Hypothalamic-pituitary-adrenal Axis Function Research Articles

Hypothalamic-pituitary-adrenal axis responsivity during adolescence in relation to psychopathic personality traits later in life

Psychopathic personality traits have been linked to low physiological arousal, particularly among high risk and forensic samples. A core indicator of physiological arousal is the activity of the hypothalamic-pituitary-adrenal (HPA) axis; however, findings of a link between HPA axis functioning and psychopathic personality traits have been inconsistent. Furthermore, given sex differences in both HPA axis responsivity and psychopathic personality traits, the association may be expected to differ between men and women. The aim of this study was to investigate the association between HPA axis responsivity in mid-adolescence and psychopathic personality traits in early adulthood and determine whether the association was moderated by sex. We examined this link in a general population sample of twins (N = 556). Adolescents participated in a psychosocial stress task during which samples of salivary cortisol were collected (11–15 years) and reported psychopathic personality traits using the Triarchic Psychopathy Measure (19–20 years). Multilevel linear regression models were estimated in which psychopathic personality traits (boldness, meanness and disinhibition), and their interactions with sex, were regressed on HPA axis responsivity. The study was pre-registered on the Open Science Framework (osf.io/gs2a8). Preliminary analyses showed that cortisol levels did not increase significantly during the stressor task but decreased during recovery. Results showed that there was no association between HPA axis responsivity in mid-adolescence and psychopathic personality traits in early adulthood. The associations were not moderated by sex. Findings suggest that HPA axis responsivity in mid-adolescence did not serve as a biological marker for psychopathic personality traits among young adults from the general population.

The Mood, Mother and Child Study: Protocol for a Prospective Longitudinal Study and Randomized Controlled Trial.

Perinatal depression affects >400,000 mother-child dyads in the United States every year and is associated with numerous adverse maternal and child developmental outcomes. Previous research implicates the dysregulation of oxytocin and the hypothalamic-pituitary-adrenal (HPA) axis functioning in mothers and children as potential mechanisms mediating or moderating the transmission of risk associated with maternal depression. The Mood, Mother and Child study will examine the psychobiological sources of risk and resilience within mother-child dyads affected by maternal depression. This manuscript describes (1) the study rationale and aims, (2) the research design and procedures and how they were altered in response to the COVID-19 pandemic, and (3) the data analysis plan to test the study hypotheses. This is a prospective longitudinal study with an embedded randomized controlled trial that examines (1) correlations among postpartum depression and anxiety symptoms, maternal and child oxytocin and HPA axis functioning, and child developmental outcomes and (2) the causal relationship between exogenous oxytocin and HPA reactivity. This study is funded by the National Institute of Child Health and Human Development with institutional review board approval. Recruitment and data collection have commenced, and the expected results will be available in 2024. Analyses are presented for testing the proposed hypotheses. The unique combination of a prospective longitudinal research design with an embedded randomized controlled trial will allow the Mood, Mother and Child study to apply a developmental lens to the study of maternal depression and anxiety symptoms from birth to middle childhood and the psychobiological mechanisms promoting risk and resiliency for both mother and child outcomes. This will be the first study that simultaneously evaluates (1) the role of oxytocin using multiple methodologies, (2) the causal relationships between exogenous oxytocin and HPA axis functioning among mothers with differing levels of depression and anxiety symptoms, and (3) the multiple mediating and moderating roles of parenting behaviors and maternal and child psychobiological characteristics. The goals of these aims are to provide insights into the psychobiological effects of oxytocin in women and inform future clinical trials to treat perinatal mood disorders. ClinicalTrials.gov NCT03593473; https://classic.clinicaltrials.gov/ct2/show/NCT03593473. DERR1-10.2196/51132.

Changes in hypothalamic–pituitary–adrenal axis function, immunity, and glucose during acute Plasmodium relictum infection in house sparrows (Passer domesticus)

Hosts of the same species vary in physiological responses to the same parasite, and some groups of individuals can disproportionately affect disease dynamics; however, the underlying pathophysiology of host-parasite interactions is poorly understood in wildlife. We tested the hypothesis that the hypothalamic–pituitary–adrenal (HPA) axis mediates host resistance and tolerance to avian malaria during the acute phase of infection by evaluating whether individual variation in circulating glucocorticoids predicted resistance to avian malaria in a songbird. We experimentally inoculated wild-caught house sparrows (Passer domesticus) with naturally sourced Plasmodium relictum and quantified baseline and restraint-induced circulating corticosterone, negative feedback ability, cellular and humoral immune function, and baseline and restraint-induced glycemia, prior to and during acute malaria infection. During peak parasitemia, we also evaluated the expression of several liver cytokines that are established pathological hallmarks of malaria in mammals: two pro-inflammatory (IFN-γ and TNF-α) and two anti-inflammatory (IL-10 and TGF-β). Although most of the host metrics we evaluated were not correlated with host resistance or tolerance to avian malaria, this experiment revealed novel relationships between malarial parasites and the avian immune system that further our understanding of the pathology of malaria infection in birds. Specifically, we found that: (1) TNF-α liver expression was positively correlated with parasitemia; (2) sparrows exhibited an anti-inflammatory profile during malaria infection; and (3) IFN-γ and circulating glucose were associated with several immune parameters, but only in infected sparrows. We also found that, during the acute phase of infection, sparrows increased the strength of corticosterone negative feedback at the level of the pituitary. In the context of our results, we discuss future methodological considerations and aspects of host physiology that may confer resistance to avian malaria, which can help inform conservation and rehabilitation strategies for avifauna at risk.

The Influence of Light Wavelength on Human HPA Axis Rhythms: A Systematic Review.

Environmental light entrains many physiological and behavioural processes to the 24 h solar cycle. Such light-driven circadian rhythms are centrally controlled by the suprachiasmatic nucleus (SCN), which receives information from the short-wavelength-sensitive intrinsically photosensitive retinal ganglion cells. The SCN synchronizes local clocks throughout the body affecting sleep/wake routines and the secretion of neuroendocrine-linked hormones such as melatonin from the pineal gland and cortisol via the hypothalamic pituitary adrenal (HPA) axis. Although the effects of light parameters on melatonin have been recently reviewed, whether the experimental variation of the spectral power distribution and intensity of light can induce changes in cortisol rhythms remains unclear. Thus, this systematic review evaluated the effects of daytime exposure to lights of different spectral wavelength characteristics and luminance intensity on the cortisol levels in healthy individuals. A search of the PubMed, Web of Science, EMBASE, CINAHL, Medline, PsycINFO and Cochrane Library databases on 19 June 2023 identified 3418 articles, of which 12 studies (profiling 337 participants) met the inclusion and risk of bias criteria. An analysis of the literature indicated that exposure to bright lights of any colour during the late night or early morning can induce significant increases in cortisol secretion relative to time-matched dim light comparison conditions. Furthermore, exposure to bright lights with stronger short-wavelength (blue/green) components in the early morning typically induced greater increases in cortisol relative to lights with stronger long-wavelength (red) components. Thus, the circadian regulation of cortisol is sensitive to the wavelength composition of environmental lighting, in line with the more commonly studied melatonin. As such, wavelength characteristics should be optimized and reported in light intervention studies (particularly for the investigation of cortisol-associated disorders and HPA axis function), and exposure to short-wavelength light during sensitive periods should be carefully considered in constructed environments (e.g., bedroom and classroom lighting and device screens).

Sex-dependent association of DNA methylation of HPA axis-related gene FKBP5 with obsessive-compulsive disorder

AimsAlthough hypothalamic-pituitary-adrenal (HPA) axis dysregulation in obsessive-compulsive disorder (OCD) has been reported, epigenetic changes in HPA axis-related genes have not been well studied in OCD. The present study investigated whether the epigenetic regulation of FK506-binding protein 51 gene (FKBP5) intron 7 is associated with OCD status in each sex. In addition, relationships among the DNA methylation levels of FKBP5 intron 7, OCD status and early-life trauma were explored. MethodsA total of 267 patients with OCD and 201 controls aged between 18 and 40 years were recruited. Demographic and clinical assessment, FKBP5 rs1360780 genotyping, and pyrosequencing of FKBP5 intron 7 were conducted. DNA was extracted from peripheral blood leucocytes. First, multivariate analysis of covariance for differential DNA methylation levels between OCD patients and controls was conducted with adjustment for FKBP5 rs1360780 genotype, early-life trauma, depressive symptoms, and age as covariates in each sex. Next, path analysis was conducted to determine the mediation effects of DNA methylation levels of FKBP5 between early-life trauma and OCD status. In addition, sensitivity analyses for medication and lifetime major depression were also performed. ResultsDNA methylation at the FKBP5 intron 7 CpG site was significantly lower in men with OCD, compared to controls (mean difference −1.33%, 95% CI −2.11 to −0.55, p < 0.001). The results remained significant for drug naïve or free subjects (mean difference −1.27%, 95% CI −2.18 to −0.37, p = 0.006, in men) and for subjects without lifetime major depressive disorder (mean difference −1.60%, 95% CI −2.54 to −0.66, p < 0.001, in men). The mediation effect of DNA methylation levels was not significant between early-life trauma and OCD status. ConclusionThese findings suggest that epigenetic factors of HPA axis-related gene FKBP5 may play a role in the pathogenesis of OCD. Further studies are needed to determine how altered DNA methylation of FKBP5 intron 7 and HPA axis function are involved in OCD.

Acute effects of mifepristone on emotional processing related brain activity: A functional MRI study

The Hypothalamic-pituitary-adrenal (HPA) axis plays an important role in the pathophysiology of mood disorders, and preliminary data suggests that glucocorticoid receptor (GR) antagonism may be an important therapeutic mechanism. The effects of modulating HPA axis function on emotional processing related brain activity, which may be abnormal in depressed mood, is poorly understood. This study used a pharmacological functional magnetic resonance imaging (fMRI) design to determine the effects of the GR and progesterone receptor antagonist mifepristone on emotional faces processing task related brain activations in 19 right-handed healthy male participants. Each participant received 600 mg mifepristone or placebo on two separate imaging days and then performed an emotional processing fMRI task four hours later. The effect of mifepristone on task related brain activations was determined using Region-of-Interest (ROI) analyses and an exploratory whole brain voxel-wise analyses. No significant changes were observed in the defined ROIs (amygdala, anterior cingulate cortex, insula) or in the exploratory whole brain analyses that was associated with mifepristone administration in either the angry vs happy faces or angry and happy faces vs implicit baseline contrasts. Task reaction times and accuracy were similar in both mifepristone and placebo conditions (all p > 0.05). Our study failed to show significant evidence of modulation of emotional processing related brain activity associated with acute mifepristone administration. Future research should use fMRI to investigate the longer-term administration effects of mifepristone on mood in healthy participants and people with mood disorders to provide a deeper understanding of the potential effects on depressive symptoms.

Parent-Child Separation and Diurnal Cortisol Rhythms Among Left-Behind Adolescents: The Moderating Role of Sex.

Prior research examining parent-child separation and the hypothalamic-pituitary-adrenal (HPA) axis functioning has primarily focused on separation due to parental divorce or loss or forced migration. Less clear is the impact of parental economic migration on adolescents' HPA axis functioning. The present study fills this gap by examining diurnal cortisol patterns among left-behind adolescents who experienced separation from their migrant parents. Participants were 293 Chinese adolescents (33.4% girls, 66.21% left-behind adolescents; Mage = 10.80 years old, SD = 0.82 years). Two-level multilevel modeling was conducted to examine the associations between parent-child separation experiences and diurnal cortisol patterns. Although no significant differences were found between left-behind adolescents and their non-left-behind peers, results revealed that left-behind adolescents who experienced parent-child separation at earlier ages had more blunted diurnal cortisol slopes (usually signaling poorer mental and physical health), compared to their counterparts who experienced separation at older ages. Left-behind adolescent girls who had more adverse separation experiences exhibited smaller waking cortisol and blunted diurnal slopes; these findings were not observed among left-behind adolescent boys. Observing the association between timing of parent-child separation and adolescents' diurnal cortisol and the moderating effects of child sex, this study contributes uniquely to the developmental science of left-behind adolescents' physiological health.

The pharmacological effects and safety of the raw and prepared folium of Epimedium brevicornu Maxim. on improving kidney-yang deficiency syndrome and sexual dysfunction.

Background: Kidney-Yang deficiency syndrome (KDS) is a group of diseases related to hypothalamic-pituitary-adrenal (HPA) axis and sexual dysfunction. The folium of Epimedium brevicornu Maxim. (FEB) includes raw and prepared slices, named RFEB and PFEB, respectively. PFEB is traditionally believed to be good for tonifying kidney-Yang and improving sexual dysfunction. However, there are few studies comparing the pharmacological effects of RFEB and PFEB, and their underlying mechanisms. In this study, we aimed to compare the effects and safety of RFEB and PFEB on the HPA axis and sexual function. Additionally, the mechanisms of their roles in relation to the neuroendocrine-immune (NEI) network in the KDS model mice were explored. Methods: Male adult C57BL/6 mice were treated with corticosterone to establish a KDS mouse model, and RFEB and PFEB were administered intragastrically. Corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), testosterone levels and oxidative damage indexes were measured. The mRNA and protein levels of CRH and ACTH in hypothalamus and pituitary, endothelial nitric oxide synthase (eNOS) and phosphodiesterase 5 (PDE5) in corpus cavernosum were examined. TNFα, IL-6, NF-κB, eNOS and PDE5 were investigated in mouse corpus cavernosum. Results: Our results showed that PFEB was more effective than RFEB in increasing corticosterone-suppressed ACTH levels, enhancing CRH levels and cAMP/cGMP ratio, and reducing oxidative damage. In vivo, PFEB significantly increased eNOS and inhibited PDE5 expression in corpus cavernosum. PFEB showed stronger protective effect on normal spleen lymphocytes from apoptosis both in vitro and in vivo. Additionally, it noticeably inhibited the levels of inflammatory cytokines in corpus cavernosum. Both RFEB and PFEB were safe and did not cause any clinical signs of toxicity in mice at the dosage of 20 times dosages of that in the Chinese Pharmacopeia. Conclusion: We demonstrated that PFEB was better than RFEB at tonifying the kidney-Yang by comparing their effects on improving the NEI network, which includes the HPA axis, immune system and corpus cavernosum. This study revealed that PFEB could significantly improve the sexual function of KDS mice by regulating the HPA axis and activating the immune system through the NEI network.

The effects of pre-hatch elevated corticosterone and post-hatch restrictive food availability on the HPA axis development of mallard ducks (Anas platyrhynchos)

Environmental changes can be stressors (altered habitat and food supply, climate change, etc.) to wild animals. Stressors trigger the hypothalamic pituitary adrenal (HPA) axis to release corticosterone (CORT) which modifies energy homeostasis. During nesting, stressed females can deposit increased concentrations of CORT into eggs, altering egg viability and offspring characteristics, constituting a significant mechanism regulating population productivity in subsequent generations. In this study, increased maternal disposition of CORT was mimicked through a 15 ng/g in ovo injection of CORT into mallard duck eggs. Growth and HPA axis function were measured during post-hatch development. For growth, changes in mass were compared at hatch, 7 weeks and 11 weeks. The HPA axis was assessed at seven weeks by measuring CORT at baseline, followed by restraint stress, dexamethasone (negative feedback) and ACTH (maximal adrenal capacity) challenges. At eleven weeks of age, ducks were subjected to a 6-day 25% feed reduction to simulate a poor quality environment to evaluate response to a chronic stressor by comparing CORT at baseline and after restraint stress. Growth and CORT concentration did not differ between treatments at seven weeks or after feed restriction (11 weeks). The CORT dosage administered did not appear to affect HPA axis development in ducklings. Mallards are a highly adaptable species and may have overcome any early alterations to their phenotype. Further research is needed to determine the effects of increased maternal CORT on growth and the development of the HPA axis in ducks. Summary statementThis study examines how maternal stress (simulated through elevated corticosterone in ovo) and post-hatch chronic stressors (food restriction) affect the development of the HPA axis in a precocial bird.

Systemic Corticosteroids for Treating Respiratory Diseases: Less Is Better, but… When and How Is It Possible in Real Life?

Systemic corticosteroids (CSs), a keystone in pulmonology, are drugs with strong antiinflammatory activity. They are cheap, easily available, and accessible, but with common and serious side effects. Moreover, the use of exogenous CSs may suppress the hypothalamic-pituitary-adrenal (HPA) axis, predisposing to adrenal insufficiency. Safe CS treatment is a challenge of pharmacological research. This narrative review examined the indications of CSs in some respiratory diseases, analyzing what types, dosages, and length of treatment are required as the dosage and duration of CS treatments need to be minimized. Chronic maintenance treatments with CSs are associated with poor prognosis, but they are still prescribed in patients with severe asthma, Chronic obstructive pulmonary disease (COPD), and interstitial lung diseases. When CS discontinuation is not possible, all efforts should be made to achieve clinically meaningful reductions. Guidelines suggest the use of methylprednisolone at a dose of 20-40mg/day or equivalent for up to 10days in subjects with COVID-19 pneumonia (but not other respiratory viral diseases) and respiratory failure, exacerbations of asthma, and COPD. Some guidelines suggest that CS treatment shorter than 10-14days can be abruptly stopped, strictly monitoring subjects with unexplained symptoms after CS withdrawal, who should promptly be tested for adrenal insufficiency (AI) and eventually treated. CSs are often used in severe community-acquired pneumonia associated with markedly increased serum inflammation markers, in acute respiratory distress syndrome (ARDS), in septic shock unresponsive to hydro-saline replenishment and vasopressors, and acute exacerbations of interstitial lung diseases. As these cases often require higher doses and longer duration of CS treatment, CS tapering should be gradual and, when useful, supported by an evaluation of HPA axis function.

Latent Trait Cortisol: Considering the Interplay of Adversity and Cultural Resilience Factors in Latino Adolescents

Latent trait cortisol (LTC) has been established across multiple samples as a stable person-level indicator of hypothalamic pituitary adrenal (HPA) axis functioning. However, extant research among predominantly White samples linking early life adversity to LTC has produced inconsistent findings, likely due to methodological and demographic differences. Using a cultural neurobiological framework, this study examined whether cultural resilience factors (ethnic racial identity [ERI], bicultural competence) may promote healthier LTC levels and protect against the deleterious effects of exposure to early adversity among Latino adolescents. Salivary cortisol was collected five times a day across three weekdays in a sample of 206 Latino high school seniors (Mage=18.1; 64.4% female). Self-reported questionnaires assessing demographics, health behaviors, adverse experiences, ERI, and bicultural competence (i.e., comfort and facility subscales) were also collected. Confirmatory factor analysis identified an adequate theory-driven model of LTC using waking and 30-minute post-waking samples and estimating within-day sample covariation. Structural equation modeling revealed that greater early adversity predicted lower LTC (b=-.11, p=.01). ERI demonstrated neither promotive nor protective effects. Bicultural facility predicted greater LTC (b=.39, p=.004) but did not moderate the association between adversity and LTC. Consistent with hypo-arousal theories, early adversity contributed to reduced LTC among Latino adolescents, whereas the ease with which youth navigate host and heritage culture demands (i.e., bicultural facility) promoted robust HPA axis functioning. Burgeoning literature establishing LTC as a stable cortisol construct should continue to be contextualized by known risk factors as well as culturally salient processes.

Perceived discrimination and stress response profiles among Mexican-origin Adolescents

The hypothalamic-pituitary-adrenal (HPA) axis is one of the major stress response systems in the human body and it is sensitive to social evaluative stress. The functioning of HPA axis is commonly measured with cortisol. Research on cortisol has focused on cortisol reactivity and its diurnal rhythm using salivary cortisol to inform short-term stress responses. Cortisol can also be measured through hair, which tracks individuals’ cumulative stress response. To more comprehensively understand cortisol levels and responses to stress, this study used a person-centered approach to examine stress response profiles based on individuals’ cortisol reactivity, diurnal cortisol rhythms, and hair cortisol concentration. Participants were 290 Mexican-origin adolescents (Mage = 17.38; 52% female). Latent profile analysis was used to characterize stress response profiles identified using three daily salivary samples across four days, seven saliva samples throughout the Trier Social Stress Test, and hair cortisol. The resulting profiles were examined in relation to discrimination and covariates. Analyses identified two stress response profiles. Most of the participants (88%) were in the “lower” profile (blunted diurnal cortisol rhythm and lower pattern of cortisol reactivity) and the remainder were in the “higher” profile (elevated diurnal cortisol rhythm and increased pattern of cortisol reactivity). Adolescents in the “lower” group reported more discrimination than those in the “higher” group. Findings of the study demonstrate the first attempt to integrate different aspects of stress responses in the HPA axis. Results also highlight the blunting effects of discrimination on Mexican-origin adolescents’ basal cortisol and responses to stress.

Differential effect of panic on the DNA methylation of the glucocorticoid receptor gene exon 1F in chronic subjective tinnitus with distress.

Tinnitus can be regarded as a chronic stressor, leading to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. There is important comorbidity with anxiety, particularly panic, potentially associated with differences in HPA axis functioning and methylation patterns of HPA axis-related genes. This study examines DNA methylation of the glucocorticoid receptor gene ( NR3C1 ) exon 1F in adults with chronic subjective tinnitus and the possible differential effect of panic. In a well characterized tinnitus sample ( n = 22, half of which had co-occurring panic attacks), and unaffected controls ( n = 31) methylation patterns of the CpG sites were determined using pyrosequencing and compared between groups through linear mixed models. Gene expression was determined using quantitative PCR on mRNA. Comparing the combined tinnitus groups to the control group, no DNA methylation differences were observed; however, the tinnitus group with panic attacks showed consistently higher mean methylation values across all CpGs compared to the tinnitus-only and the control group ( P = 0.03 following Tukey correction), which became even more pronounced when accounting for childhood trauma ( P = 0.012). Moreover, a significant positive correlation was found between methylation of the CpG7 site and the Beck Anxiety Inventory total score ( P = 0.001) in the total population. NR3C1 -1F expression was not significantly different between the three groups. Panic is associated with higher DNA methylation of the NR3C1 exon 1F in adults with chronic subjective tinnitus, consistent with the reduced negative glucocorticoid feedback and HPA axis hyperfunction observed in individuals with panic disorder.

Unpredictable fasting transiently alters corticosterone and feeding behavior but not body mass or later HPA axis function in zebra finches (Taeniopygia guttata)

The hypothalamic-pituitary-adrenal (HPA) axis is commonly activated in response to unpredictable conditions, including unstable or inadequate food supply. Extended exposure to unpredictable food resources can alter HPA axis function, with the potential for negative fitness consequences. We addressed the interrelationships of unpredictable food resources, HPA axis activity, and food intake in adult and juvenile zebra finches (Taeniopygia guttata). Finches exposed to prolonged periods of unpredictable food elevate corticosterone (the primary avian glucocorticoid) when food is unavailable; however, whether they experience chronic elevation in baseline corticosterone during periods of unpredictability, even when food is available, is unclear. We subjected adults and juveniles to an extended period of temporally unpredictable food (consisting of a random daily fast) or predictable food supply. We investigated baseline corticosterone under fed conditions and in response to an acute fast (mimicking the daily fasting periods in the unpredictable treatment), and assessed differences in body mass, food intake, and corticosterone responses to restraint. Regardless of sex and age, individuals in both treatment groups elevated corticosterone when fasted, and baseline corticosterone under fed conditions was indistinguishable between groups. Thus, corticosterone levels were not persistently elevated in the unpredictably fed group. Treatment groups did not differ in body mass or corticosterone responses to restraint, but unpredictably fed birds consumed food more rapidly when food was available. Our findings suggest that the unpredictably fed birds experienced repeated, moderate elevations in corticosterone. Such elevations may aid birds in coping with unpredictable food sources, in part by activating compensatory changes in foraging behavior.

Targeting the Arginine Vasopressin V1b Receptor System and Stress Response in Depression and Other Neuropsychiatric Disorders.

A healthy stress response is critical for good mental and overall health and promotes neuronal growth and adaptation, but the intricately balanced biological mechanisms that facilitate a stress response can also result in predisposition to disease when that equilibrium is disrupted. The hypothalamic-pituitary-adrenal (HPA) axis neuroendocrine system plays a critical role in the body's response and adaptation to stress, and vasopressinergic regulation of the HPA axis is critical to maintaining system responsiveness during chronic stress. However, exposure to repeated or excessive physical or emotional stress or trauma can shift the body's stress response equilibrium to a "new normal" underpinned by enduring changes in HPA axis function. Exposure to early life stress due to adverse childhood experiences can also lead to lasting neurobiological changes, including in HPA axis function. HPA axis impairment in patients with depression is considered among the most reliable findings in biological psychiatry, and chronic stress has been shown to play a major role in the pathogenesis and onset of depression and other neuropsychiatric disorders. Modulating HPA axis activity, for example via targeted antagonism of the vasopressin V1b receptor, is a promising approach for patients with depression and other neuropsychiatric disorders associated with HPA axis impairment. Despite favorable preclinical indications in animal models, demonstration of clinical efficacy for the treatment of depressive disorders by targeting HPA axis dysfunction has been challenging, possibly due to the heterogeneity and syndromal nature of depressive disorders. Measures of HPA axis function, such as elevated cortisol levels, may be useful biomarkers for identifying patients who may benefit from treatments that modulate HPA axis activity. Utilizing clinical biomarkers to identify subsets of patients with impaired HPA axis function who may benefit is a promising next step in fine-tuning HPA axis activity via targeted antagonism of the V1b receptor.

High-Fat Diet Exacerbates Stress Responsivity in Juvenile Traumatic Brain Injury.

Abstract Traumatic brain injury (TBI) is one of the leading causes of death for children in the United States. Juveniles are more likely to sustain TBIs than most other age groups, and TBI has been shown to result in increased anxiety and stress behaviors. In addition, the hypothalamic-pituitary-adrenal (HPA) axis has previously been shown to become dysregulated after a TBI. Further, many children consume diets high in saturated fats and refined sugars, which are also connected to alterations in HPA axis function and behavior disorders. The goal of the current study was to identify a potential relationship between high-fat diet (HFD) consumption and TBI on HPA axis function in juvenile rats. In the present study, male juvenile Long-Evans rats were fed either a combination of an HFD with a high-fructose corn syrup solution or a standard chow diet. On post-natal Day 30, subjects sustained either a sham TBI or a TBI via the Closed-Head Injury Model of Engineered Rotational Acceleration (CHIMERA). Subjects participated in a trial of the open field test (OFT) following injury. In addition, some rats performed in an acute restraint stress test. All subjects were euthanized 7 days post-injury. Brain and blood plasma samples were collected for use in real-time polymerase chain reaction (RT-PCR), immunohistochemistry, and corticosterone or adrenocorticotropic hormone (ACTH) assays. Immediately following TBI, injured juveniles had increased time to righting and walking, with HFD-fed TBI rats having increased time to walking over Chow-fed TBI rats. HFD-fed TBI rats had a reduced number of entries to the center of the OFT, in addition to reduced time spent in the center compared with HFD Sham controls and Chow TBI rats. During the acute restraint stress test, HFD-fed TBI rats had elevated pre-stress ACTH and corticosterone and post-stress ACTH levels. Pre-stress ACTH levels were significantly elevated in HFD TBI compared with Chow TBI. Further, pre-stress ACTH:corticosterone ratios were elevated in HFD TBI compared with Chow TBI. cFos immunoreactivity in the paraventricular nucleus (PVN) of the hypothalamus following the acute restraint stress test was elevated in HFD-fed TBI rats. HFD TBI rats had greater activation of cFos in the PVN compared with Chow TBI. In addition, RT-PCR showed significantly reduced expression of relevant HPA axis genes, NR3C1, NR3C2, and CRHR2, in the hypothalamus of TBI subjects compared with Sham subjects. Further, AVP and CRHR2 in the hypothalamus were significantly reduced in HFD TBI compared with Chow TBI. These results offer evidence that TBI paired with high-fat diet consumption can cause HPA axis dysfunction, resulting in more anxiety-like behaviors.

Understanding the relationships between physiological and psychosocial stress, cortisol and cognition.

Stress is viewed as a state of real or perceived threat to homeostasis, the management of which involves the endocrine, nervous, and immune systems. These systems work independently and interactively as part of the stress response. The scientific stress literature, which spans both animal and human studies, contains heterogeneous findings about the effects of stress on the brain and the body. This review seeks to summarise and integrate literature on the relationships between these systems, examining particularly the roles of physiological and psychosocial stress, the stress hormone cortisol, as controlled by the hypothalamic-pituitary-adrenal (HPA) axis, and the effects of stress on cognitive functioning. Health conditions related to impaired HPA axis functioning and their associated neuropsychiatric symptoms will also be considered. Lastly, this review will provide suggestions of clinical applicability for endocrinologists who are uniquely placed to measure outcomes related to endocrine, nervous and immune system functioning and identify areas of intervention.

Effectiveness of mindfulness training on pregnancy stress and the hypothalamic-pituitary-adrenal axis in women in China: A multicenter randomized controlled trial.

In the past two decades, mindfulness-based intervention programs have gradually become popular.Many studies have confirmed that these programs can effectively alleviate prenatal stress and negative emotion.The mindfulness-based stress-buffering hypothesis suggests that mindfulness training can induce changes in the levels of the cortisol secreted by the HPA axis, thereby reducing stress susceptibility. However, to date, only a few high-quality evidence-based medical studies have analyzed the effect of the mindfulness-based intervention in a maternal population.Thus, this study investigated the effects of a mindfulness-based psychosomatic intervention on pregnancy stress and the HYPERLINK "javascript:;" hypothalamic-pituitary-adrenal (HPA) axis of pregnant Chinese women. Women experiencing first-time pregnancy (n = 117) were randomly allocated to the intervention group or parallel active control group, and data were collected at baseline and post-intervention periods. The participants completed questionnaires regarding mindfulness and pregnancy stress. Saliva samples was collected at the time of waking up, and 30, 45, and 60 min after waking up for analyzing the salivary cortisol levels. We analyzed differences between the two groups and changes within the same group before and after the intervention. A total of 95 participants completed the trial. Compared with the parallel active control group, the intervention group exhibited lower levels of stress after the intervention (P = 0.047). For HPA-axis-related indicators after the intervention, Delta value (P = 0.01) and AUCM value (P = 0.031) of the intervention group were significantly higher than that of the control group. Mindfulness-based interventions effectively reduced the level of pregnancy stress and adjusted the HPA axis function in pregnant women in China. https://www.chictr.org.cn, identifier ChiCTR 2000033149.

Estradiol regulates voltage-gated potassium currents in corticotropin-releasing hormone neurons.

Corticotropin-releasing hormone (CRH) neurons are the primary neural population controlling the hypothalamic-pituitary-adrenal (HPA) axis and the secretion of adrenal stress hormones. Previous work has demonstrated that stress hormone secretion can be regulated by circulating levels of estradiol. However, the effect of estradiol on CRH neuron excitability is less clear. Here, we show that chronic estradiol replacement following ovariectomy increases two types of potassium channel currents in CRH neurons: fast inactivating voltage-gated A-type K+ channel currents (IA) and non-inactivating M-type K+ channel currents (IM). Despite the increase in K+ currents following estradiol replacement, there was no overall change in CRH neuron spiking excitability assessed with either frequency-current curves or current ramps. Together, these data reveal a complex picture whereby ovariectomy and estradiol replacement differentially modulate distinct aspects of CRH neuron and HPA axis function.

Maternal separation and TNBS-induced gut inflammation synergistically alter the sexually differentiated stress response in rats

BackgroundNeonatal maternal separation (MS) has been used to model long-lasting changes in behavior caused by neuroplastic changes associated with exposure to early-life stress. Earlier studies showed that transient gut inflammation can influence the development of irritable bowel syndrome (IBS). A prevailing paradigm of the etiology of IBS is that transient noxious events lead to long-lasting sensitization of the neural pain circuit, despite complete resolution of the initiating event. This study characterizes the changes in behaviors and neuroendocrine parameters after MS and early-phase trinitrobenzene sulfonic acid (TNBS)-induced colitis. We tested the hypothesis that MS and gut inflammation synergistically induce (1) hyperactivity in male rats and anxiety-like behaviors in female rats and (2) activation of the HPA axis in female rats and deactivation of the HPA axis in male rats after colorectal distention (CRD).MethodsMale and female rat pups were separated from their dams for 180 min daily from postnatal day (PND) 2 to PND 14 (MS). Early-phase colitis was induced by colorectal administration with TNBS on PND 8. The elevated plus-maze test was performed at 7 weeks. Tonic CRD was performed at 60 mmHg for 15 min at 8 weeks. Plasma ACTH and serum corticosterone were measured at baseline or after the CRD. Analysis of variance was performed for comparison among controls, TNBS, MS, and MS + TNBS.ResultsIn male rats, the time spent in open arms significantly differed among the groups (p < 0.005). The time spent in open arms in male MS + TNBS rats was significantly higher than that of controls (p < 0.009) or TNBS rats (p < 0.031, post hoc test). Female rats showed no difference in the time spent in open arms among the groups. MS and gut inflammation induced an increase in plasma ACTH in female rats but not in male rats at baseline.ConclusionsThese findings suggest that MS and gut inflammation synergistically induce hyperactive behavior or exaggerated hypothalamic–pituitary–adrenal axis function depending on sex.