Hypothalamic-pituitary-adrenal Axis Response Research Articles

Repetitive neonatal procedural pain affects stress-induced plasma corticosterone increase in young adult females but not in male rats.

Exposure to repetitive painful procedures in the neonatal intensive care unit results in long-lasting effects, especially visible after a "second hit" in adulthood. As the nociceptive system and the hypothalamic-pituitary-adrenal (HPA) axis interact and are vulnerable in early life, repetitive painful procedures in neonates may affect later-life HPA axis reactivity. The first aim of the present study was to investigate the effects of repetitive neonatal procedural pain on plasma corticosterone levels after mild acute stress (MAS) in young adult rats. Second, the study examined if MAS acts as a "second hit" and affects mechanical sensitivity. Fifty-two rats were either needle pricked four times a day, disturbed, or left undisturbed during the first neonatal week. At 8weeks, the animals were subjected to MAS, and plasma was collected before (t0), after MAS (t20), and at recovery (t60). Corticosterone levels were analyzed using an enzyme-linked immunosorbent assay, and mechanical sensitivity was assessed with von Frey filaments. Results demonstrate that repetitive neonatal procedural pain reduces stress-induced plasma corticosterone increase after MAS only in young adult females and not in males. Furthermore, MAS does not affect mechanical sensitivity in young adult rats. Altogether, the results suggest an age- and sex-dependent effect of repetitive neonatal procedural pain on HPA axis reprogramming.

Physiological stress response to urbanisation differs between native and invasive squirrel species

Novel pressures derived from urbanisation can alter native habitats and ultimately impact wildlife. Coping with such human-driven changes might induce shifts in species phenotypic traits, such as physiological responses to anthropogenic stressors. Preadaptation to face those challenges has been suggested to favour settlement and spread of invasive alien species in urbanised areas which, consequently, might respond differently than ecologically similar native species to stressors posed by urbanisation. The activation of the hypothalamic-pituitary-adrenal (HPA) axis and the subsequent release of glucocorticoids (GCs) has been suggested to mediate responses to anthropogenic disturbance in vertebrates. Furthermore, intraspecific competition, in conjunction with stressors related to urbanisation, might affect invasive and native species physiological stress responses differently. Using a parallel pseudo-experimental study system we measured faecal glucocorticoid metabolite (FGM) concentrations of the native Eurasian red squirrel and the invasive alien Eastern grey squirrel along a rural-urban gradient and in relation to conspecific density. The two species responded differently to challenges posed by the synergic effect of urbanisation and intraspecific competition. Association of FGMs and conspecific density in native red squirrels varied between rural and suburban sites, potentially depending on differential HPA axis responses. In urban sites, this relationship did not differ significantly from that in rural and suburban ones. Conversely, invasive grey squirrels' FGMs did not vary in relation to conspecific density, nor differed along the rural-urban gradient. Improving knowledge about native and competing invasive species' physiological responses to anthropogenic stressors can support conservation strategies in habitats altered by man. Our findings suggested that the invasive squirrels might be preadapted to cope with these challenges in urbanised areas, potentially increasing their success under the future global change scenario.

Chronically stressed male and female mice show a similar peripheral and central pro-inflammatory profile after an immune challenge.

Although acute stressors are known for stimulating the production of glucocorticoids and pro-inflammatory cytokines in rodents, the effects of chronic stressors on cytokine levels and the activation of the hypothalamic-pituitary-adrenal (HPA) axis, especially in response to a subsequent challenge, are less clear. In this study, male and female mice were exposed to 6 weeks of chronic variable stress (CVS) and the peripheral and central levels of IL-1β, IL-6, and TNF-α, as well as the HPA axis reactivity, were measured after an acute injection of LPS. The findings indicate that the pro-inflammatory profile in the plasma, regardless of stress exposure, was similar between male and female animals, whereas there was a region-, sex-, and stress-dependent pattern in the brain. Exposure to chronic stressors blunted the HPA reactivity to the LPS challenge, indicating a modulatory effect on the stress axis responsiveness.

Sex differences in stress-induced hyperalgesia and its mechanisms.

Chronic stress induces a variety of physiological and/or psychological abnormalities, including hyperalgesia. Researchers have discovered sex differences in the prevalence of stress-induced hyperalgesia (SIH) in recent years. Sex differences may be one of the reasons for the heterogeneity of susceptibility to stress-related diseases. In this review, the potential mechanisms of sex differences in SIH are discussed, such as hypothalamus-pituitary-adrenal axis responses, regulation of sex hormones, and immune system responses.

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.

Associations between cortisol stress responses and limbic volume and thickness in young adults: An exploratory study.

The investigation of the relationship between neural measures of limbic structures and hypothalamic pituitary adrenal axis responses to acute stress exposure in healthy young adults has so far focused in particular on task-based and resting state functional connectivity studies. Thus, the present study examined the association between limbic volume and thickness measures and acute cortisol responses to the psychosocial stress paradigm ScanSTRESS. Using Permutation Analysis of Linear Models controlling for sex, age and total brain volume, the associations between (sex-specific) cortisol increases and human connectome project style anatomical variables of limbic structures (i.e. volume and thickness) were investigated in 66 healthy and young (18-33 years) subjects (35 men, 31 women taking oral contraceptives). In addition, exploratory (sex-specific) bivariate correlations between cortisol increases and structural measures were conducted. The present data provide interesting new insights into the involvement of striato-limbic structures in psychosocial stress processing, suggesting that acute cortisol stress responses are also associated with mere structural measures of the human brain. Thus, our preliminary findings suggest that not only situation- and context-dependent reactions of the limbic system (i.e. blood oxygenation level-dependent reactions) are related to acute (sex-specific) cortisol stress responses but also basal and somewhat more constant structural measures. Our study hereby paves the way for further analyses in this context and highlights the relevance of the topic.

Parity and housing effects on the behavioural and hypothalamic–pituitary–adrenal axis responses of pregnant ewes

It is common in many countries for sheep to be housed during winter from mid-gestation until lambing to protect ewes and lambs from adverse conditions and improve late gestation nutritional management. Keeping ewes indoors, however, has its own challenges as the animals may be mixed with unfamiliar conspecifics, have limited floor and feeding space, experience changes to their diet and increased handling by humans. Therefore, the objective of this study was to investigate the effect of variation in housing management (space allowance and social stability) on the behaviour and hypothalamic–pituitary–adrenal (HPA) axis responses of pregnant ewes from mid-to-late gestation (weeks 11–18 of pregnancy). Seventy-seven ewes (41 primiparous, 36 multiparous) were divided into two groups: ‘Control’ and ‘Restricted space and mixed’ (RS-Mix), where RS-Mix ewes were allocated half the amount of space (1.27 vs 2.5 m2 for RS-Mix and Control, respectively) and feedface (concentrate feeder space) allowance (36 vs 71 cm per ewe) given to the Control group and were also subjected to two social mixing events. Aggressive behaviour at the feedface and time spent standing, lying, walking, feeding and ruminating were recorded and faecal samples were collected for assessment of faecal glucocorticoid metabolite (FGM) concentrations. Higher aggression was observed in RS-Mix ewes during the first week of observation (P = 0.044), which gradually declined to the same level as Control ewes by the end of the study (P = 0.045). RS-Mix ewes were significantly less likely to be able to freely join the feedface compared to Controls (P = 0.022). No other significant treatment effects on aggressive behaviour or FGM during gestation were found. RS-Mix ewes displayed significantly higher ruminating behaviour at week 18 of gestation compared to Control ewes (P < 0.001), but no other effects were seen on general pen behaviour. However, the effect of indoor housing had a significant impact on primiparous ewes, who had lower weight gain (P = 0.015) and higher FGM concentrations (P = 0.014) compared to multiparous ewes regardless of treatment group. The data suggest that, although no sustained effects on behaviour or HPA axis responses were seen with the differences in space and feeder allowance or social stability at the levels used in this study, inexperienced (primiparous) ewes may find indoor housing more stressful; and are less able to adapt compared to multiparous ewes. These effects may influence the behaviour of the ewe at lambing time, and her offspring.

SAT270 Parity Increases Corticosterone Response To Restraint-induced Stress After Mild Blast Traumatic Brain Injury In Mice

Abstract Disclosure: S. Anisowicz: None. M. Bodemeier Loayza Careaga: None. T. Wu: None. Background: Traumatic brain injury (TBI) is a common problem worldwide, with an estimated incidence of 69 million injuries per year. In the US military, one of the most common forms of TBI during operational deployments after Sep 11, 2001 was the blast TBI, thought to be responsible for over 80% of TBI sustained in theater. One consequence of TBI is dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis. HPA axis dysregulation is linked to increased risk for psychiatric disorders. Furthermore, prior research has shown that TBI may dysregulate the HPA axis in a sex-dependent manner. Throughout a female’s life span, there are several sentinel events of hormonal consequence, including pubarche, menopause, and parity, which are known to be times of changes in risks for psychiatric disorders. Objectives: The role of parity on TBI response has not yet been studied, though parity has been shown to decrease fear-related behaviors and decreased corticosterone load in multiparous mice when compared to nulliparous (NP) controls. Our objective is to determine if parity alters corticosterone (CORT) response to restraint, a mild psychological stressor, in mice exposed to mild blast TBI (mbTBI). Methods: One hundred thirteen NP or primiparous (PP) C57Bl6/J mice were randomly assigned to receive sham or mbTBI. Among those that received mbTBI (19.2 ± 0.12 psi), 32 were NP and 24 were PP. Among sham mice, 32 were NP and 26 were PP. All mice received isoflurane anesthesia prior to sham or mbTBI treatment. At 7-8 days after mbTBI, half the mice within each treatment group were subjected to a mild 20-min restraint before being anesthetized by CO2 followed by collection of trunk blood. Serum was harvested and analyzed for CORT concentrations by ELISA (Enzo Life Sciences). Results: All mice that received mbTBI had a longer (p&amp;lt;0.05) righting time compared to those that did not. There was no main effect of parity in the righting time (p&amp;gt;0.1). PP mice who experienced mbTBI demonstrated a greater (p&amp;lt;0.05) CORT response to restraint (157.3 ± 21 pg/mL) when compared to NP mice (95.9 ± 7.2 pg/mL). CORT response to restraint did not differ (p&amp;gt;0.1) between NP and PP mice who did not experience mbTBI (96.1 ± 7.6 vs 109.2 ± 16 pg/mL). Conclusions: Our data indicates that mbTBI alters HPA axis reactivity in PP mice compared to NP mice, increasing the CORT response to restraint induced stress. Parity alone did not alter CORT response to restraint stress or baseline CORT levels. The results of our finding highlight the importance of parity as a factor in an individual’s lifespan. Presentation: Saturday, June 17, 2023

Neural basis for fasting activation of the hypothalamic-pituitary-adrenal axis.

Fasting initiates a multitude of adaptations to allow survival. Activation of the hypothalamic-pituitary-adrenal (HPA) axis and subsequent release of glucocorticoid hormones is a key response that mobilizes fuel stores to meet energy demands1-5. Despite the importance of the HPA axis response, the neural mechanisms that drive its activation during energy deficit are unknown. Here, we show that fasting-activated hypothalamic agouti-related peptide (AgRP)-expressing neurons trigger and are essential for fasting-induced HPA axis activation. AgRP neurons do so through projections to the paraventricular hypothalamus (PVH), where, in a mechanism not previously described for AgRP neurons, they presynaptically inhibit the terminals of tonically active GABAergic afferents from the bed nucleus of the stria terminalis (BNST) that otherwise restrain activity of corticotrophin-releasing hormone (CRH)-expressing neurons. This disinhibition of PVHCrh neurons requires γ-aminobutyric acid (GABA)/GABA-B receptor signalling and potently activates the HPA axis. Notably, stimulation of the HPA axis by AgRP neurons is independent of their induction of hunger, showing that these canonical 'hunger neurons' drive many distinctly different adaptations to the fasted state. Together, our findings identify the neural basis for fasting-induced HPA axis activation and uncover a unique means by which AgRP neurons activate downstream neurons: through presynaptic inhibition of GABAergic afferents. Given the potency of this disinhibition of tonically active BNST afferents, other activators of the HPA axis, such as psychological stress, may also work by reducing BNST inhibitory tone onto PVHCrh neurons.

Physiological response to pain in female adolescents with nonsuicidal self-injury as a function of severity

BackgroundPreliminary evidence indicates altered hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) response to experimental pain in individuals with nonsuicidal self-injury (NSSI). This study investigated effects of NSSI severity and severity of psychopathology on the HPA axis and ANS response to pain. MethodsN = 164 adolescents with NSSI and n = 45 healthy controls received heat pain stimulation. Salivary cortisol, α-amylase and blood pressure were repeatedly assessed before and after painful stimulation. Heart rate (HR) and heart rate variability (HRV) were assessed continuously. NSSI severity and comorbid psychopathology were derived from diagnostic assessments. Main and interaction effects of time of measurement and NSSI severity, adjusted for severity of adverse childhood experiences, borderline personality disorder and depression, on HPA axis and ANS response to pain were examined using regression analyses. ResultsIncreasing NSSI severity predicted an increasing cortisol response (χ2(3) = 12.09, p = .007) to pain. After adjusting for comorbid psychopathology, greater NSSI severity predicted decreased α-amylase levels following pain (χ2(3) = 10.47, p = .015), and decreased HR (χ2(2) = 8.53, p = .014) and increased HRV(χ2(2) = 13.43, p = .001) response to pain. LimitationsFuture research should implement several NSSI severity indicators, potentially revealing complex associations with the physiological response to pain. Assessing physiological responses to pain in NSSI in a naturalistic setting presents a promising avenue for future research in NSI. ConclusionsFindings indicate an increased pain-related HPA axis response and an ANS response characterized by reduced sympathetic and increased parasympathetic activity associated with NSSI severity. Results support claims for dimensional approaches to NSSI and its related psychopathology alongside shared, underlying neurobiological correlates.

Relationship of stress-reactive cortisol to suicidal intent of prior attempts in major depression

Higher intent suicide attempts carry elevated risk of future suicidal behavior. Abnormal functioning of the hypothalamic-pituitary-adrenal (HPA) axis is both linked to nonfatal suicidal behavior and suicide deaths in major depressive disorder. Few studies, however, have identified biological markers of a high-intent suicidal subgroup. We examined HPA axis output and reactivity to the Trier Social Stress Test (TSST) via salivary cortisol in depressed individuals (N=68) with a suicide attempt (SA) history. A median split of higher and lower suicidal intent scores was used to define groups. Individuals with high intent SA had attenuated total cortisol output (AUCg), F(1,60)=10.04, SE=5.095, p=.003, and lower HPA-axis stress responsivity to the TSST (AUCi), F(1,60)=4.50, SE=4.604, p=.039, compared with the low intent SA group. The high intent group also reported more pronounced negative affect than the low intent group (F[1,61]=6.413, SE=10.55, p=.014) both at baseline (meandiff=22.32, p=.038) and in response to the stressor task (meandiff=37.62, p=.003). Vulnerability to suicidal behavior in high-intent individuals may be related to the combined profile of impaired physiological responses to stress and greater negative affectivity. This clinical and biologic subgroup may benefit from targeted suicide prevention interventions.

Neural habituation during acute stress signals a blunted endocrine response and poor resilience.

A blunted hypothalamic-pituitary-adrenal (HPA) axis response to acute stress is associated with psychiatric symptoms. Although the prefrontal cortex and limbic areas are important regulators of the HPA axis, whether the neural habituation of these regions during stress signals both blunted HPA axis responses and psychiatric symptoms remains unclear. In this study, neural habituation during acute stress and its associations with the stress cortisol response, resilience, and depression were evaluated. Seventy-seven participants (17-22 years old, 37 women) were recruited for a ScanSTRESS brain imaging study, and the activation changes between the first and last stress blocks were used as the neural habituation index. Meanwhile, participants' salivary cortisol during test was collected. Individual-level resilience and depression were measured using questionnaires. Correlation and moderation analyses were conducted to investigate the association between neural habituation and endocrine data and mental symptoms. Validated analyses were conducted using a Montreal Image Stress Test dataset in another independent sample (48 participants; 17-22 years old, 24 women). Neural habituation of the prefrontal cortex and limbic area was negatively correlated with cortisol responses in both datasets. In the ScanSTRESS paradigm, neural habituation was both positively correlated with depression and negatively correlated with resilience. Moreover, resilience moderated the relationship between neural habituation in the ventromedial prefrontal cortex and cortisol response. This study suggested that neural habituation of the prefrontal cortex and limbic area could reflect motivation dysregulation during repeated failures and negative feedback, which might further lead to maladaptive mental states.

Molecular changes in hippocampal energy metabolism in mice selectively bred for extremes in stress reactivity: relevance of mitochondrial dysfunction for affective disorders.

Affective disorders, such as major depression, are frequently associated with metabolic disturbances involving mitochondria. Although dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is known to alter energy metabolism, the precise mechanisms linking stress and metabolic disturbances are not sufficiently understood. We used a mouse model of affective disorders to investigate the impact of a genetic predisposition for extremes in stress reactivity on behavioural and metabolic phenotypes as well as energy metabolism. Adult males of three independent mouse lines selectively bred for high, intermediate or low HPA axis reactivity were tested for exploratory and locomotor activity as well as stress-coping behaviour. Additionally, basal and stress-induced plasma corticosterone levels, body weight, food intake and body composition were measured. At the molecular level, the hippocampal transcriptome was analysed using microarray, serial analysis of gene expression and qRT-PCR. Finally, mitochondrial DNA copy number, damages and mitochondrial respiration were assessed. We found clear effects of the differential stress reactivity on the behavioural, morphometric and metabolic measures. Remarkably, the hyperactive behavioural and neuroendocrine stress-coping style of High Reactivity mice was associated with significant changes in the expression of an extended list of genes involved in energy metabolism and several mitochondrial functions. Yet, only minor changes were found in mitochondrial DNA copy number, damages and respiration. Thus, our findings support a prominent role of glucocorticoids in shaping the major endophenotypes of the stress reactivity mouse model and contribute towards understanding the important role of HPA axis dysregulation and changes in energy metabolism in the pathophysiology of affective disorders.

0131 Sleep Deprivation Alters Two Physiological Systems' Responses to Repeated Stressors Differentially

Abstract Introduction The hypothalamic-pituitary-adrenal (HPA) and sympathetic-adrenal-medullary (SAM) axes activate in response to stressors. Real-world exposure to stressors often co-occurs with total sleep deprivation (TSD). The SAM response to a single stressor appears unchanged by TSD, but salivary alpha-amylase (sAA) has shown that TSD blunts the SAM response to repeated stressor exposure. Using salivary cortisol concentration (SCC), we investigated the HPA response to repeated stressors under well-rested and TSD conditions. Methods N=10 healthy adults (ages 28.3±5.78; 5f) completed a 4-day/3-night in-laboratory study with 38h TSD preceded and followed by 10h sleep opportunities. On day 2 (well-rested) and day 3 (TSD), participants completed two stressor sessions in a high-fidelity shooting simulator, separated by 30min. Acting as police officers, civilian participants verbally interacted with emergency response scenarios and decided whether to use (simulated) deadly force. Seven saliva samples were collected each day: pre-stressor, and 0min, 15min, and 30min after each session. Samples were assayed for SCC and normalized against each day’s pre-stressor sample. Results Mixed-effects ANOVA showed a significant effect of sample time (F[5,99]=19.85, p&amp;lt; 0.001), with SCC peaking 15min after the first stressor session and steadily declining thereafter. The SCC peak was significantly blunted during TSD compared to well-rested (t[99]=2.84, p=0.006). Correlations with previously reported, simultaneously assessed sAA concentrations, which peaked right after the first stressor session, were not significant (p&amp;gt;0.2). Additionally, whereas sAA showed a second peak after the second stressor session when participants were well-rested, no second peak was found in SCC. Conclusion The SCC response after one stressor session with simulated emergency response scenarios was blunted during TSD, unlike the sAA response. However, while sAA peaked twice in response to repeated stressor exposure when participants were well-rested (though not during TSD), SCC continued to decline after the first stressor exposure, potentially indicating a HPA refractory mechanism or habituation. Also, over participants there was no significant relationship between the magnitude of the stressor response between SCC and sAA. Taken together, our results suggest fundamentally distinct SAM and HPA axis responsivity to repeated acute stressors, with differential impact of TSD. Support (if any) ONR N00014-13-1-0302, PRMRP W81XWH-20-1-0442.

Targeting PDK2 rescues stress-induced impaired brain energy metabolism.

Depression is a mental illness frequently accompanied by disordered energy metabolism. A dysregulated hypothalamus pituitary adrenal axis response with aberrant glucocorticoids (GCs) release is often observed in patients with depression. However, the associated etiology between GCs and brain energy metabolism remains poorly understood. Here, using metabolomic analysis, we showed that the tricarboxylic acid (TCA) cycle was inhibited in chronic social defeat stress (CSDS)-exposed mice and patients with first-episode depression. Decreased mitochondrial oxidative phosphorylation was concomitant with the impairment of the TCA cycle. In parallel, the activity of pyruvate dehydrogenase (PDH), the gatekeeper of mitochondrial TCA flux, was suppressed, which is associated with the CSDS-induced neuronal pyruvate dehydrogenase kinase 2 (PDK2) expression and consequently enhanced PDH phosphorylation. Considering the well-acknowledged role of GCs in energy metabolism, we further demonstrated that glucocorticoid receptors (GR) stimulated PDK2 expression by directly binding to its promoter region. Meanwhile, silencing PDK2 abrogated glucocorticoid-induced PDH inhibition, restored the neuronal oxidative phosphorylation, and improved the flux of isotope-labeled carbon (U-13C] glucose) into the TCA cycle. Additionally, in vivo, pharmacological inhibition and neuron-specific silencing of GR or PDK2 restored CSDS-induced PDH phosphorylation and exerted antidepressant activities against chronic stress exposure. Taken together, our findings reveal a novel mechanism of depression manifestation, whereby elevated GCs levels regulate PDK2 transcription via GR, thereby impairing brain energy metabolism and contributing to the onset of this condition.

The association between stress, emotional states, and tinnitus: a mini-review.

Extensive literature supporting the view of tinnitus induced stress in patients is available. However, limited evidence has been produced studying the opposite, that is, does stress cause tinnitus? The hypothalamus pituitary adrenal axis, one of the main neuroendocrine systems involved in stress response, is commonly disturbed in tinnitus patients. Patients with chronic tinnitus have been shown to develop abnormal responses to psycho-social stress, where the hypothalamus pituitary adrenal axis response is weaker and delayed, suggesting chronic stress contributes to the development of chronic tinnitus. The sympathetic branch of the autonomic nervous system also plays a major role in stress response and its chronic hyperactivity seems to be involved in developing tinnitus. Psycho-social stress has been shown to share the same probability of developing tinnitus as occupational noise and contributes to worsening tinnitus. Additionally, exposure to high stress levels and occupational noise doubles the likelihood of developing tinnitus. Interestingly, short-term stress has been shown to protect the cochlea in animals, but chronic stress exposure has negative consequences. Emotional stress also worsens pre-existing tinnitus and is identified as an important indicator of tinnitus severity. Although there is limited body of literature, stress does seem to play a vital role in the development of tinnitus. This review aims to highlight the association between stress, emotional states, and the development of tinnitus while also addressing the neural and hormonal pathways involved.

Neurobiological mechanisms involved in maternal deprivation-induced behaviours relevant to psychiatric disorders.

Parental care is essential for proper development of stress response and emotion-related behaviours. Epidemiological studies show that parental loss in childhood represents a major risk factor for the development of mental disorders throughout the lifespan, including schizophrenia, depression, and anxiety. In most mammalian species, the mother is the main source of care and maternal behaviours regulate several physiological systems. Maternal deprivation (DEP) for 24 h is a paradigm widely used to disinhibit the hypothalamic-pituitary-adrenal axis response to stress during the stress hyporesponsive period. In this mini-review we will highlight the main DEP-induced neurobiological and behavioural outcomes, including alterations on stress-related hormones, neurogenesis, neurotransmitter/neuromodulatory systems and neuroinflammation. These neurobiological changes may be reflected by aberrant behaviours, which are relevant to the study of mental disorders. The evidence indicates that DEP consequences depend on the sex, the age when the DEP takes place and the age when the animals are evaluated, reflecting dynamic plasticity and individual variability. Individual variability and sex differences have a great relevance for the study of biological factors of stress resilience and vulnerability and the DEP paradigm is a suitable model for evaluation of phenotypes of stress- and emotion-related psychopathologies.

Magnesium suppresses in vivo oxidative stress and ex vivo DNA damage induced by protracted ACTH treatment in rats.

Oxidative stress, arising from disrupted balance between reactive oxygen/nitrogen species (ROS/RNS) and antioxidant defences, has been implicated in the pathogenesis of stress-related disorders. There is a growing body of evidence that supports the relationship between the activity of the hypothalamic-pituitary-adrenal (HPA) stress system, oxidative stress and magnesium (Mg) homeostasis. The present study aimed to explore the gap in our current understanding of antigenotoxic and protective effects of Mg supplementation against excessive ROS production in male rats during chronic treatment with adrenocorticotropic hormone (ACTH). Our findings show that exposure to exogenous ACTH (10μg/day, s.c., for 21 days), as one of the key mediators of the HPA axis and stress response, produced an increase in superoxide anion levels and a decrease in superoxide dismutase activity in plasma. We observed that Mg supplementation, starting seven days prior to ACTH treatment and lasting 28 days (300mg/L of drinking water, per os), abolished these effects in experimental animals. Moreover, our study reveals that ACTH increased the susceptibility of peripheral blood lymphocytes to ex vivo H2O2-induced total and high-level oxidative DNA damage, while Mg completely reversed these effects. Collectively, these results highlight the promising role of Mg in stress-related conditions accompanied by increased oxidative stress in animals and support further investigation using human dietary trials.

Methylation and expression of glucocorticoid receptor exon-1 variants and FKBP5 in teenage suicide-completers

A dysregulated hypothalamic-pituitary-adrenal (HPA) axis has repeatedly been demonstrated to play a fundamental role in psychiatric disorders and suicide, yet the mechanisms underlying this dysregulation are not clear. Decreased expression of the glucocorticoid receptor (GR) gene, which is also susceptible to epigenetic modulation, is a strong indicator of impaired HPA axis control. In the context of teenage suicide-completers, we have systematically analyzed the 5’UTR of the GR gene to determine the expression levels of all GR exon-1 transcript variants and their epigenetic state. We also measured the expression and the epigenetic state of the FK506-binding protein 51 (FKBP5/FKBP51), an important modulator of GR activity. Furthermore, steady-state DNA methylation levels depend upon the interplay between enzymes that promote DNA methylation and demethylation activities, thus we analyzed DNA methyltransferases (DNMTs), ten-eleven translocation enzymes (TETs), and growth arrest- and DNA-damage-inducible proteins (GADD45). Focusing on both the prefrontal cortex (PFC) and hippocampus, our results show decreased expression in specific GR exon-1 variants and a strong correlation of DNA methylation changes with gene expression in the PFC. FKBP5 expression is also increased in both areas suggesting a decreased GR sensitivity to cortisol binding. We also identified aberrant expression of DNA methylating and demethylating enzymes in both brain regions. These findings enhance our understanding of the complex transcriptional regulation of GR, providing evidence of epigenetically mediated reprogramming of the GR gene, which could lead to possible epigenetic influences that result in lasting modifications underlying an individual’s overall HPA axis response and resilience to stress.

Mild daily stress, in interaction with NR3C1 DNA methylation levels, is linked to alterations in the HPA axis and ANS response to acute stress in early adolescents

BackgroundDaily Hassles (DH) or daily stress - is a mild type of stressor with unique contributions to psychological distress. Yet, most prior studies that investigate the effects of stressful life experiences focus on childhood trauma or on early life stress and little is known about the effects of DH on epigenetic changes in stress system related genes and on the physiological response to social stressors. MethodsIn the present study, conducted among 101 early adolescents (mean age = 11.61; SD = 0.64), we investigated whether Autonomic Nervous System (ANS) (namely heart rate and heart rate variability) and Hypothalamic-Pituitary-Adrenal (HPA) axis functioning (measured as cortisol stress reactivity and recovery) are associated with DNA methylation (DNAm) in the glucocorticoid receptor gene (NR3C1), the level of DH and their interaction. To assess the stress system functioning the TSST protocol was used. ResultsOur findings show that higher NR3C1 DNAm in interaction with higher levels of daily hassles, is associated with blunted HPA axis reactivity to psychosocial stress. In addition, higher levels of DH are associated with extended HPA axis stress recovery. In addition, participants with higher NR3C1 DNAm had lower ANS adaptability to stress, specifically lower parasympathetic withdrawal; for heart rate variability this effect was strongest for participants with higher level of DH. ConclusionsThe observation that interaction effects between NR3C1 DNAm levels and daily stress on the functioning of the stress-systems, are already detectable in young adolescents, highlights the importance of early interventions, not only in the case of trauma, but also daily stress. This might help to prevent stress-induced mental and physical disorders later in life.