "night owls" and prefer an evening chronotype compared to younger children and adults, so these teenagers will have a higher likelihood of being exposed to light-at-night. Making matters worse is the prevalence of high-school start times of 8 am or earlier - a combination of too early school start times, light exposure during the night, and preference for evening chronotypes is a recipe for reduced and poorer sleep, which can contribute to increased susceptibility for behavioral issues for this population. As such, this mini-review will show, using both human and rodent model studies, how light-at-night affects behavioral outcomes and stress responses, connecting photic signaling and the circadian timing system to the hypothalamic-pituitary adrenal axis. Additionally, this review will also demonstrate that adolescents are more likely to exhibit abnormal behavior in response to light-at-night due to changes in development and hormone regulation during this time period, as well as discuss potential interventions that can help mitigate these negative effects.

Salivary cortisol captures endocrine response to an acute stressor in captive female tufted capuchin monkeys (Sapajus apella).

Measuring glucocorticoids such as cortisol is a useful tool for exploring relationships among behavior, physiology, and well-being in primates. As cortisol circulates in blood, it moves into biological matrices such as hair, urine, feces, and saliva. Saliva sampling is a simple, noninvasive method to measure cortisol that can be easily implemented by training animals to voluntarily provide samples. The temporal lag between elevation of cortisol in the blood and elevation of cortisol in saliva likely varies by species and must be characterized to identify appropriate sampling regimens. In the present study we characterized the time course of cortisol changes in saliva following an acute psychological stressor in captive tufted capuchin monkeys (Sapajus apella). We trained eight free-moving female tufted capuchin monkeys to voluntarily produce clean saliva samples. We exposed them to the acute stressor of a veterinary catch net and observed behavior pre and post exposure. We collected salivary samples immediately pre exposure (0 min) and 30, 45, 60, 75, 90, and 120 min after exposure. Salivary cortisol was quantified using a Salimetrics kit. Behavioral and cortisol measures were compared within individuals to a control condition in which no stressor was presented. Capuchins showed a clear behavioral response to the stressor by demonstrating increased freezing and pacing, decreased feed foraging, nonsocial play, and scratching, and decreased willingness to provide saliva samples after stressor presentation. After stressor presentation, average salivary cortisol began to increase at 30 min and continued to increase through the 120 min sample period. There was individual variation in absolute cortisol levels, the timing of the cortisol increase, and the timing of the peak. Our results suggest that no single time-point can be reliably used to evaluate salivary cortisol response to an acute stressor across individuals, and instead we recommend the collection of a prolonged time series.

Corticosterone administration immediately after peripuberty stress exposure does not prevent protracted stress-induced behavioral alterations.

Stress-related disorders are commonly associated with abnormalities in hypothalamic-pituitary-adrenal (HPA) axis activity. Preliminary studies with cortisol administration in the aftermath of trauma suggest that this HPA axis hormone can potentially prevent maladaptive behavioral and biological stress responses. However, the efficacy of glucocorticoid administration during the peripuberty period has not been tested yet, although this lifetime is a critical time window in brain development and is highly sensitive to the harmful effects of stress. To further examine the short and long-lasting impact of glucocorticoids treatment given during the post-peripubertal stress period, the present study utilized a rat model of peripubertal stress-induced psychopathology and animals were subjected to a battery of tests to assess anxiety-like behaviors, exploratory behavior and reactivity to novelty at late adolescence and sociability, anhedonia and stress coping behaviors at adulthood. All the experiments were performed in males and females to evaluate the potential behavioral sex differences. Overall, our results demonstrated that rats exposed to peripubertal stress show decreased sociability in adulthood without differences in anxiety and depression-like behaviors. Moreover, this study shows that the administration of corticosterone after stress exposure at peripuberty does not prevent stress-induced behavioral alterations. However, we observed that some stress-induced behavioural alterations and corticosterone responses are sex-specific. Thus, the data obtained highlight that delineating sex differences in stress-related studies may ultimately contribute to the development of effective therapeutic interventions for each sex.

Effects of improved on-farm crop storage on DNA methylation of mothers and their infants: evidence from a randomized controlled trial in Kenya.

BACKGROUND: Stress during pregnancy can lead to adverse maternal and infant health outcomes through epigenetic changes in the hypothalamic-pituitary-adrenal axis. Among farmers in low-income countries, one important stressor is food insecurity, which can be reduced using hermetic storage bags. This study aimed to determine, for the first time, whether a hermetic storage bag intervention during pregnancy positively affects maternal and infant DNA methylation of the hypothalamic-pituitary-adrenal axis-related genes FKBP5 and NR3C1. We further analyzed whether anthropometrics, stress, and mental health were associated with DNA methylation. METHODS: This study was part of a larger matched-pair randomized controlled trial focusing on the impact of improved on-farm storage on food security, poverty, and net income of smallholder farming households. A total of N = 149 mothers were recruited by telephone and invited to attend a study appointment at health facilities in Kakamega County, Western Kenya, with their infants in April or May 2021. During the appointment, anthropometric measurements were taken, questionnaires on stress and mental health were administered, and saliva samples were collected. Logistic and multiple linear regression were used to examine the effect of the intervention and related measures on DNA methylation. RESULTS: Mothers in the intervention group showed higher mean NR3C1 methylation levels than those in the control group, corrected for multiple testing. Maternal postpartum body mass index was positively associated with infant NR3C1 CpG3 DNA methylation. The more stressful life events a mother had experienced in the previous 12 months (including during pregnancy), the lower her FKBP5 CpG3 methylation levels. CONCLUSIONS: Food insecurity and stressful life events during pregnancy seem to exert significant effects on maternal DNA methylation. While these stressors did not appear to impact infant DNA methylation in the present study, maternal postpartum body mass index was significantly related to infant methylation. These findings suggest that while infants may be protected from excessive maternal glucocorticoids by placental barrier activity, maternal metabolic status is still reflected in their epigenetic make-up. Trial registration This study was part of a larger matched-pair randomized controlled trial on the impact of improved on-farm crop storage on welfare, nutrition, and human health. Registration can be found in the American Economic Association (AEA) RCT Registry, RCT ID: AEARCTR-0005845.

Mechanisms of stress-attributed breast cancer incidence and progression.

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths in women, with psychosocial stress commonly cited by patients as one of its causes. While there is conflicting epidemiological evidence investigating the association between psychosocial stress and breast cancer incidence and progression, there is reason to believe that interventions aimed at reducing stress pharmacologically or psychologically may improve breast cancer outcomes. The aim of this review is to discuss the molecular and biological mechanisms of stress-attributed breast cancer incidence and progression, including the induction of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), as well as decreased immune function and stress hormone-induced resistance to chemotherapy. Moreover, these mechanisms have been cited as potential therapeutic targets of pharmacologic and psychological interventions that may improve the care, well-being and survival of breast cancer patients. Further research is recommended to investigate whether interventions in the primary care setting for women with risk factors for breast cancer development may lead to a decreased incidence of invasive breast tumors.

The oral microbiome is associated with HPA axis response to a psychosocial stressor.

Intense psychosocial stress during early life has a detrimental effect on health-disease balance in later life. Simultaneously, despite its sensitivity to stress, the developing microbiome contributes to long-term health. Following stress exposure, HPA-axis activation regulates the "fight or flight" response with the release of glucose and cortisol. Here, we investigated the interaction between the oral microbiome and the stress response. We used a cohort of 115 adults, mean age 24, who either experienced institutionalisation and adoption (n = 40) or were non-adopted controls (n = 75). Glucose and cortisol measurements were taken from participants following an extended socially evaluated cold pressor test (seCPT) at multiple time points. The cohort´s oral microbiome was profiled via 16S-V4 sequencing on microbial DNA from saliva and buccal samples. Using mixed-effect linear regressions, we identified 12 genera that exhibited an interaction with host's cortisol-glucose response to stress, strongly influencing intensity and clearance of cortisol and glucose following stress exposure. Particularly, the identified taxa influenced the glucose and cortisol release profiles and kinetics following seCPT exposure. In conclusion, our study provided evidence for the oral microbiome modifying the effect of stress on the HPA-axis and human metabolism, as shown in glucose-cortisol time series data.

Escin alleviates cerebral ischemia-induced intestinal pyroptosis via the GR-dependent p38 MAPK/NF-κB signaling and NLRP3 inflammasome activation.

Cerebral ischemia-induced systemic inflammation and inflammasome-dependent pyroptotic cell death in ileum, causing serious intestinal injury. Glucocorticoid receptor (GR) mediates the effects of glucocorticoids and participates in inflammation. Escin has corticosteroid-like, neuroprotective, and anti-intestinal dysfunction effects. This study aimed to investigate the effect of Escin on the intestinal barrier injury in rats subjected to middle cerebral artery occlusion (MCAO) and on Caco-2 cells exposed to lipopolysaccharides. The MCAO-caused brain injury was evaluated by assessing neurological function, cerebral infarct volume, and plasma corticosterone (Cort) levels. Intestinal injury was evaluated by observing the histopathological changes, assessing the intestinal barrier function, and determining blood FD4, endotoxin and IL-1ß levels. The levels of the tight-junction proteins such as claudin-1, occludin, and ZO-1, and proteins involved in the GR/p38 MAPK/NF-κB pathway and NLRP3-inflammasome activation were evaluated using western blotting or immunofluorescence. Administration of Escin suppressed the cerebral ischemia-induced increases in Garcia-test scores and infarct volume, alleviated the injury to the intestinal barrier, and decreased the levels of Cort, endotoxin, and IL-1ß. Additionally, Escin upregulated GR and downregulated phospho(p)-p65, p-p38MAPK, NLRP3, GSDMD-N, and cleaved-caspase-1 in the intestine. The effects of Escin could be suppressed by the GR antagonist RU486 or enhanced by the p38 MAPK antagonist SB203580. We revealed details how Escin improves cerebral ischemia-induced intestinal barrier injury by upregulating GR and thereby inhibiting the pyroptosis induced by NF-κB-mediated NLRP3 activation. This study will provide a experimental foundation for the features of glucocorticoid-like activity and the discovery of new clinical application for Escin.

Hypothalamus-pituitary-adrenal axis (HPA axis) suppression with inappropriate use of steroids in recalcitrant dermatophytosis - A cross-sectional study.

Background: Improper use of over-the-counter (OTC) steroid medication has been linked to recalcitrant dermatophytosis. There is proven evidence of HPA axis suppression by the use of long-term oral steroids. This study aims to determine the prevalence and pattern of inappropriate OTC steroid use and its effects on the hypothalamus-pituitary-adrenal (HPA) axis in adults with recalcitrant dermatophytosis. Materials and Methods: This cross-sectional study of 2 months was conducted in a hospital setting and included patients of recalcitrant dermatophytosis with a history of OTC steroid use. Clinico-demographic details and basal serum cortisol levels were recorded in all and analyzed. Result: Of a total of 103 patients, 59.22% (n = 61/103) were males, and the mean duration of steroid abuse was 17.78 months. About 48.54% (n = 50/103), 3.88% (n = 4/103), and 47.57% (n = 49/103) patients reported the use of topical steroids, oral steroids, and both oral and topical steroids, respectively. Among all the topical steroid users (n = 99), clobetasol propionate 48.48% (n = 48/99), while among oral steroid users (n = 53), prednisolone 45.28% (n = 24/53) were the most commonly used agents, respectively. The morning serum cortisol levels (8-9 AM) were found to be decreased in 42.7% (n = 44/103), with a mean value of 44.28 ± 17.34 µg/dL. Conclusion: Improper OTC steroid use in recalcitrant dermatophytosis leads to HPA axis suppression. This highlights the need for intervention from apex health officials.

Exogenous glucocorticoids to improve extinction learning for post-traumatic stress disorder patients with hypothalamic-pituitary-adrenal-axis dysregulation: a study protocol description.

Background: Trauma-focused treatments for post-traumatic stress disorder (PTSD) are effective for many patients. However, relapse may occur when acquired extinction memories fail to generalize beyond treatment contexts. A subgroup of PTSD patients - potentially with substantial exposure to early-life adversity (ELA) - show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which results in lower cortisol levels. Glucocorticoids, including cortisol, appear to facilitate strength and generalization of emotional memories.Objective: We describe the protocol of an integrated PTSD study. We investigate (A) associations between HPA-axis dysregulation, ELA, epigenetic markers, and PTSD treatment outcome (observational study); and (B) effects of exogenous glucocorticoids on strength and generalization of extinction memories and associated neural mechanisms [pharmacological intervention study with functional magnetic resonance imaging (fMRI)]. The objective is to provide proof of concept that PTSD patients with HPA-axis dysregulation often experienced ELA and may show improved strength and generalization of extinction learning after glucocorticoid administration.Method: The observational study (n = 160 PTSD group, n = 30 control group) assesses ELA, follow-up PTSD symptoms, epigenetic markers, and HPA-axis characteristics (salivary cortisol levels during low-dose dexamethasone suppression test and socially evaluated cold-pressor test). The pharmacological intervention study (n = 80 PTSD group, with and without HPA-axis dysregulation) is a placebo-controlled fMRI study with a crossover design. To investigate strength and generalization of extinction memories, we use a differential fear acquisition, extinction, and extinction recall task with spatial contexts within a virtual environment. Prior to extinction learning, 20 mg hydrocortisone or placebo is administered. During next-day recall, strength of the extinction memory is determined by recovery of skin conductance and pupil dilation differential responding, whereas generalization is assessed by comparing responses between different spatial contexts.Conclusion: The integrated study described in the current protocol paper could inform a personalized treatment approach in which these PTSD patients may receive glucocorticoids as a treatment enhancer in trauma-focused therapies.Trial registration: The research project is registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database, https://eudract.ema.europa.eu/, EudraCT number 2020-000712-30.

This protocol reports a proof-of-concept study for glucocorticoids as an enhancer for PTSD treatment.The study examines whether glucocorticoids enhance the strength and generalization of extinction memory.A further aim is to identify HPA-axis-related PTSD subgroups that may particularly benefit.

Dissimilar Changes in Serum Cortisol after Epileptic and Psychogenic Non-Epileptic Seizures: A Promising Biomarker in the Differential Diagnosis of Paroxysmal Events?

The hypothalamic-pituitary-adrenal axis is known to be involved in the pathogenesis of epilepsy and psychiatric disorders. Epileptic seizures (ESs) and psychogenic non-epileptic seizures (PNESs) are frequently differentially misdiagnosed. This study aimed to evaluate changes in serum cortisol and prolactin levels after ESs and PNESs as possible differential diagnostic biomarkers. Patients over 18 years with ESs (n = 29) and PNESs with motor manifestations (n = 45), captured on video-EEG monitoring, were included. Serum cortisol and prolactin levels as well as hemograms were assessed in blood samples taken at admission, during the first hour after the seizure, and after 6, 12, and 24 h. Cortisol and prolactine response were evident in the ES group (but not the PNES group) as an acute significant increase within the first hour after seizure. The occurrence of seizures in patients with ESs and PNESs demonstrated different circadian patterns. ROC analysis confirmed the accuracy of discrimination between paroxysmal events based on cortisol response: the AUC equals 0.865, with a prediction accuracy at the cutoff point of 376.5 nmol/L 0.811 (sensitivity 86.7%, specificity 72.4%). Thus, assessments of acute serum cortisol response to a paroxysmal event may be regarded as a simple, fast, and minimally invasive laboratory test contributing to differential diagnosis of ESs and PNESs.

cAMP-PKA signaling pathway and anxiety: Where do we go next?

Cyclic adenosine monophosphate (cAMP) is an intracellular second messenger that is derived from the conversion of adenosine triphosphate catalysed by adenylyl cyclase (AC). Protein kinase A (PKA), the main effector of cAMP, is a dimeric protein kinase consisting of two catalytic subunits and two regulatory subunits. When cAMP binds to the regulatory subunits of PKA, it leads to the dissociation and activation of PKA, which allows the catalytic subunit of PKA to phosphorylate target proteins, thereby regulating various physiological functions and metabolic processes in cellular function. Recent researches also implicate the involvement of cAMP-PKA signaling in the pathologenesis of anxiety disorder. However, there are still debates on the prevention and treatment of anxiety disorders from this signaling pathway. To review the function of cAMP-PKA signaling in anxiety disorder, we searched the publications with the keywords including "cAMP", "PKA" and "Anxiety" from Pubmed, Embase, Web of Science and CNKI databases. The results showed that the number of publications on cAMP-PKA pathway in anxiety disorder tended to increase. Bioinformatics results displayed a close association between the cAMP-PKA pathway and the occurrence of anxiety. Mechanistically, cAMP-PKA signaling could influence brain-derived neurotrophic factor and neuropeptide Y and participate in the regulation of anxiety. cAMP-PKA signaling could also oppose the dysfunctions of gamma-aminobutyric acid (GABA), intestinal flora, hypothalamic-pituitary-adrenal axis, neuroinflammation, and signaling proteins (MAPK and AMPK) in anxiety. In addition, chemical agents with the ability to activate cAMP-PKA signaling demonstrated therapy potential against anxiety disorders. This review emphasizes the central roles of cAMP-PKA signaling in anxiety and the targets of the cAMP-PKA pathway would be potential candidates for treatment of anxiety. Nevertheless, more laboratory investigations to improve the therapeutic effect and reduce the adverse effect, and continuous clinical research will warrant the drug development.

Prediction of suicidal thoughts and behaviors based on the diurnal cortisol pattern and THC dosage in continued cannabis users, a 5 year population-based matched cohort study.

It appears that the THC dosage is the link between dysregulation of the hypothalamic pituitary adrenal (HPA) axis and suicidal thoughts and behaviors (STB). We proposed a new model to understand the underlying pathophysiological mechanism of STB based on the interaction of cortisol and THC dosage. From September 1, 2019, to January 1, 2024, we conducted a population-based, matched-pair, nested case-control study resulting from a three-wave complete longitudinal, multicenter cohort study on a sample of congress 60 clients. A total of 368 male continued cannabis users (CCu) were allocated to four categories, including low, moderate and high THC dosages and relapse, using optimal matching. Several HPA axis measures were analyzed in the saliva using liquid chromatography with tandem mass spectrometry (LC-MS-MS), and carboxylic acids levels in the urine were assessed via gas chromatography/mass spectrometry (GC-MS). We used structural equation modeling (SEM) to examine the relationship between the variables of interest and the model fit test, and used the Akaike information criterion (AIC) to compare the model fit and select the best-fitting model. Population attributable fractions (PAFs) and cumulative risk score were also calculated for the best-fitting pattern. The analysis showed that the likelihood of STB in individuals with a cortisol awakening response (CAR) and a blunted diurnal cortisol slope (DCS) and higher area under the curve (AUC) who reported heavy cannabis use was more than three times higher than the control group (OR 3.2, 95 % CI 2.4-4.1). These findings indicate the importance of the specific cortisol secretion pattern in the increased clinical expression of STB and may be an important factor for guiding preventive efforts in this area.

Dietary Anthocyanins Mitigate High-Fat Diet-Induced Hippocampal Inflammation in Mice.

BACKGROUND: Obesity and consumption of high-fat diets (HFD) are associated with intestinal permeabilization and increased paracellular transport of endotoxins, which can promote neuroinflammation. Inflammation can affect the hypothalamic pituitary adrenal (HPA) axis, which controls responses to stress and downregulates the brain-derived neurotrophic factor (BDNF), which can promote anxiety and depression, conditions frequently found in obesity. We previously showed that consumption of anthocyanins (AC) mitigate HFD-induced insulin resistance, intestinal permeability, and inflammation. OBJECTIVES: This study investigated if a dietary supplementation with a cyanidin- and delphinidin-rich extract (CDRE) could counteract HFD/obesity-induced hippocampal inflammation in mice. METHODS: C57BL/6J male mice were fed for 14 wk on one of the following diets: 1) a control diet containing 10% total calories from fat (C), 2) a control diet supplemented with 40 mg AC/kg body weight (BW) (CAC), 3) a HFD containing 60% total calories from fat (lard) (HF), or 4) the HFD supplemented with 2, 20, or 40 mg AC/kg BW (HFA2, HFA20, and HFA40, respectively). In plasma and in the hippocampus, parameters of neuroinflammation and the underlying cause (endotoxemia) and consequences (alterations to the HPA and BDNF downregulation) were measured. RESULTS: Consumption of the HFD caused endotoxemia. Accordingly, hippocampal Tlr4 mRNA levels were 110% higher in the HF group, which were both prevented by CDRE supplementation. Consumption of the HFD also caused: 1) microgliosis and increased expression of genes involved in neuroinflammation, that is, Iba-1, Nox4, Tnfα, and Il-1ß, 2) alterations of HPA axis regulation, that is, with low expression of mineralocorticoid (MR) and glucocorticoid (GR) receptors; and 3) decreased Bdnf expression. Supplementation of HFD-fed mice with CDRE mitigated neuroinflammation, microgliosis, and MR and BDNF decreases. CONCLUSIONS: CDRE supplementation mitigates the negative effects associated with HFD consumption and obesity in mouse hippocampus, in part by decreasing inflammation, improving glucocorticoid metabolism, and upregulating BDNF.

HPA activity mediates the link between trait impulsivity and boredom.

Boredom, a complex emotional state with implications for mental health and well-being, has garnered attention across disciplines, yet remains relatively understudied in psychiatric research. Here, we explored the intricate relationship between trait-impulsivity, stress, and boredom across two studies. Participants completed self-report measures of trait-impulsivity and boredom and boredom-inducing tasks. Study 1, involving 80 participants (42 women and 38 men, aged 20-63), replicates previous findings, by demonstrating that impulsive individuals report greater boredom following a boring task. Study 2 then extends this, using 20 participants (9 women and 12 men, aged 18-24), to show that hypothalamic-pituitary-adrenal (HPA) axis activity, specifically heightened salivary cortisol responses, mediate the link between impulsivity and boredom following a boring task. Collectively, these results demonstrate that HPA axis activity may underline the relationship between trait-impulsivity and boredom by extending previous work and offering a novel insight into potential mechanisms. These findings offer promise for personalised interventions, designed for high impulsivity individuals, to alleviate the negative impacts of boredom and potentially break the identified feedback loop.

Diurnal cortisol profiles in autistic adolescents and young adults: Associations with social difficulties and internalizing mental health symptoms.

Several autism-related characteristics, such as social difficulties, may contribute to high perceived stress and increased exposure to stressful life events in some autistic individuals. Repeated exposure to stress might lead to the dysfunction of the hypothalamic-pituitary-adrenocortical-axis and be a vulnerability factor for developing mental health difficulties. Previous studies show contradictory findings on salivary cortisol in autism. In the current study, we investigated diurnal cortisol profiles in autistic adolescents and young adults, as well as their associations with social difficulties, stress exposure, and mental health symptoms. Autistic (n = 48, Mage = 17.6) and nonautistic (n = 51, Mage = 18.4) participants collected salivary cortisol at home six times a day for 2 days. Social difficulties, exposure to stressful life events/bullying, and mental health symptoms were assessed with questionnaires and clinical interviews. Similar diurnal cortisol slopes (DCS) and cortisol awakening responses were observed between the groups, but autistic participants showed higher total cortisol output (AUCG, area under the curve with respect to ground) during the day (b = 19.09, p = 0.009). In the autistic group, more severe social difficulties were associated with flatter DCS (b = 0.01, p = 0.007). Finally, cortisol alterations were associated with self-reported mental health symptoms, especially in autistic females in analyses uncorrected for multiple comparisons. In conclusion, our results do not indicate autism-related group-level alterations in most diurnal cortisol measures, but autistic youth showed higher total cortisol (AUCG) compared with nonautistic peers. More detailed investigation of interindividual variability in cortisol profiles within autistic people might give us important insights into vulnerability to developing stress-related mental health difficulties.