HPA Axis Dysregulation Research Articles

The Stress Axis in Obesity and Diabetes Mellitus: An Update

The hypothalamic–pituitary–adrenal axis is a tightly regulated system that represents one of the body’s mechanisms for responding to acute and chronic stress. Prolonged stress and/or inadequate regulation of the stress system can lead to a condition of chronic hypercortisolism or, in some cases, a blunted cortisol response to stress, contributing to insulin resistance, increased adiposity and type 2 diabetes mellitus. Moreover, acute and chronic stress can exacerbate or worsen metabolic conditions by supporting an inflammatory state and a tight relationship between stress, inflammation and adipose tissue has been reported and has been a growing subject of interest in recent years. We reviewed and summarized the evidence supporting hypothalamic–pituitary–adrenal axis dysregulation as an important biological link between stress, obesity, inflammation and type 2 diabetes mellitus. Furthermore, we emphasized the possible role of infectious-related stress such as SarsCov2 infection in adrenal axis dysregulation, insulin resistance and diabetes in a bidirectional link. Understanding and better defining the links between stress and obesity or diabetes could contribute to further definition of the pathogenesis and the management of stress-related complications, in which the HPA axis dysregulation has a primary role.

Role of NR3C1 and SLC6A4 methylation in the HPA axis regulation in burnout

BackgroundWork-related stress and burnout have become major occupational health concerns. Dysregulation of HPA axis is considered one of the central mechanisms and is potentially moderated through epigenetics. In the present study, we aim to investigate epigenetic regulation of the HPA axis in burnout, by focusing on salivary cortisol and cortisone and DNA methylation of the glucocorticoid receptor gene (NR3C1) and the serotonin transporter gene (SLC6A4). MethodsWe conducted a cross-sectional study with 59 subjects with burnout and 70 healthy controls recruited from the general population. All participants underwent a clinical interview and psychological assessment. Saliva samples were collected at 0, 30 and 60 min after awakening and were used to quantify cortisol and cortisone. Pyrosequencing was performed on whole blood-derived DNA to assess DNA methylation. ResultsThere were no between-group differences in cortisol levels, whereas burnout participants had higher levels of cortisone. Job stress was associated with increased cortisol and cortisone. We observed both increased and decreased NR3C1 and SLC6A4 methylation in the burnout group compared to the control group. Some of these methylation changes correlated with burnout symptoms dimensionally. Increased methylation in a specific CpG in the SLC6A4 promoter region moderated the association between job stress and burnout. DNA methylation in this CpG was also associated with increased cortisol. In addition, average methylation of NR3C1 was negatively associated with cortisone levels. LimitationsThis is a cross-sectional study and therefore no conclusions on causality could be made. ConclusionsWe provide first evidence of changes in DNA methylation of NR3C1 and SLC6A4 in burnout, which were further associated with cortisol and cortisone. Further, increased cortisol and cortisone seemed to reflect job stress rather than burnout itself.

Mediation of perceived stress and cortisol in the association between neuroticism and global cognition in older adults: Alongitudinal study.

Neuroticism has been associated with a greater dementia risk, but its association with cognitive decline in healthy older adults remains unclear. Stress has been proposed as one of the mechanisms that could explain this relationship. Our aim was to analyse, in healthy older people, the mediating role of perceived stress and the Hypothalamic-Pituitary-Adrenal (HPA) axis in the association between neuroticism and global cognition. At Waves 1 and 2 (4-year follow-up), 87 older people (49.4% women; M age=65.08, SD=4.54 at Wave 1) completed a neuropsychological battery and the Perceived Stress Scale (PSS), and provided saliva samples on two (Wave 1) and three (Wave 2) consecutive days to measure the wake-to-bed slope. In Wave 2, neuroticism was assessed with the NEO-Five-Factor Inventory. PSS, but not the wake-to-bed slope, mediated the negative associations between neuroticism and global cognition (Waves 1, 2 and change). Regarding gender differences, PSS (Waves 1, 2 and change) and the wake-to-bed slope (Wave 2 and change) mediated these associations in men. Our results suggest that perceived stress and HPA-axis dysregulation could act as mechanisms underlying the association between neuroticism and cognitive functioning and decline, at least in older men.

3-O-Acetyl-11-keto-β-boswellic acid ameliorates chronic unpredictable mild stress induced HPA axis dysregulation in relation with glutamate/GABA aberration in depressive rats.

Overt expression of brain glucocorticoid receptor (GR) leads to elevation of glutamate release causes cerebral excitotoxicity which in turn produce neuropsychological disorders. The aim of our work is to study the consequence of 3-O-Acetyl-11-keto-β-boswellic acid (AKBA) on chronic unpredictable mild stress (CUMS) induced HPA axis dysregulation in relative to glutamate and GABA irregularity in depressive rats. AKBA (5, 10 &15mg/kg) was administered for 28days parallel with CUMS induction in rats. Behavioural studies, tail suspension test (TST), open field exploratory (OFT) and forced swim test (FST) were performed. Biochemical studies including plasma corticosterone, glutamate GABA and glutamic acid decarboxylase (GAD) enzyme activity were studied. Glucocorticoid receptor expression and brain histology were studied to observe the effect of AKBA. CUMS induction results in depressive state of the animals were confirmed by the sucrose preference test. The administration of AKBA significantly reduced the immobility time and improved the exploratory behaviour. Plasma corticosterone and brain glutamate level was decreased and GABA level were increased significantly evident with GAD activation in AKBA-treated animals, further confirmed with decreased GR expression improves architecture of prefrontal cortex region. Correlation study illustrates behavioural improvements undeviating the biochemical alteration and GR expression after AKBA treatment during depression. AKBA significantly reversed the CUMS-induced glutamate/GABA abnormalities through the adaptation of central HPA axis regulation. Hence this study concludes that AKBA can be a better alternative to treat depressive disorders.

Diurnal Cortisol Rhythm in Female Flight Attendants.

The work of flight attendants is associated with exposure to long-term stress, which may cause increased secretion of cortisol. The aim of the study is to determine the circadian rhythm of cortisol and to seek factors of potential influence on the secretion of cortisol in female flight attendants working within one time zone as well as on long-distance flights. The prospective study covers 103 women aged 23–46. The study group (I) was divided into two subgroups: group Ia, comprising female flight attendants flying within one flight zone, and group Ib, comprising female flight attendants working on long-distance flights. The control group (II) are women of reproductive age who sought medical assistance due to marital infertility in whom the male factor was found to be responsible for problems with conception in the course of the diagnostic process. The assessment included: age, BMI, menstrual cycle regularity, the length of service, the frequency of flying, diurnal profile of the secretion of cortisol, testosterone, estradiol, 17-OH progesterone, SHBG, androstenedione, and progesterone concentration. Descriptive methods and inferential statistics methods were used to compile the data. Comparing the profile of flight attendants from groups Ia and Ib shows that the curve flattened among women flying within one time zone. The secretion curve is also more flattened in women with less years worked and in flight attendants working less than 60 h per month. Due to the character of work, the female flights attendants do not have hypersecretion of cortisol. Frequency of flying and length of work affect the dysregulation of HPA axis.

Indirect effects of HPA axis dysregulation in the association between peer victimization and depressed affect during early adolescence

ObjectivePrevious research has identified a link between peer victimization and depressive symptoms during adolescence. The goal of the current study is to examine the possible indirect effects of HPA axis dysregulation in the link between adolescent peer victimization and depressive symptoms. MethodA total of 113 boys (n = 61) and girls (n = 52) participants from grade 5 (M age = 10.31 years) and grade 6 (M age = 11.33 years) who were predominantly European-Canadian completed self-report measures of peer victimization and depressed affect as well as, measures of salivary cortisol and self-reports of negative experiences collected in conjunction with one another five times per day over the course of four school days. ResultsMulti-level structural equation modeling found that peer victimization was indirectly associated with depressive symptoms via blunted cortisol reactivity (i.e. increases in cortisol in response to a negative event) but only at high rates of chronic peer victimization. ConclusionThe findings suggest that future studies should focus on HPA axis dysregulation for better understand the development, as well as the stability of depression over time and that interventions targeting peer victimization may want to put a special focus on those who are chronically experiencing peer victimization over time.

Merging the Multi-Target Effects of Kleeb Bua Daeng, a Thai Traditional Herbal Formula in Unpredictable Chronic Mild Stress-Induced Depression.

Major depressive disorder (MDD) is a common and debilitating psychiatric disease characterized by persistent low mood, lack of energy, hypoactivity, anhedonia, decreased libido, and impaired cognitive and social functions. However, the multifactorial etiology of MDD remains largely unknown due the complex interaction between genetics and environment involved. Kleeb Bua Daeng (KBD) is a Thai traditional herbal formula that has been used to promote brain health. It consists of a 1:1:1 ratio of the aerial part of Centella asiatica, Piper nigrum fruit, and the petals of Nelumbo nucifera. According to the pharmacological activities of the individual medicinal plants, KBD has good potential as a treatment for MDD. The present study investigated the antidepressant activity of KBD in an unpredictable chronic mild stress (UCMS) mouse model. Daily administration of KBD to UCMS mice ameliorated both anhedonia, by increasing 2% sucrose intake, and hopeless behavior, by reducing immobility times in the forced swimming test (FST) and tail suspension test (TST) without any effect on locomotor activity. The mechanism of KBD activity was multi-modal. KBD promoted neurogenesis by upregulation of brain-derived neurotrophic factor (BDNF) and cyclic AMP-responsive element binding (CREB) mRNA expression in the frontal cortex and hippocampus. Daily treatment with KBD significantly reversed UCMS-induced HPA axis dysregulation by upregulating the glucocorticoid receptor (GR) while downregulating serum- and glucocorticoid-inducible kinase 1 (SGK1) and FK506 binding protein 5 (FKBP5) mRNA expression. KBD treatment also normalized proinflammatory cytokine expression including tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-1β and IL-6. KBD and its component extracts also exhibited an inhibitory effect in vitro on monoamine oxidase (MAO) A and B. The multiple antidepressant actions of KBD emphasize its potential as an effective, novel treatment for MDD.

Maternal precarity and HPA axis functioning shape infant gut microbiota and HPA axis development in humans.

BackgroundEarly life exposure to adverse environments, and maternal stress in particular, has been shown to increase risk for metabolic diseases and neurobehavioral disorders. While many studies have examined the hypothalamic-pituitary-adrenal axis (HPA axis) as the primary mechanism behind these relationships, emerging research on the brain-gut axis suggests that the microbiome may play a role. In this study, we tested the relationships among maternal precarity and HPA axis dysregulation during the peripartum period, infant gut microbiome composition, and infant HPA axis functioning.MethodsData come from 25 mother-infant dyads in the Galápagos, Ecuador. Women completed surveys on precarity measures (food insecurity, low social support, depression, and stress) and gave salivary cortisol samples during and after pregnancy. Infant salivary cortisol and stool were collected in the postpartum. Statistical significance of differences in microbial diversity and relative abundance were assessed with respect to adjusted linear regression models.ResultsMaternal precarity was associated with lower diversity and higher relative abundance of Enterobacteriaceae and Streptococcaceae and a lower relative abundance of Bifidobacterium and Lachnospiraceae. These patterns of colonization for Enterobacteriaceae and Bifidobacterium mirrored those found in infants with HPA axis dysregulation. Maternal HPA axis dysregulation during pregnancy was also associated with a greater relative abundance of Veillonella.ConclusionsOverall, exposures to precarity and HPA axis dysregulation were associated with an increase in groups that include potentially pathogenic bacteria, including Enterobacteriaceae, Streptococcaceae, and Veillonella, and a decrease in potentially protective bacteria, including Bifidobacterium and Lachnospiraceae, as well as a decrease in overall diversity.

Ambient air pollutants are associated with morning serum cortisol in overweight and obese Latino youth in Los Angeles

BackgroundHypothalamic-pituitary-adrenal (HPA)-axis dysfunction has been associated with a variety of mental health and cardio-metabolic disorders. While causal models of HPA-axis dysregulation have been largely focused on either pre-existing health conditions or psychosocial stress factors, recent evidence suggests a possible role for central nervous system activation via air pollutants, such as nitrogen dioxide (NO2), ozone (O3) and particulate matter (PM). Therefore, in an observational study of Latino youth, we investigated if monthly ambient NO2, O3, and PM with aerodynamic diameter ≤ 2.5 (PM2.5) exposure were associated with morning serum cortisol levels.MethodsIn this cross-sectional study, morning serum cortisol level was assessed after a supervised overnight fast in 203 overweight and obese Latino children and adolescents (female/male: 88/115; mean age: 11.1 ± 1.7 years; pre-pubertal/pubertal/post-pubertal: 85/101/17; BMI z-score: 2.1 ± 0.4). Cumulative concentrations of NO2, O3 and PM2.5 were spatially interpolated at the residential addresses based on measurements from community monitors up to 12 months prior to testing. Single and multi-pollutant linear effects models were used to test the cumulative monthly lag effects of NO2, O3, and PM2.5 on morning serum cortisol levels after adjusting for age, sex, seasonality, social position, pubertal status, and body fat percent by DEXA.ResultsSingle and multi-pollutant models showed that higher O3 exposure (derived from maximum 8-h exposure windows) in the prior 1–7 months was associated with higher serum morning cortisol (p < 0.05) and longer term PM2.5 exposure (4–10 months) was associated with lower serum morning cortisol levels (p < 0.05). Stratification by pubertal status showed associations in pre-pubertal children compared to pubertal and post-pubertal children. Single, but not multi-pollutant, models showed that higher NO2 over the 4–10 month exposure period associated with lower morning serum cortisol (p < 0.05).ConclusionsChronic ambient NO2, O3 and PM2.5 differentially associate with HPA-axis dysfunction, a mechanism that may serve as an explanatory pathway in the relationship between ambient air pollution and metabolic health of youth living in polluted urban environments. Further research that uncovers how ambient air pollutants may differentially contribute to HPA-axis dysfunction are warranted.

Maternal stress, placental 11β-hydroxysteroid dehydrogenase type 2, and infant HPA axis development in humans: Psychosocial and physiological pathways

IntroductionPrenatal stress is known to influence fetal hypothalamic-pituitary-adrenal axis (HPA axis) development. Placental 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) is a central gene in this pathway, but little is known about what influences its functioning. We assess how maternal distress influences HSD11B2 functioning, and how HSD11B2 in turn, is associated with infant HPA axis development. MethodsData come from 24 mother-infant dyads on the Galápagos Islands. Using adjusted linear regression models, we assess the effects of maternal psychosocial (stress and depressive symptoms, measured by the Perceived Stress Scale and the Patient Health Questionnaire-8, respectively) and physiological (HPA axis dysregulation) distress during pregnancy on HSD11B2 methylation and expression and then test how these HSD11B2 measures influence infant HPA axis development. ResultsMaternal HPA axis dysregulation during pregnancy is associated with lower placental HSD11B2 expression, which is associated with an exaggerated cortisol reactivity in infants. Sex-specific analyses revealed that maternal depressive symptoms may influence the functioning of placental HSD11B2 differently in girls (n = 11, 46%) than in boys (n = 13, 54%), though the sample size was small. DiscussionThese results support a disrupted adaptive framework, in which the ability to upregulate HSD11B2 expression in response to acute stress diminishes as maternal stress becomes chronic. In this model, chronic stress may exhaust the protective mechanism of HSD11B2, leaving the infant vulnerable to high levels of maternal cortisol, which could injure the fetal HPA axis and disrupt long-term neurobehavioral and metabolic development. While larger studies will be needed to confirm these findings, this study offers exploratory results on the effects of maternal distress on both HSD11B2 methylation and expression and the effect of HSD11B2 on offspring HPA axis development.

Mechanisms of Cardiometabolic Disparities: Stressor Characteristics Linked to HPA-Axis Dysregulation

Diurnal cortisol slopes are stress-sensitive HPA-axis biomarkers implicated in cardiometabolic health outcomes and disparities. This study used two longitudinal cohort studies (CREATE and TRIAD) with harmonized variables to comprehensively examine what types of exposure to stressors are most salient for cortisol dysregulation in later life, and whether the characteristics of stressor exposure accounts for Black-White disparities in cortisol dysregulation (merged sample N=209, 65% male, mean age 61, 17% Black). Black participants reported greater stressor exposure than Whites along some dimensions (e.g., # recent major stressors, appraised severity of lifetime stressors, all p<.02) but comparable exposure in others (e.g., # of lifetime stressors and life domains). Stressor exposure measures that captured psychological components (i.e., appraised severity, psychological distress) and pervasiveness (i.e., # life domains with major stressors) were more closely related to cortisol dysregulation than more objective measures (e.g., # of recent /lifetime stressors). Everyday discrimination was associated with racial disparities.

Pathophysiological implications of neuroinflammation mediated HPA axis dysregulation in the prognosis of cancer and depression

Cancer patients are more likely to develop depressive symptoms and show a poor prognosis compared to the normal healthy individuals. Cancer occurrence and the anticancer treatments result in the pro-inflammatory cytokines-mediated inflammation, which dysregulates the HPA-axis activity that may result in depression-like behaviour. Conversely, depression causes the activation of the HPA-axis that results in the downstream release of endogenous glucocorticoids which may result in depressive signs and symptoms in some cancer patients. Depression may also result in non-adherence to treatment and increased mortality in cancer patients. In this review, we have focused on the role of neuroimmune axis and hyperactive HPA-axis in case of both cancer and depression. Therefore, therapeutics targeting the HPA-axis dysregulation could be effective in ameliorating symptoms of depression in cancer patients.

Increased methylation of NR3C1 and SLC6A4 is associated with blunted cortisol reactivity to stress in major depression

BackgroundEpigenetic changes are considered the main mechanisms behind the interplay of environment and genetic susceptibility in major depressive disorder (MDD). However, studies focusing on epigenetic dysregulation of the HPA axis stress response in MDD are lacking. Our objective was to simultaneously asses DNA methylation of the glucocorticoid receptor gene (NR3C1) and serotonin transporter gene (SLC6A4) and HPA axis response to stress in MDD. MethodsWe recruited 80 depressed inpatients and 58 gender and age matched healthy controls. All participants underwent the Trier Social Stress Test (TSST) and salivary cortisol was repeatedly measured to assess HPA axis reactivity. DNA methylation of the NR3C1 (exon 1 F) and SLC6A4 CpG islands was quantified from whole blood DNA. In the MDD group, clinical assessment was repeated at 8-week follow-up to test the predictive potential of DNA methylation for symptom improvement. ResultsDepressed patients had blunted cortisol reactivity to TSST compared to healthy controls (p = 0.01). In addition, they presented with increased average SLC6A4 (p = 0.003) and NR3C1 methylation (p = 0.03), as well as methylation of two individual NR3C1 CpG loci overlapping with the NGFI-A-binding sites (CpG12 and CpG20). Methylation of one of these two loci (CpG20) predicted lower symptom improvement at the follow-up (p = 0.007). Both, average NR3C1 and SLC6A4 methylation were associated with lower cortisol reactivity in the MDD group and explained about 16% of variability in cortisol response to TSST. ConclusionsWe provide evidence of the role of NR3C1 and SLC6A4 DNA methylation in HPA axis dysregulation in MDD, which needs to be further explored.

Personality and Hypothalamic-Pituitary-Adrenal Axis in Older Men and Women.

Personality has been related to health and mortality risk, which has created interest in the biological pathways that could explain this relationship. Although a dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis has been associated with health outcomes and aging, few studies have explored the association between personality and HPA axis functioning in older adults. In addition, it has been suggested that sex could moderate the relationship between personality and HPA axis functioning. Thus, our aim was to analyze the relationship between the big five personality traits and the diurnal cortisol pattern in older adults, as well as sex differences in this relationship. To do so, 79 older people (40 men and 39 women) from 59 to 81 years old (M = 69.19, SD = 4.60) completed the NEO-Five-Factor Inventory (FFI) to measure neuroticism, conscientiousness, extraversion, openness, and agreeableness. Saliva samples were provided on three consecutive days (awakening; 15, 30, and 45 min post-awakening; and bedtime) in order to analyze the diurnal cortisol pattern and, specifically, two cortisol indexes: the cortisol awakening response (CAR) and the diurnal cortisol slope (DCS). Results showed that neuroticism and conscientiousness moderated the diurnal cortisol pattern. Thus, individuals with higher neuroticism and lower conscientiousness scores showed higher bedtime cortisol levels, suggesting a less healthy diurnal cortisol pattern. Regarding the cortisol indexes, higher neuroticism and lower conscientiousness were related to greater CAR and DCS. Sex moderated the association between extraversion and the DCS. Specifically, higher extraversion was related to a lower DCS only in women. Openness and agreeableness were not related to the diurnal cortisol pattern. In conclusion, our results show that in older adults, neuroticism is a vulnerability factor for HPA axis dysregulation, with possible adverse effects on health. By contrast, conscientiousness, and extraversion only in women, appear to be protective factors of HPA axis functioning, with potential beneficial effects on health.

Self-Critical Perfectionism, Depressive Symptoms, and HPA-Axis Dysregulation: Testing Emotional and Physiological Stress Reactivity

Self-critical perfectionism confers vulnerability for depressive symptoms, but research suggests vulnerability persists after treatment. Dysregulation of physiological stress systems is a potential mechanism for depression vulnerability, and yet it remains under-studied in research on perfectionism, stress, and depression. We aimed to address this gap by testing the influence of self-critical perfectionism, stress generation, and stress reactivity on depressive symptoms and on diurnal cortisol. A sample of undergraduates (N = 127) completed questionnaires and provided samples of salivary cortisol twice daily (morning and evening) over three days. Data were analyzed using path analysis with diurnal cortisol activity modeled using latent growth modeling. People high in self-critical perfectionism showed a greater propensity toward depressive symptoms through stress generation and stress reactivity processes. Although self-critical perfectionism did not directly predict diurnal cortisol, results supported physiological stress reactivity. Specifically, people high in self-critical perfectionism showed increased waking cortisol in high and low stress conditions, whereas people low in this trait showed higher cortisol only in the context of high daily hassles. Results suggest prolonged physiological activity may be an important factor to consider in future research and points toward the development of bio-psycho-social models when understanding how self-critical perfectionism confers vulnerability to depressive symptoms in the context of stress generation and reactivity.

Dysregulation of Hypothalamic-Pituitary-Adrenal Axis Explain the Dynamic Association Between Glucose Fluctuation and Cognitive

Objective—Type 2 diabetes mellitus is a risk factor for cognitive dysfunction. However, the underlying mechanism of cognitive decline in patients with type 2 diabetes mellitus is still elusive. Dysregulation of HPA axis is related to cognitive impairment. The present study aims to calculate explanation of the association between glucose fluctuation and cognitive function by HPA axis in type 2 diabetes mellitus patients. Methods—The mean amplitude of glycemic excursion (MAGE) was analyzed by a continuous glucose monitoring system (CGMS) for 3 days in 330 elderly type 2 diabetes mellitus patients. All the subjects received a set of neuropsychological test battery for cognitive assessment. The diurnal rhythm of cortisol was also analyzed. Linear multivariate regression analysis was performed to explore the relationship between glucose fluctuation, cortisol parameters and cognitive parameters. Results—MAGE was observed to be associated with diurnal cortisol fall but with neither cortisol awakening response (CAR) nor overall mean cortisol levels (t = –2.195, P = 0.030). Linear multivariate regression analysis displayed that MAGE and average diurnal cortisol fall were uniquely associated with some cognitive parameters, such as AVLT trial, FAS, and TMT (P &lt; 0.05). Conclusion—Glucose fluctuation was strongly associated with cognitive impairment in elderly type 2 diabetes mellitus patients. Especially in executive function, attention and processing speed. Dysregulation of HPA axis was probably the cause of cognitive dysfunction in these patients.

Effects of childhood trauma, daily stress, and emotions on daily cortisol levels in individuals vulnerable to suicide.

Suicide is a leading cause of mortality worldwide. Dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity, as measured by cortisol levels, has been identified as 1 potential risk factor. Evidence has indicated that childhood trauma is associated with dysregulated cortisol reactivity to stress in adulthood. The current study investigated for the first time whether childhood trauma and daily stressors and emotions were associated with diurnal cortisol levels over a 7-day study in individuals vulnerable to suicide. One hundred and forty-two participants were categorized according to their suicidal history into 3 groups: suicide attempt, suicidal ideation, or control group. Participants completed questionnaires before commencing a 7-day study. Cortisol samples were provided immediately upon waking, at 15 min, 30 min, 45 min, 3 hr, 6 hr, 9 hr, and 12 hr on 7 consecutive days. Measures of daily stressors, mood, defeat, and entrapment were completed at the end of each day. Participants in the suicide attempt and ideation groups released significantly lower cortisol upon awakening (CAR) and had a tendency toward flatter wake-peak to 12 hr (WP-12) cortisol slopes compared to controls. Childhood trauma was found to be associated with significantly lower CAR and a tendency toward flatter WP-12 cortisol slope. Childhood trauma also had an indirect effect on suicide vulnerability group membership via lower daily CAR levels. Lower CAR was associated with increased suicide ideation at 1 month but not 6 months. Daily stress and emotion measures were not associated with cortisol levels. This is the first 7-day daily diary investigation of naturally fluctuating cortisol levels in individuals vulnerable to suicide. The results indicate that dysregulated HPA axis activity is associated with suicidal ideation and behavior. Childhood trauma appears to be an important distal factor associated with HPA-axis dysregulation. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Pituitary dysmaturation affects psychopathology and neurodevelopment in 22q11.2 Deletion Syndrome

Background22q11.2 Deletion Syndrome (22q11DS) confers strongly increased genetic risk for multiple psychiatric disorders. Similarly to the general population, rates of psychiatric comorbidity suggest that common disease mechanisms are shared across dimensions of psychopathology. Such pleiotropic disease mechanisms remain however currently unknown. We hypothesized that pituitary dysmaturation, indicative of HPA-axis dysregulation, could correlate to reduced tolerance to daily life stressors and reflect pleiotropic risk factor for psychopathology. Moreover HPA-axis dysregulation could affect atypical cortical and hippocampal development previously described in 22q11DS. MethodsPituitary volume, hippocampal volume and cortical thickness measures were obtained from T1-weighted MRI images in a large longitudinal cohort of youth with 22q11DS (115 subjects, 260 scans, age-range = 5.4–31.6) and healthy controls (151 subjects, 280 scans, age-range = 5.1–32.3). We explored effects of pituitary dysmaturation on tolerance to stress, psychopathology and neurodevelopment employing mixed-models linear regression. Associations of pituitary and cortical development were correlated with the expression pattern of glucocorticoid receptor gene NR3C1 obtained from the Allen-Human-Brain-Atlas. ResultsWe observed aberrant pituitary developmental trajectories in 22q11DS, with volumetric reductions emerging by young-adulthood (P = 0.0006). Longitudinal pituitary decline was associated with to reduced tolerance to stress (P = 0.04), higher overall psychopathology (P = 0.0003) and increased risk of psychiatric comorbidity (P = 0.02). Moreover, pituitary decline correlated with blunted growth of the right hippocampus (P = 0.03) and to increased cortical thinning of mostly temporal and orbitofrontal regions mediated by NR3C1 gene expression. ConclusionAtypical pituitary development could reflect progressive extinction of HPAA due to chronic hyper-activation, in agreement with existing biochemical evidence in 22q11DS. HPAA dysregulation could represent and endophenotype that confers pleiotropic vulnerability to psychopathology and atypical neurodevelopment in 22q11DS.

Is AD a Stress-Related Disorder? Focus on the HPA Axis and Its Promising Therapeutic Targets.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that has important health and economic impacts in the elderly. Despite a better understanding of the molecular mechanisms leading to the appearance of major pathological hallmarks (senile plaques and neurofibrillary tangles), effective treatments are still lacking. Sporadic AD forms (98% of all cases) are multifactorial, and a panoply of risk factors have been identified. While the major risk factor is aging, growing evidence suggests that chronic stress or stress-related disorders increase the probability to develop AD. An early dysregulation of the hypothalamic-pituitary-adrenal axis (HPA axis or stress axis) has been observed in patients. The direct consequence of such perturbation is an oversecretion of glucocorticoids (GC) associated with an impairment of its receptors (glucocorticoid receptors, GR). These steroids hormones easily penetrate the brain and act in synergy with excitatory amino acids. An overexposure could be highly toxic in limbic structures (prefrontal cortex and hippocampus) and contribute in the cognitive decline occurring in AD. GC and GR dysregulations seem to be involved in lots of functions disturbed in AD and a vicious cycle appears, where AD induces HPA axis dysregulation, which in turn potentiates the pathology. This review article presents some preclinical and clinical studies focusing on the HPA axis hormones and their receptors to fight AD. Due to its primordial role in the maintenance of homeostasis, the HPA axis appears as a key-actor in the etiology of AD and a prime target to tackle AD by offering multiple angles of action.

Developmental nicotine exposure elicits multigenerational disequilibria in proBDNF proteolysis and glucocorticoid signaling in the frontal cortices, striata, and hippocampi of adolescent mice

Maternal smoking of conventional or vapor cigarettes during pregnancy, a form of developmental nicotine exposure (DNE), enhances the risk of neurodevelopmental disorders such as ADHD, autism, and schizophrenia in children. Modeling the multigenerational effects of smoking during pregnancy and nursing in the first- (F1) and second- (F2) generation adolescent offspring of oral nicotine-treated female C57BL/6J mice, we have previously reported that DNE precipitates intergenerational transmission of nicotine preference, hyperactivity and impulsivity-like behaviors, altered rhythmicity of home cage activity, corticostriatal nicotinic acetylcholine receptor and dopamine transporter dysfunction, and corticostriatal global DNA methylome deficits. In aggregate, these DNE-evoked behavioral, neuropharmacological, and epigenomic anomalies mirror fundamental etiological aspects of neurodevelopmental disorders including ADHD, autism, and schizophrenia. Expanding this line of research, the current study profiled the multigenerational neurotrophic and neuroendocrine consequences of DNE. Results reveal impaired proBDNF proteolysis as indicated by proBDNF-BDNF imbalance, downregulation of the proBDNF processing enzyme furin, atypical glucocorticoid receptor (GR) activity as implied by decreased relative nuclear GR localization, and deficient basal plasma corticosterone (CORT) levels in adolescent DNE offspring and grandoffspring. Collectively, these data recapitulate the BDNF deficits and HPA axis dysregulation characteristic of neurodevelopmental disorders such as ADHD, autism, and schizophrenia as well as the children of maternal smokers. Notably, as BDNF is a quintessential mediator of neurodevelopment, our prior findings of multigenerational DNE-induced behavioral and neuropharmacological abnormalities may stem from neurodevelopmental insults conferred by the proBDNF-BDNF imbalance detected in DNE mice. Similarly, our findings of multigenerational GR hypoactivity may contribute to the increased risk-taking behaviors and aberrant circadian rhythmicity of home cage activity that we previously documented in first- and second-generation DNE mice.