Hypothalamic-pituitary-adrenal Axis Activity Research Articles

The effects of lowering barometric pressure on pain behavior and the stress hormone in mice with neuropathic pain.

Lowering barometric pressure (LP) can exacerbate neuropathic pain. However, animal studies in this field are limited to a few conditions. Furthermore, although sympathetic involvement has been reported as a possible mechanism, whether the sympathetic nervous system is involved in the hypothalamic-pituitary-adrenal (HPA) axis remains unknown. To address these issues, we investigated LP-induced hyperalgesia by focusing on the cumulative effect of LP and measuring plasma corticosterone levels as a marker of HPA axis activation in mice. Mice with chronic constriction injury (CCI) were used in this study. For behavioral tests, two types of LP stimulation were adopted: a single LP at 20 hPa (Single LP) and three consecutive LPs at 20 hPa (3LPs). Twelve mice were used for each protocol. The no-pressure-change protocol was used as the control. The mechanical sensitivity was tested before and after LP stimulation using von Frey filaments (vF). For corticosterone measurements, six CCI and six intact mice were exposed to 3LPs (CCI-3LPs and INT-3LPs), and another six CCI and six intact mice were exposed to the no-pressure-change protocol (CCI-NP and INT-NP). Blood samples were collected immediately after exposure. Plasma corticosterone levels were measured by ELISA. The number of paw elevations by vF before and after LP stimulation did not differ significantly in either the Single LP or the no-pressure-change protocol. For the 3LPs, the number of paw elevations after LP stimulation was significantly greater than before stimulation. Plasma corticosterone levels in the CCI-3LPs were significantly higher than those in CCI-NPs. In intact mice, there was no significant difference in plasma corticosterone levels between the INT-3LPs and INT-NPs. LP has a cumulative effect on neuropathic pain. Hypothalamic-pituitary-adrenal axis activation may have an important relationship with LP-induced pain in mice.

Adolescent social isolation induces sex-specific behavioral and neural alterations.

Adversities associated with isolation during adolescence, including the lack of appropriate emotional and social experiences, can jeopardize the individual development leading to the onset of mental illnesses such as major depressive disorder. Girls have higher rates of depression compared to boys; however, the relative contribution of biological and cultural factors to such a gender-dependent difference remains unclear. To identify the role of biological factors in this distinct susceptibility, we exposed adolescent C57BL/6 male and female mice (n = 12-14) to social isolation and we evaluated their behavioral responses, investigating both emotional and cognitive competencies during adolescence. In addition, we assessed alterations in immune activation and brain plasticity by measuring the expression levels of several pro- and anti-inflammatory cytokines and neural plasticity markers. Finally, we investigated the hormonal stress response by evaluating the hypothalamic-pituitary-adrenal (HPA) axis reactivity. Our findings indicate that adolescent social isolation leads to the development of depressive- and anxiety-like traits, although it impacts distinct behavioral domains with varying degrees in males and females. Both genders exhibited deficiencies in the emotional realm, displaying enhanced anhedonia and anxiety compared to their respective control groups. Moreover, males exhibited cognitive impairments linked to an altered HPA axis activity. Remarkably, social isolation influenced immune activation in both sexes, resulting in decreased pro-inflammatory markers. Overall, these results affirm the significant impact of social experiences during adolescence on neurodevelopment. Notably, our study reveals that both males and females are equally susceptible to the effects of isolation, although sex-specific differences become apparent in the alterations observed at both behavioral and physiological levels.

Fluoxetine treatment reverses chronic stress-induced promotion on Fk506-binding protein 5 expression and multiple effects on glucocorticoid receptor phosphorylation in the paraventricular nucleus of mice

BackgroundFluoxetine is widely used as a first-line antidepressant. However, the molecular mechanisms for its antidepressant effects are still not fully understood. Hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis is a core pathogenic mechanism contributing to depression, and fluoxetine treatment prevents this dysfunction. The glucocorticoid receptor (GR) is a major negative feedback regulator of the HPA axis, while Fk506-binding protein 5 (Fkbp5) is a negative regulator of the GR signaling. Therefore, we examined the effects of fluoxetine on Fkbp5 and the GR signaling in the hypothalamic paraventricular nucleus (PVN) of depressed mice. MethodsMice were exposed to chronic social defeat stress (CSDS), chronic unpredictable mild stress (CUMS), or chronic restraint stress (CRS) with or without fluoxetine treatment (intraperitoneally injected, 20 mg/kg) and examined for changes in depression-like behaviors and HPA axis activity as well as Fkbp5 expression and GR phosphorylation in the PVN. We then examined if adeno-associated virus (AAV)-mediated Fkbp5 overexpression in the PVN affected the antidepressant actions of fluoxetine in mice. ResultsFluoxetine treatment significantly mitigated CSDS-, CUMS-, and CRS-induced depression-like behaviors and HPA axis hyperactivity in mice. Subsequent western blotting analyses showed that fluoxetine treatment fully reversed not only chronic stress-induced upregulation of Fkbp5 and CRH but also chronic stress-induced increase in Ser203 phosphorylation and decrease in Ser211 and Ser234 phosphorylation in GR in the PVN. Moreover, quantitative real-time reverse transcription PCR (qRT-PCR) analyses revealed that the enhanced mRNA levels of Fkbp5 and CRH in PVN neurons of mice subjected to CSDS/CUMS/CRS were also notably reversed by fluoxetine administration. Conversely, Fkbp5 overexpression in the PVN significantly eliminated the antidepressant effects of fluoxetine in mice without affecting their locomotor activity. ConclusionThese results together suggest that fluoxetine treatment reverses chronic stress-induced promotion on Fkbp5 expression and multiple effects on GR phosphorylation in the PVN of mice. Significance statementThe selective serotonin reuptake inhibitor fluoxetine (sold as Prozac) is a widely used treatment for depression, but the full spectrum of therapeutic mechanisms is still debated. Recent evidence suggests that these therapeutic mechanisms include suppression of chronic stress-activated hypothalamus–pituitary–adrenal (HPA) axis. The current study presents the first in vivo evidence showing that suppression of HPA axis hyperactivity by fluoxetine treatment involves reversal of glucocorticoid receptor (GR) phosphorylation via modulation of the GR negative regulator Fk506-binding protein 5 (Fkbp5) in the hypothalamic paraventricular nucleus (PVN). Fluoxetine treatment not only inhibited chronic stress-induced depression-like behaviors and HPA axis hyperactivity but also reversed Fkbp5 upregulation and GR phosphorylation changes in the PVN, while adeno-associated virus (AAV)-based Fkbp5 overexpression in the PVN eliminated the antidepressant effects of fluoxetine. These findings may expand our understanding of the pharmacological effects of fluoxetine, and further identify Fkbp5 as a possible target for novel antidepressants.

Sex-related hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axis adaptation during military training.

Reproductive endocrine function adapts to psychological, environmental, and energy-associated stressors. Multistressor environments upregulate hypothalamic-pituitary-adrenal (HPA) axis, causing suppression of the hypothalamic-pituitary-gonadal (HPG) axis, but it is not known if this pattern or its magnitude is sex biased. We compared HPG and HPA axis activity in 9 men and 34 women undergoing Army training. One-hour low-dose gonadorelin and Synacthen tests were conducted at 1 and 29 wk, measuring gonadotrophins and cortisol. Cortisol was measured from hair every 3 mo. Morning and evening salivary cortisol and psychometric questionnaires were measured at six timepoints. Sexes were compared over time by two-way ANOVA. Gonadotrophin responses were significantly higher in women than men in week 1, but no sex difference was seen at week 29 (no significant sex × time interaction). Week 1 cortisol response was higher among men, but week 29 cortisol response was higher among women (sex × time F(1,44) = 18.0, P < 0.001). Hair cortisol was higher among women than men beforehand, not different between sexes during the first 3 mo, and significantly higher among women during training months 5-11 (F(3,15) = 3.25, P = 0.024). Morning salivary cortisol was higher among women in weeks 8 and 14, but higher among men in week 29 (F(4,76) = 4.0, P = 0.005). No differences were seen in evening salivary cortisol. Psychometrics did not change or differ between sexes. HPA axis responses to military training were greater among women than men. HPG axis responses suggest greater downregulation among women. These findings will enable equitable and individualized management of people undergoing periods of intensive physical stress.NEW & NOTEWORTHY We conducted a comprehensive comparison of adrenal and reproductive function in men and women undergoing 11-mo military training. We found progressively elevated cortisol levels and dynamic cortisol response to stress among women, but not men, and suppression of reproductive function among women. The physiological impact of stressful military training was greater among women than men; this could not be explained by energy balance, and sex-specific effects of sleep, socio-ethnographic, or other stressors may be responsible.

Depression decreases immunity and PD-L1 inhibitor efficacy via the hypothalamic–pituitary–adrenal (HPA) axis in triple-negative breast cancer

BackgroundDepression weakens antitumor immunity, yet the underlying mechanisms linking depression and tumor growth remain unclear. This study examines the influence of depression on the hypothalamic–pituitary–adrenal (HPA) axis, immunological function, and effectiveness of immunotherapy in triple-negative breast cancer (TNBC) patients. MethodsA mouse model of comorbid TNBC and depression was established via chronic restraint stress (CRS) and 4T1 tumor transplantation. A programmed cell death ligand 1 (PD-L1) inhibitor was used to manage mice with TNBC, and the ability of metyrapone to reverse the immune system changes induced by HPA axis activation in depression was evaluated. Mouse peripheral blood was used to measure HPA axis activity, immune cell numbers and cytokine levels. ResultsDepression activates the HPA axis, leading to increased levels of glucocorticoids. Depression led to an increase in the B-cell number and a reduction in the CD4+ T-cell and CD8+ T-cell numbers, without a statistically significant difference in the regulatory T (Treg) cell number. Furthermore, depression increased the levels of the cytokines interferon-gamma (IFN-γ), interleukin (IL)-1β, IL-4, IL-6, IL-8, and tumor necrosis factor (TNF)-α while decreasing the levels of IL-2 and IL-10. Similar results were observed in the context of PD-L1 inhibitor therapy. The depressed mice presented an increased tumor burden and a poor response to the PD-L1 inhibitor. The application of metyrapone during PD-L1 inhibitor treatment resulted in partial restoration of these depression-related alterations. ConclusionsDepression reduces the effectiveness of PD-L1 inhibitors by altering the number of immune cells and the levels of cytokines through activation of the HPA axis. Translational relevanceDepression is common in breast cancer patients and is associated with reduced antitumor immunity. There is limited knowledge regarding the specific mechanisms through which depression impairs antitumor immunity. Immunotherapy, which promotes the restoration of antitumor immunity, represents a promising treatment strategy for TNBC patients. However, the efficacy of immunotherapy can be compromised by depressive symptoms and the administration of glucocorticoids during treatment. It is still uncertain whether increasing glucocorticoid levels can reduce the efficacy of immunotherapy in patients with depression. The potential benefits of combining immunotherapy with glucocorticoid inhibitors compared with immunotherapy alone need to be evaluated for TNBC patients with concurrent depressive symptoms. Therefore, further clarification of the specific mechanisms by which depression impairs antitumor immunity is needed to inform future optimization of immunotherapy strategies.

Interventions to modify the habituation of biological responses to repeated stress in healthy adults: a randomized controlled trial

BackgroundChanges in response patterns of biological stress systems, including responses of the sympathetic nervous system (SNS) and the hypothalamus–pituitary–adrenal (HPA) axis to repeated stress, can promote the development and progression of chronic diseases via changes in downstream inflammatory processes. The aim of this project is thus to investigate, whether habituation of biological stress system activity including responses of the inflammatory system can be modified. Aiming to test for possible paths of action, a randomized controlled study with two intervention programs designed to manipulate cognitive coping strategies will be carried out. By increasing either ruminative or self-compassionate thoughts among healthy young adults, the intervention programs are expected to affect the regulation of occurring emotions as expressed by the responsiveness of biological systems during repeated stress exposure.MethodsIn this study, a total of 120 healthy adults will complete the Trier Social Stress Test (TSST) on two consecutive days. Immediately after the first stress induction, participants will be randomly assigned to two experimental conditions designed to manipulate cognitive coping strategies (rumination vs. self-compassion) or a control condition. Measures of HPA axis (salivary cortisol) and autonomic activity (salivary alpha amylase, heart rate, heart rate variability) as well as inflammatory markers (plasma interleukin(IL)-6, expression rates of pro- and anti-inflammatory cytokine genes) will be repeatedly assessed throughout the experimental sessions. Response and habituation indices of these measures will be calculated and compared between the experimental conditions and the control condition.DiscussionThe results should provide insight into whether modifying response patterns of biological stress systems could reverse a significant biological mechanism in the development of stress-related diseases.Trial registrationGerman Clinical Trials Register (DKRS), DRKS00034790. Registered on August 12, 2024, https://www.drks.de/DRKS00034790.

Hypothalamic-Pituitary-Adrenal Axis Activity and Metabolic Disorders in Kidney Transplant Recipients on Long-Term Glucocorticoid Therapy.

Background/Objectives: Glucocorticoids are commonly used for maintenance immunosuppressive therapy in kidney transplant recipients (KTRs). We aimed to investigate the prevalence of hypothalamic-pituitary-adrenal (HPA) axis suppression and its association with metabolic disorders in stable KTRs on low-dose glucocorticoids. Methods: This cross-sectional study included adult KTRs on low-dose glucocorticoids. HPA axis suppression was defined as baseline morning cortisol < 5 μg/dL. Adrenocorticotropic hormone (ACTH), dehydroepiandrosterone-sulphate (DHEAS) and 24 h urinary free cortisol (UFC) levels were also assessed. Examined metabolic disorders included hypertension, dyslipidemia, central obesity and post-transplant diabetes mellitus (PTDM). Results: Eighty adult KTRs with a median 57 months (IQR 24-102) since transplantation were included in the study. The mean prednisolone dose was 5.0 ± 1.3 mg/day. Baseline cortisol < 5.0 μg/dL was observed in 27.5% of the KTRs. Participants with baseline cortisol < 5.0 μg/dL were older (55.1 vs. 47.4 years, p = 0.023) and had had a transplant for a longer time (101.4 vs. 67.0 months, p = 0.043), compared with the rest of the cohort. Baseline cortisol correlated positively with ACTH (rho = 0.544, p < 0.001), DHEAS (rho:0.459, p < 0.001) and UFC (rho: 0.377, p = 0.002). The area under the receiver-operating characteristic curve for ACTH as a predictor of baseline cortisol > 5.0 μg/dL was 0.79 [95% confidence interval (CI): 0.68-0.89]. After adjustment for covariates, HPA axis suppression was not associated with the examined metabolic disorders. Conclusions: Our study showed that stable KTRs on chronic low-dose glucocorticoids exhibited an increased prevalence of HPA axis suppression. ACTH may serve as a surrogate biomarker for HPA axis activity in this population. Further research could evaluate the association of glucocorticoid-induced HPA axis inhibition with metabolic disorders.

Perinatal running training reversed postnatal anxiety and depressive-like behavior and cognitive impairment in mice following prenatal subchronic variable stress

BackgroundPregnancy is a very complex and highly stressful time in women. Despite the high prevalence of postpartum depression, more than 50 % of mothers are undiagnosed or untreated, showing an urgent need to explore an effective preventive strategy. Regular physical activity has been suggested to be associated with an increased quality of life in pregnant and postpartum women. The purpose of this study was to determine whether perinatal running training can affect maternal care stress-related anxiety, depressive-like behavior, and cognitive changes in postpartum dams and to explore the possible underlying mechanism. Methods40 female C57BL/6J mice were divided into four groups: prenatal control (NC) and running training (EX) group (NC+EX), prenatal control and nonrunning training (RE) group (NC+RE), prenatal subchronic variable stress (SCVS) and running training group (SCVS+EX) and prenatal SCVS and non-running training group (SCVS+RE). Mice in prenatal stress groups were subjected to SCVS after pregnancy confirmed. Mice in running training groups subjected to running training throughout pregnancy and lactation. Then after the delivery, maternal behavior, cognitive changes, anxiety and depressive-like behaviors were tested. Then we measured the serum prolactin (PRL), hypothalamic–pituitary adrenal (HPA) axis activity, and adult hippocampus neurogenesis (AHN) in dams. ResultsCompared to NC+RE, prenatal SCVS caused cognitive impairments, the decrease in maternal behavior, and anxiety and depressive-like behavior in SCVS+RE dams, accompanying increase in HPA axis activity and decreased the PRL levels and AHN in postpartum period. Then compared to SCVS+RE, perinatal running training mitigates cognitive impairments, increased maternal behavior, and alleviates anxiety and depressive-like behavior in SCVS+EX dams, accompanying the decreased HPA axis activity, and the increased PRL levels and AHN in postpartum period. ConclusionOverall, this study suggests that perinatal running training might improve maternal care and reverse prenatal stress-related cognitive impairment and anxiety and depressive-like behavior in postpartum dams.

Ventral subiculum control of avoidance behavior and hypothalamic-pituitary-adrenal axis reactivity via the bed nucleus of the stria terminalis in male and female mice – ISPNE 2024 Dirk Helhammer Award

Avoidance or anxiety-like behavior is accompanied by corresponding changes in hypothalamic-pituitary-adrenal (HPA) axis activation. The underlying neural circuitry for this coordinated behavioral and neuroendocrine control is not well established. Prior studies pointed to a neural projection from the ventral subiculum (vSub) to the bed nucleus of the stria terminalis (BNST) that can inhibit the HPA axis response to stress. Here, we used chemogenetics to investigate the role of vSub neurons and their projection to the anterior BNST (aBNST) in avoidance behavior and the accompanying corticosterone response in male and female mice. Surprisingly, we found that chemogenetic activation of ventral subiculum neurons increased the HPA axis response to an open field test in male and female mice, which was also seen with selective activation of vSub neurons projecting to the anterior BNST (vSub-aBNST neurons). On the other hand, VSub neuron and vSub-aBNST neuron activation had different effects on avoidance behavior, suggesting that the behavioral role of the VSub is variable and is dissociable from its neuroendocrine effects. In conclusion, our results reveal a surprising and novel role for the ventral subiculum in HPA axis activation via the anterior BNST. We also show that, like the ventral hippocampus, ventral subiculum neurons can increase or decrease avoidance behavior depending on their downstream projection.

Antidepressant-like and antistress effects of the ACTH(4–10) synthetic analogs Semax and Melanotan II on male rats in a model of chronic unpredictable stress

Current antidepressant therapy shows substantial limitations, and there is an urgent need for the development of new treatment strategies for depression. Stressful events and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis play an important role in the pathogenesis of depression. HPA axis activity is self-regulated by negative feedback at several levels including adrenocorticotropic hormone (ACTH)-mediated feedback. Here, we investigated whether noncorticotropic synthetic analogs of the ACTH(4–10) fragment, ACTH(4–7)-Pro-Gly-Pro (Semax) and Ac-Nle4-cyclo[Asp5-His6-D-Phe7-Arg8-Trp9-Lys10]ACTH(4–10)-NH2 (Melanotan II (MTII), a potent agonist of melanocortin receptors), have potential antidepressant activity in a chronic unpredictable stress (CUS) rat model of depression. Stressed and control male adult Sprague-Dawley rats received daily intraperitoneal injections of saline or a low dose (60 nmol/kg of body weight (BW)) of Semax or MTII. Rats were monitored for BW and hedonic status, as measured in the sucrose preference test. We found that chronic treatment with Semax and MTII reversed or substantially attenuated CUS-induced anhedonia, BW gain suppression, adrenal hypertrophy and a decrease in the hippocampal levels of BDNF. In the forced swim test, no effects of the CUS procedure or peptides on the duration of rat immobility were detected. Our findings show that in the CUS paradigm, systemically administered ACTH(4–10) analogs Semax and MTII exert antidepressant-like effects on anhedonia and hippocampal BDNF levels, and attenuate markers of chronic stress load, at least in male rats. The results support the argument that ACTH(4–10) analogs and other noncorticotropic melanocortins may have promising therapeutic potential for the treatment and prevention of depression and other stress-related pathologies.

Blunted Cortisol Awakening Response Is Associated with External Attribution Bias Among Individuals with Personality Disorders.

The dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been associated with various mental disorders. One of the most commonly described parameters of HPA axis functioning is the cortisol awakening response (CAR). To date, few studies have been conducted on the relationship between personality disorders and CAR. The present study aimed to compare the CAR between individuals with personality disorders and healthy controls. Moreover, the study aimed to assess the association of CAR with cognitive biases and psychopathological symptoms in people with personality disorders. A total of 43 individuals with personality disorders and 45 healthy controls were enrolled. Participants completed questionnaires measuring the severity of depressive symptoms, anxiety, cognitive biases, and psychotic-like experiences. Cortisol levels were measured in four morning saliva samples: immediately after awakening, and after 15, 30, and 45 min. A significantly lower CAR was found among individuals with personality disorders, even after adjustment for age, sex, and the level of education. However, the receiver operating characteristic (ROC) curve analysis showed a relatively low area under the curve (AUC = 0.362). Furthermore, a significant negative correlation was observed between the CAR and the level of external attribution bias among individuals with personality disorders. No significant associations of the CAR with psychopathological symptoms and other cognitive biases were observed. Findings from this study indicate that the HPA axis activity might be altered in personality disorders. However, the clinical utility of this observation needs further studies in larger samples. External attribution might be related to the HPA axis alterations in this population.

Exploring the associations between momentary cortisol levels and psychotic-like experiences in young adults: Results from a temporal network analysis of daily-life data.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the development of psychosis and subthreshold psychotic symptoms commonly referred to as psychotic-like experiences (PLEs). The exact mechanisms linking the HPA axis responses with the emergence of PLEs remain unknown. The present study aimed to explore real-life associations between stress, negative affect, salivary cortisol levels (a proxy of the HPA axis activity) as well as PLEs together with their underlying cognitive biases (i.e., threat anticipation and aberrant salience). The study was based on the experience sampling method scheduled over 7 consecutive days in the sample of 77 drug-naïve, young adults (18-35 years). The saliva samples were collected with each prompt to measure cortisol levels. A temporal network analysis was used to explore the directed associations of tested variables. Altogether, 3234 data entries were analyzed. Data analysis revealed that salivary cortisol levels did not directly predict next-moment fluctuations of PLEs. However, higher salivary cortisol levels were associated with higher next-moment levels of PLEs through the effects on threat anticipation and negative affect. In turn, PLEs appeared to predict cortisol levels through the effects on negative affect and event-related stress. Negative affect and threat anticipation were the most central nodes in the network. There might be bidirectional associations between the HPA axis responses and PLEs. Threat anticipation and negative affect might be the most important mediators of these associations. Interventions targeting these mediators might hold promise for disrupting the connection between the HPA axis dysregulation and PLEs.

PPARα suppresses low-intensity-noise-induced body weight gain in mice: the activated HPA axis plays an critical role.

As the second most risky environmental pollution, noise imposes threats to human health. Exposure to high-intensity noise causes hearing impairment, psychotic disorders, endocrine modifications. The relationship among low-intensity noise, obesity and lipid-regulating nuclear factor PPARα is not yet clear. In this study, male wild-type (WT) and Pparα-null (KO) mice on a high-fat diet (HFD) were exposed to 75 dB noise for 12 weeks to explore the effect of low-intensity noise on obesity development and the role of PPARα. 3T3-L1 cells were treated with dexamethasone (DEX) and sodium oleate (OA) to verify the down-stream effect of hypothalamic-pituitary-adrenal (HPA) axis activation on the adipose tissues. The average body weight gain (BWG) of WT mice on HFD exposed to noise was inhibited, which was not observed in KO mice. The mass and adipocyte size of adipose tissues accounted for the above difference of BWG tendency. In WT mice on HFD, the adrenocorticotropic hormone level was increased by the noise challenge. The aggravation of fatty liver by noise exposure occurred in both mouse lines, and the transport of hepatic redundant lipid to adipose tissues were similar. The lipid metabolism in adipose tissue driven by HPA axis accorded with the BWG inhibition in vivo, validated in 3T3-L1 adipogenic stem cells. Chronic exposure to low-intensity noise aggravated fatty liver in both WT and KO mice. BWG inhibition was observed only in WT mice, which covered up the aggravation of fatty liver by noise exposure. PPARα mediates the activation of HPA axis by noise exposure in mice on HFD. Elevated adrenocorticotropic hormone (ACTH) promoted lipid metabolism in adipocytes, which contributed to the disassociation of BWG and fatty liver development in male WT mice. Summary of PPARα suppresses noise-induced body weight gain in mice on high-fat-diet. Chronic exposure to low-intensity noise exposure inhibited BWG by PPARα-dependent activation of the HPA axis.

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

BackgroundHyperactivity 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.MethodsPartial 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.ResultsOur 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.ConclusionEA alleviates HPA axis hyperactivity and anxiety-like behaviors caused by surgical trauma through inhibition of Nesfatin-1/ERK/CREB pathway in the hypothalamus.

Non-invasive TMS attenuates neuropathic pain after spinal cord injury associated with enhancing brain functional connectivity and HPA axis activity

Patients with spinal cord injury (SCI) often suffer from varying degrees of neuropathic pain.Non-invasive repetitive transcranial magnetic stimulation (TMS) has been shown to improve neuropathic pain, while the appropriate intervention strategies of TMS treatment and how TMS affects brain function after SCI were not entirely clear. To investigate the effects and mechanisms of TMS on neuropathic pain after SCI, high-frequency TMS on primary motor cortex (M1) of mice was performed after SCI and pain response was evaluated through an electronic Von-Frey device and cold/hot plates. Functional magnetic resonance imaging (fMRI), bulk RNA sequencing, immunofluorescence and molecular experiments were used to evaluate brain and spinal cord function changes and mechanisms. TMS significantly improved SCI induced mechanical allodynia, cold and thermal hyperalgesia with a durative effect, and TMS intervention at 1 week after SCI had pain relief advantages than at 2 weeks. TMS intervention not only affected the functional connections between the primary motor cortex and the thalamus, but also increased the close connection of multiple brain regions. Importantly, TMS treatment activated the hypothalamic pituitary adrenal (HPA) axis and increased the transcript levels of genes encode hormone proteins, accompanied with the attenuation of inflammatory microenvironment in spinal cord associated with pain relief. Totally, these results elucidate that early intervention with TMS could improve neuropathic pain after SCI associated with enhancing brain functional connectivity and HPA axis activity which should be harnessed to modulate neuropathic pain after SCI.

Hypothalamic-Pituitary-Adrenal (HPA) Axis: Unveiling the Potential Mechanisms Involved in Stress-Induced Alzheimer's Disease and Depression.

The hypothalamic-pituitary-adrenal (HPA) axis plays a pivotal role in the body's response to stress, orchestrating the release of glucocorticoids. In chronic scenarios, these glucocorticoids contribute to various neurological disorders, including Alzheimer's disease (AD) and depression. This abstract explores the potential mechanisms through which HPA axis dysregulation links stress-induced pathways to the pathogenesis of AD and subsequent depression. Chronic stress triggers prolonged HPA axis activation, resulting in elevated cortisol levels, which can lead to hippocampal atrophy, synaptic dysfunction, and neuroinflammation, recognized as key pathological features of AD. These alterations impair cognitive function and may exacerbate amyloid-beta plaque formation and tau hyperphosphorylation, hallmarks of AD. Concurrently, persistent cortisol elevation affects the prefrontal cortex and limbic structures, contributing to depressive symptoms. The interplay between chronic stress, HPA axis dysregulation, and neuroinflammation is crucial in understanding the comorbidity of AD and depression. Unveiling these mechanisms provides insights into potential therapeutic targets aimed at modulating the HPA axis and reducing stress-induced neurodegeneration, offering a dual benefit in managing both AD and depression. Further research is essential to elucidate the precise molecular pathways and develop effective interventions to mitigate the impact of chronic stress on brain health.

Luteal phase sertraline treatment of premenstrual dysphoric disorder (PMDD): Effects on markers of hypothalamic pituitary adrenal (HPA) axis activation and inflammation

RationalePremenstrual dysphoric disorder (PMDD) is characterized by severe affective symptoms during the luteal phase of the menstrual cycle. There is some evidence of altered interactions between the hypothalamic pituitary gonadal (HPG) and hypothalamic pituitary adrenal (HPA) axes in PMDD. There is also evidence that similar affective disorders such as major depression and perinatal depression are associated with dysregulation in immune factors, but this has not been characterized in PMDD. AimsThe goals of this exploratory study were to identify 1) whether HPA-HPG axis interactions and immune markers differ between PMDD patients and controls across the menstrual cycle; 2) how luteal phase sertraline treatment impacts stress and inflammatory markers. MethodsParticipants were females age 18–50 with regular menstrual cycles, not using psychotropic or hormonal medications, and were assigned to a control group or PMDD group based on prospective daily symptom ratings and clinical interview. Blood was drawn in the follicular and luteal phases, during laboratory sessions involving a mildly stressful task. In a second luteal phase, PMDD participants received open-label sertraline (50 mg/d) from ovulation to menses. Serum cortisol and ACTH were measured via ELISA and operationalized as area under the curve with respect to ground (AUCg), and peak level following laboratory task. Serum TNF-α, IL-6, CXCL-8, and IL-1β were measured using multiplex kits. Serum allopregnanolone (ALLO) was measured by gas chromatography/mass spectroscopy. To characterize HPA-HPG axis interactions across the menstrual cycle in PMDD participants and controls, multilevel linear models predicted cortisol and ACTH from the interaction of cycle phase (controlling for sertraline treatment), ALLO, and group. To determine the effects of sertraline treatment on inflammatory markers and how groups might differ in cyclical change on each marker, multilevel linear models predicted inflammatory markers from cycle phase (controlling for sertraline treatment) and group. A final set of exploratory models tested whether inflammatory markers predict premenstrual symptom score severity. ResultsThe sample included n=77 participants (41 controls, 36 PMDD); 28 participants with PMDD completed sertraline treatment. Group x phase x ALLO interactions showed that higher ALLO levels predicted lower cortisol peak in the treated luteal phase (interaction between phase and ALLO, p=0.042), and there was a higher cortisol peak in the treated luteal phase than the untreated luteal phase (p=0.038). CXCL-8 was significantly associated with premenstrual symptom severity after controlling for group and cycle phase (p=0.011). There were no main effects of group, phase, or ALLO on cortisol AUCg, ACTH AUCg, IL-6, CXCL-8, IL-1β, nor TNF-α (p’s>0.05). ConclusionSerum markers of HPA axis and immune function did not vary by menstrual cycle phase nor PMDD status. However, sertraline treatment in the luteal phase was associated with higher ALLO levels predicting lower cortisol peak in response to mild laboratory stress, suggesting that sertraline treatment may normalize HPG-HPA axis interactions among individuals with PMDD. Greater premenstrual symptomatology was associated with higher levels of the inflammatory marker CXCL-8, but further research is needed into the potential role of inflammation in PMDD.

Metabolic rate and saliva cortisol concentrations in socially housed adolescent guinea pigs

An individual’s energetic demands and hence metabolic rate can strongly change during adolescence, a phase characterized by profound morphological, physiological, and endocrine changes. Glucocorticoid hormones (e.g. cortisol) are released in response to hypothalamic–pituitary–adrenal–axis activity, modulate several metabolic processes, and can also be linked to increased metabolic rate. In domestic guinea pigs (Cavia aperea f. porcellus) housed in same-sex groups, cortisol concentrations increase during adolescence in males but remain stable in females, which was suggested to be related to different energetic demands by age. We therefore measured metabolic rate through oxygen (O2) consumption over 2.5 h in male and female guinea pigs housed in same-sex groups during adolescence at ages of 60, 120, and 180 days, which was paralleled by analyses of saliva cortisol concentrations before and after the measurement. The statistical analyses involved whole body metabolic rate (ml O2/h), body mass-corrected metabolic rate (ml O2/h/kg), and body mass-independent metabolic rate (ml O2/h statistically corrected for body mass). We found increasing cortisol concentrations with age in males only, but none of the three metabolic rate analyses revealed a sex difference by age. On the individual level, repeatability across ages was found in metabolic rate as well as in body mass and cortisol concentrations after the measurement, but not in “basal” cortisol concentrations. Our results suggest no sex-specific changes in metabolic rate and hence equal energetic demands in male and female guinea pigs during adolescence. Moreover, metabolic rate clearly represents a highly stable physiological trait already early in a guinea pig’s life irrespective of rather fluctuating cortisol concentrations.

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.

Associations between adrenal gland volume and adipose tissue compartments – a whole body MRI study

BackgroundObesity is associated with alterations in the hypothalamic–pituitary–adrenal (HPA) axis. Effects of glucocorticoids on adipose tissues appear to depend on the specific adipose depot, in which they take place. In this study, we aimed to investigate the role of MRI-based adrenal gland volume as an imaging marker in association with different adipose tissue compartments.MethodsThe study cohort derives from the population-based research platform KORA (Cooperative Health Research in the Augsburg Region, Germany) MRI sub-study, a cross-sectional sub-study investigating the interactions between subclinical metabolic changes and cardiovascular disease in a study sample of 400 participants. Originally, eligible subjects underwent a whole-body MRI. MRI-based segmentations were performed manually and semi-automatically for adrenal gland volume, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), epi- and pericardial fat and renal sinus fat. Hepatic and pancreatic lipid content were measured as pancreatic proton density fraction (PDFF) and MR-spectroscopic hepatic fat fraction (HFF). Multivariable linear regression analyses were performed.ResultsA number of 307 participants (56.2 ± 9.1 years, 60.3% male, 14.3% with type 2 diabetes (T2DM), 30.6% with obesity, 34.2% with hypertension) were included. In multivariable analyses, strong positive associations between adrenal gland volume and VAT, total adipose tissue (TAT) as well as HFF persisted after extensive step-wise adjustment for possible metabolic confounders (VAT: beta = 0.31, 95%-CI [0.71, 0.81], p < 0.001; TAT: beta = 0.14, 95%-CI [0.06, 0.23], p < 0.001; HFF: beta = 1.17, 95%-CI [1.04, 1.31], p = 0.009). In contrast, associations between adrenal gland volume and SAT were attenuated in multivariate analysis after adjusting for BMI. Associations between pancreatic PDFF, epi- and pericardial fat and renal sinus fat were mediated to a great extent by VAT (pancreatic PDFF: 72%, epicardial adipose tissue: 100%, pericardial adipose tissue: 100%, renal sinus fat: 81.5%).ConclusionOur results found MRI-based adrenal gland volume as a possible imaging biomarker of unfavorable adipose tissue distribution, irrespective of metabolic risk factors. Thus, adrenal gland volume may serve as a potential MRI-based biomarker of metabolic changes and contributes to an individual characterization of metabolic states and individual risk stratification. Future studies should elucidate in a longitudinal study design, if and how HPA axis activation may trigger unfavorable adipose tissue distribution and whether and to which extent this is involved in the pathogenesis of manifest metabolic syndrome.