Optogenetic induction of chronic glucocorticoid exposure in early-life leads to blunted stress-response in larval zebrafish.

Early life stress (ELS) exposure alters stress susceptibility in later life and affects vulnerability to stress-related disorders, but how ELS changes the long-lasting responsiveness of the stress system is not well understood. Zebrafish provides an opportunity to study conserved mechanisms underlying the development and function of the stress response that is regulated largely by the neuroendocrine hypothalamus-pituitary-adrenal/interrenal (HPA/I) axis, with glucocorticoids (GC) as the final effector. In this study, we established a method to chronically elevate endogenous GC levels during early life in larval zebrafish. To this end, we employed an optogenetic actuator, beggiatoa photoactivated adenylyl cyclase, specifically expressed in the interrenal cells of zebrafish and demonstrate that its chronic activation leads to hypercortisolaemia and dampens the acute-stress evoked cortisol levels, across a variety of stressor modalities during early life. This blunting of stress-response was conserved in ontogeny at a later developmental stage. Furthermore, we observe a strong reduction of proopiomelanocortin (pomc)-expression in the pituitary as well as upregulation of fkbp5 gene expression. Going forward, we propose that this model can be leveraged to tease apart the mechanisms underlying developmental programming of the HPA/I axis by early-life GC exposure and its implications for vulnerability and resilience to stress in adulthood.

Salivary testosterone and cortisol response in acute stress modulated by seven sessions of mindfulness meditation in young males.

Stress is an established risk factor for negative health outcomes. Salivary cortisol and testosterone concentrations increase in response to acute psychosocial stress. It's crucial to reduce stress for health and well-being through evidence-based interventions. Body-mind interventions such as meditation and Tai Chi have shown reduced cortisol levels but mixed results in testosterone concentration after stress. To address this research gap, we conducted a pilot randomized controlled trial to examine the modulating effects of a short-term (seven 20-minute sessions) mindfulness meditation on testosterone and cortisol in response to acute stress. Using one form of mindfulness meditation - Integrative Body-Mind Training (IBMT) and an active control-relaxation training (RT), we assessed salivary cortisol and testosterone concentrations at three stages of stress intervention - rest, stress, and an additional 20-min IBMT or RT practice. We found increased cortisol and testosterone concentrations after acute stress in both groups, but testosterone rise was not associated with cortisol rise. Moreover, an additional practice immediately after stress produced higher testosterone concentrations in the IBMT group than the RT group, whereas cortisol concentration increased in the RT group than in the IBMT group at the same time point. These findings indicate that brief mindfulness intervention modulates a dual-hormone profile of testosterone and cortisol in response to acute stress presumably via the co-regulation of hypothalamus-pituitary-adrenal and hypothalamus-pituitary-testicular axes.

Alterations in Serum miR-126-3p Levels over Time: A Marker of Pituitary Insufficiency following Head Trauma.

INTRODUCTION: Traumatic brain injuries (TBIs) pose a high risk of pituitary insufficiency development in patients. We have previously reported alterations in miR-126-3p levels in sera from patients with TBI-induced pituitary deficiency. METHODS: To investigate why TBI-induced pituitary deficiency develops only in some patients and to reveal the relationship between miR-126-3p with hormone axes, we used mice that were epigenetically modified with miR-126-3p at the embryonic stage. These modified mice were subjected to mild TBI (mTBI) according to the Marmarou's weight-drop model at 2 months of age. The levels of miR-126-3p were assessed at 1 and 30 days in serum after mTBI. Changes in miR-126-3p levels after mTBI of wild-type and miR-126-3p* modified mouse lines validated our human results. Additionally, hypothalamus, pituitary, and adrenal tissues were analyzed for transcripts and associated serum hormone levels. RESULTS: We report that miR-126-3p directly affects hypothalamus-pituitary-adrenal (HPA) axis upregulation and ACTH secretion in the acute phase after mTBI. We also demonstrated that miR-126-3p suppresses Gnrh transcripts in the hypothalamus and pituitary, but this is not reflected in serum FSH/LH levels. The increase in ACTH levels in the acute phase may indicate that upregulation of miR-126-3p at the embryonic stage has a protective effect on the HPA axis after TBI. Notably, the most prominent transcriptional response is found in the adrenals, highlighting their role in the pathophysiology of TBI. CONCLUSION: Our study revealed the role of miR-126-3p in TBI and pituitary deficiency developing after TBI, and the obtained data will significantly contribute to elucidating the mechanism of pituitary deficiency development after TBI and development of new diagnostic and treatment strategies.

Predicting postoperative hypocortisolism in patients with non-aldosterone-producing adrenocortical adenoma: a retrospective single-centre study.

BACKGROUND: Limited information exists on postoperative hypocortisolism and hypothalamus-pituitary-adrenal axis recovery in patients with adrenal incidentaloma following unilateral adrenalectomy. We evaluated frequency of postoperative hypocortisolism and predictors for recovery in non-aldosterone-producing adrenocortical adenoma patients after unilateral adrenalectomy. METHODS: A retrospective analysis of 32 adrenal incidentaloma patients originally included in the ITACA trial (NCT04127552) with confirmed non-aldosterone-producing adrenocortical adenoma undergoing unilateral adrenalectomy from September 2019 to April 2023 was conducted. Preoperative assessments included adrenal MRI, anthropometrics, evaluation of comorbidities, adrenal function assessed via ACTH, urinary free cortisol, and 1 mg dexamethasone suppression test. ACTH and serum cortisol or Short Synacthen test were performed within 6 days, 6 weeks, 6 months, and a year after surgery. RESULTS: Six days postoperative, 18.8% of patients had normal adrenal function. Among those with postoperative hypocortisolism, 53.8% recovered by 6 weeks. Patients with earlier adrenal recovery (6 weeks) had lower preoperative 1 mg dexamethasone suppression test (median 1 mg dexamethasone suppression test 76.2 [61.8-111.0] nmol/L vs 260.0 [113.0-288.5] nmol/L, p < 0.001). Univariate analysis showed preoperative 1 mg dexamethasone suppression test negatively related with baseline ACTH levels (r = - 0.376; p = 0.041) and negatively associated with the 6-week baseline (r = - 0.395, p = 0.034) and 30-min cortisol levels during Short Synacthen test (r = - 0.534, p = 0.023). Logistic regression analysis demonstrated preoperative 1 mg dexamethasone suppression test as the only biochemical predictor for 6-week adrenal recovery: ROC curve identified a 1 mg dexamethasone suppression test threshold of 131 nmol/L predicting 6-week recovery with 89.5% sensitivity and 72.7% specificity (AUC 0.87; 95% CI 66.9-98.7, p < 0.001). Other preoperative assessments (tumor size, ACTH levels and anthropometrics) were not associated with postoperative hypothalamus-pituitary-adrenal axis function, but the presence of diabetes was associated with a lower probability of recovery (OR = 24.55, p = 0.036). ACTH levels increased postoperatively in all patients but did not predict hypothalamus-pituitary-adrenal axis recovery. CONCLUSIONS: The preoperative 1 mg dexamethasone suppression test cortisol value and presence of diabetes are the only relevant predictor of hypothalamus-pituitary-adrenal axis recovery in patients with non-aldosterone- producing adrenocortical adenoma undergoing surgery, regardless other clinical and biochemical variables. Notably, pre- and postoperative ACTH levels did not predict hypothalamus-pituitary-adrenal axis recovery. These findings point towards the potential for saving resources by optimizing their allocation during follow-up assessments for patients with non-aldosterone-producing adrenocortical adenoma undergoing unilateral adrenalectomy.

Effects of social environments on male primate HPG and HPA axis developmental programming.

Developmental plasticity is particularly important for humans and other primates because of our extended period of growth and maturation, during which our phenotypes adaptively respond to environmental cues. The hypothalamus-pituitary-gonadal (HPG) and hypothalamus-pituitary-adrenal (HPA) axes are likely to be principal targets of developmental "programming" given their roles in coordinating fitness-relevant aspects of the phenotype, including sexual development, adult reproductive and social strategies, and internal responses to the external environment. In social animals, including humans, the social environment is believed to be an important source of cues to which these axes may adaptively respond. The effects of early social environments on the HPA axis have been widely studied in humans, and to some extent, in other primates, but there are still major gaps in knowledge specifically relating to males. There has also been relatively little research examining the role that social environments play in developmental programming of the HPG axis or the HPA/HPG interface, and what does exist disproportionately focuses on females. These topics are likely understudied in males in part due to the difficulty of identifying developmental milestones in males relative to females and the general quiescence of the HPG axis prior to maturation. However, there are clear indicators that early life social environments matter for both sexes. In this review, we examine what is known about the impact of social environments on HPG and HPA axis programming during male development in humans and nonhuman primates, including the role that epigenetic mechanisms may play in this programming. We conclude by highlighting important next steps in this research area.

Role of Epigenetic Modification in the Intergeneration Transmission of War Trauma.

War trauma has been linked to changes in the neuroendocrine and immunological systems and increases the risk of physical disorders. Traumatic events during the war may have long-term repercussions on psychological and biological parameters in future generations, implying that traumatic stress may have transgenerational consequences. This article addresses how epigenetic mechanisms, which are a key biological mechanism for dynamic adaptation to environmental stressors, may help explain the long-term and transgenerational consequences of trauma. In war survivors, epigenetic changes in genes mediating the hypothalamus-pituitary-adrenal axis, as well as the immune system, have been reported. These genetic modifications may cause long-term changes in the stress response as well as physical health risks. Also, the finding of biomarkers for diagnosing the possibility of psychiatric illnesses in people exposed to stressful conditions such as war necessitates extensive research. While epigenetic research has the potential to further our understanding of the effects of trauma, the findings must be interpreted with caution because epigenetic molecular mechanisms is only one piece of a complicated puzzle of interwoven biological and environmental components.

Neurobiological correlates of antisociality across adolescence and young adulthood: a multi-sample, multi-method study.

BACKGROUND: Antisociality across adolescence and young adulthood puts individuals at high risk of developing a variety of problems. Prior research has linked antisociality to autonomic nervous system and endocrinological functioning. However, there is large heterogeneity in antisocial behaviors, and these neurobiological measures are rarely studied conjointly, limited to small specific studies with narrow age ranges, and yield mixed findings due to the type of behavior examined. METHODS: We harmonized data from 1489 participants (9-27 years, 67% male), from six heterogeneous samples. In the resulting dataset, we tested relations between distinct dimensions of antisociality and heart rate, pre-ejection period (PEP), respiratory sinus arrhythmia, respiration rate, skin conductance levels, testosterone, basal cortisol, and the cortisol awakening response (CAR), and test the role of age throughout adolescence and young adulthood. RESULTS: Three dimensions of antisociality were uncovered: 'callous-unemotional (CU)/manipulative traits', 'intentional aggression/conduct', and 'reactivity/impulsivity/irritability'. Shorter PEPs and higher testosterone were related to CU/manipulative traits, and a higher CAR is related to both CU/manipulative traits and intentional aggression/conduct. These effects were stable across age. CONCLUSIONS: Across a heterogeneous sample and consistent across development, the CAR may be a valuable measure to link to CU/manipulative traits and intentional aggression, while sympathetic arousal and testosterone are additionally valuable to understand CU/manipulative traits. Together, these findings deepen our understanding of the fundamental mechanisms underlying different components of antisociality. Finally, we illustrate the potential of using current statistical techniques for combining multiple datasets to draw robust conclusions about biobehavioral associations.

Sex-specific behavioral and physiological changes during single parenting in a biparental species, Columba livia.

Many species exhibit biparental care to maximize fitness. When a partner is lost, the surviving partner may alter their behavior to compensate offspring. Whether both sexes use the same physiological mechanisms to manifest their change in behavior remains elusive. We investigated behaviors and mechanisms associated with the alteration of parental care post-partner removal in a biparental avian species, the rock dove (Columba livia). We hypothesized that rock dove single parents experience sex-biased changes in neural genomic transcription and reproductive behaviors, and these changes are related to chick development. We manipulated parental partner presence and measured parental attendance, offspring growth, gene expression of glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) in the pituitary, and GR, MR, and estrogen receptor beta (ER-ß) in the hypothalamus. We also measured circulating plasma concentrations of the stress-associated hormone corticosterone and the parental care-associated hormone prolactin. We also quantified prolactin gene (PRL) expression changes in the pituitary, as well as prolactin receptor (PRLR) expression in the hypothalamus and pituitary. We found that single mothers and fathers maintained similar provisioning levels as paired parents, but spent less cumulative time brooding chicks. Chicks of single parents were smaller than paired-parented chicks after three days post-hatch. Mothers in both treatment groups experienced higher expression of hypothalamic GR as compared to fathers. Single parents experienced lower PRL gene expression in the pituitary as compared to paired parents. No significant differences were found for the circulating hormones or other genes listed.

A Prospective Analysis of the Metyrapone Short Test Using Targeted and Untargeted Metabolomics.

INTRODUCTION: The present study aimed to prove the metyrapone short test in a day clinic to be suitable for examining the integrity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with suspected secondary and tertiary adrenal insufficiency and to identify novel effector molecules in acute stress response. METHODS: 44 patients were prospectively enrolled. Based on stimulated 11-deoxycortisol levels, patients were divided into a physiological (11-deoxycortisol ≥70 µg/L) and a pathological (11-deoxycortisol <70 µg/L) response group. Clinical follow-up examination was performed for validation. Ultraperformance liquid chromatography tandem mass spectrometry and a Fourier-transform-ion-cyclotron-resonance-mass-spectrometry were used for targeted and untargeted steroid metabolomics. RESULTS: At baseline, lower levels of cortisone (42 vs. 50 nmol/L, p = 0.048) and 17-OH-progesterone (0.6 vs. 1.2 nmol/L, p = 0.041) were noted in the pathological response group. After metyrapone administration, the pathological response group exhibited significantly lower 11-deoxycortisol (39.0 vs. 94.2 µg/L, p < 0.001) and ACTH (49 vs. 113 pg/mL, p < 0.001) concentrations as well as altered upstream metabolites. Untargeted metabolomics identified a total of 76 metabolites to be significantly up- or downregulated by metyrapone. A significant increase of the bile acid glycochenodeoxycholic acid (GCDC, p < 0.01) was detected in both groups with an even stronger increase in the physiological response group. After a mean follow-up of 17.2 months, an 11-deoxycortisol cut-off of 70 µg/L showed a high diagnostic performance (sensitivity 100%, specificity 96%). CONCLUSION: The metyrapone short test is safe and feasible in a day clinic setting. The alterations of the bile acid GCDC indicate that the liver might be involved in the acute stress response of the HPA axis.

The Involvement of the Hypothalamus-Pituitary-Adrenal Axis in the Development of Hyperalgesia during the Early Postoperative Period.

INTRODUCTION: Hyperalgesia frequently occurs after surgery and is associated with adverse effects on surgical outcomes. Thus, we aimed to examine whether the hypothalamus-pituitary-adrenal (HPA) axis function after surgery is involved in the development of postoperative hyperalgesia. METHODS: Surgery- and pain-related variables were measured 24 and 48 h after the first and second total knee arthroplasties (TKAs) in postmenopausal patients undergoing 1-week-interval staged bilateral TKA. Two sets of saliva samples were consecutively collected from patients before (pre-T1) and 1 week after (post-T1) the first TKA (n = 69). HPA axis function was analyzed in a subgroup of 20 patients with a typical cortisol awakening response (CAR) in both the sets of saliva samples. RESULTS: Surgery-related variables were comparable between the first and second TKAs. However, pain-related variables (pain ratings and the amount of opioid analgesics consumed) were greater after the second than the first TKA. Cortisol and dehydroepiandrosterone (DHEA) secretion during the post-awakening period (CARauc and Daucawk, respectively) was higher at post-T1 than at pre-T1, but the molar CARauc/Daucawk ratio was comparable between the time points examined. No relationship was observed between the pre-T1 CARauc and pain ratings after the first TKA. However, post-T1 CARauc showed a positive correlation with pain ratings after the second TKA. Postoperative pain ratings were negatively correlated with Daucawk and positively correlated with the molar CARauc/Daucawk ratio at all examined time points. DISCUSSION/CONCLUSION: The results suggest that adrenocortical steroidogenic activity favoring the production of cortisol over DHEA after surgery may contribute to the development of hyperalgesia during the early postoperative period.

Immediate and Delayed Salivary Cytokine Responses during Repeated Exposures to Cold Pressor Stress.

INTRODUCTION: Excessive stress is increasingly recognized as an important trigger of many diseases prevalent in modern societies, and monitoring such stress-related effects could aid prevention. The measurement of salivary markers of inflammation is emerging as a promising tool to non-invasively quantify stress' effects on immune processes in everyday life and thereby detect early aberrations before the manifestation of serious health problems. However, more laboratory-controlled research is needed in order to establish the timescale and determinants of salivary cytokine responses to acute stress. METHODS: We repeatedly exposed participants to Cold Pressor Stress Test (CPT) or a control procedure and measured a wide array of salivary cytokines as well as subjective, cardiovascular, and cortisol stress reactions. CPT exposure was repeated every 15 min, 3 times in total, with a duration of 3 min each. Saliva was sampled immediately after the first two exposures as well as in 15-min intervals until 60 min after the onset of the first intervention. RESULTS: We found that many cytokines were detectable in saliva. Specific stress effects were limited to IL-8 and IL-6, however, which decreased immediately or 15 min after stress onset, respectively. Moreover, IL-8 was negatively correlated to cortisol output in the stress but not in the control group. Significant increases were also observed in salivary TNFα and IFNγ; however, these effects were similar under both stress and control conditions. DISCUSSION: Our results show that particular salivary cytokines may be sensitive to immediate effects of acute CPT-induced stress and also highlight the importance of employing control procedures to discern stress effects from unrelated variations in salivary cytokines.

Resilience as a predictor of habituation.

Habituation refers to the physiological adaptation to recurrent stressors, which can be measured by cortisol levels, and is considered a central mechanism in reducing allostatic load. Resilience, a potential factor influencing stress reduction, is the focus of this study. Specifically, the study aims to investigate the impact of resilience, as assessed by the Brief Resilience Scale (BRS), on habituation. The Trier Social Stress Test (TSST) was used as the recurrent stressor, and it was administered to each of the 56 subjects at 4 consecutive measurements. To assess habituation, various physiological parameters including the area under the curve with respect to the ground (AUCg) and with respect to the increase (AUCi), cortisol peak, slope from baseline to peak, and recovery were calculated. Mixed linear models were employed to examine the differences in the influence of resilience on habituation across the different time points. The findings indicate that the influence of resilience significantly varies from the first to the fourth measurement time point for AUCg (p = .048), while no significant differences were observed for the other cortisol parameters. The effects plot suggests that individuals with higher levels of resilience exhibit lower AUCg values throughout the measurements. These findings provide initial evidence supporting resilience as a predictor of cortisol habituation. However, future studies should also consider dynamic resilience models, utilizing longitudinally assessed resilience as a predictor for habituation, to explore whether resilience acts as a determinant of habituation or if habituation itself constitutes a resilience mechanism.

Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress.

Stress-induced cortical alertness is maintained by a heightened excitability of noradrenergic neurons innervating, notably, the prefrontal cortex. However, neither the signaling axis linking hypothalamic activation to delayed and lasting noradrenergic excitability nor the molecular cascade gating noradrenaline synthesis is defined. Here, we show that hypothalamic corticotropin-releasing hormone-releasing neurons innervate ependymal cells of the 3rd ventricle to induce ciliary neurotrophic factor (CNTF) release for transport through the brain's aqueductal system. CNTF binding to its cognate receptors on norepinephrinergic neurons in the locus coeruleus then initiates sequential phosphorylation of extracellular signal-regulated kinase 1 and tyrosine hydroxylase with the Ca2+-sensor secretagogin ensuring activity dependence in both rodent and human brains. Both CNTF and secretagogin ablation occlude stress-induced cortical norepinephrine synthesis, ensuing neuronal excitation and behavioral stereotypes. Cumulatively, we identify a multimodal pathway that is rate-limited by CNTF volume transmission and poised to directly convert hypothalamic activation into long-lasting cortical excitability following acute stress.

A transient reduction in circulating corticosterone reduces object neophobia in male house sparrows.

Aversive reactions to novelty (or "neophobia") have been described in a wide variety of different animal species and can affect an individual's ability to exploit new resources and avoid potential dangers. However, despite its ecological importance, the proximate causes of neophobia are poorly understood. In this study, we tested the role of glucocorticoid hormones in neophobia in wild-caught house sparrows (Passer domesticus, n = 11 males) by giving an injection of the drug mitotane that reduced endogenous corticosterone for several days or a vehicle control, and then examined the latency to feed when the food dish was presented with or without a novel object in, on, or near the dish. Each sparrow was exposed to multiple novel object and control trials and received both vehicle control and mitotane treatments, with a week between treatments to allow the drug to wash out. As found previously, all novel objects significantly increased sparrows' latency to feed compared to no object present. Reducing corticosterone using mitotane significantly reduced the latency to feed in the presence of novel objects. In control trials without objects, mitotane had no significant effects on feeding time. Although we have shown that corticosterone affects neophobia, further studies using specific receptor agonists and antagonists will help clarify the neurobiological mechanisms involved and determine whether baseline or stress-induced corticosterone is driving this effect. These results suggest that increased glucocorticoids (e.g., due to human-induced stressors) could increase neophobia, affecting the ability of individuals to exploit novel resources, and, ultimately, to persist in human-altered environments.

Brain Transcriptome Responses to Dexamethasone Depending on Dose and Sex Reveal Factors Contributing to Sex-Specific Vulnerability to Stress-Induced Disorders.

BACKGROUND: Glucocorticoid (GC) receptor (GR) signaling in the hypothalamus (Hyp) and in the superordinate limbic structures, such as the hippocampus (Hip), conveys feedback regulation of the neuroendocrine stress response and acts upon other neurobiological functions that ultimately influence mental health. These responses are strongly influenced by sex, but the molecular causes are still largely unexplored. METHODS: To investigate GR targets and their GC sensitivity in the Hyp and Hip, we treated juvenile male and female piglets with 10 (D10) or 60 (D60) µg/kg dexamethasone (DEX), a selective GR agonist, and analyzed transcriptome responses compared to a saline control group using RNA sequencing. RESULTS: Both doses influenced similar biological functions, including cellular response to lipid and immune cell-related functions, but the transcriptional response to D10 was considerably weaker, particularly in the Hip. Weighted Gene Co-expression Network Analysis revealed a network of genes coordinately regulated by DEX in both structures, among which the alpha-arrestin ARRDC2 takes a central position. Distinct functional groups of genes were differentially regulated by DEX between sexes depending on the dose; at D10, these included particularly mitochondrial genes, whereas at D60 interferon signaling and lipid homeostasis genes were enriched. The general and sex-specific transcriptional responses to DEX highlight microglia as the prominent target. Several key marker genes of disease-associated microglia were regulated by DEX depending on sex, such as TREM2 and LPL. CONCLUSION: The discovered expression signatures suggest that DEX induced a dysfunctional state of microglia in males, while in females microglia were primed, which could entail predisposition for different mental disorders.

Chronic stress and captivity alter the cloacal microbiome of a wild songbird.

There are complex interactions between an organism's microbiome and its response to stressors, often referred to as the 'gut-brain axis'; however, the ecological relevance of this axis in wild animals remains poorly understood. Here, we used a chronic mild stress protocol to induce stress in wild-caught house sparrows (Passer domesticus), and compared microbial communities among stressed animals, those recovering from stress, captive controls (unstressed) and a group not brought into captivity. We assessed changes in microbial communities and abundance of shed microbes by culturing cloacal samples on multiple media to select for aerobic and anaerobic bacteria and fungi. We complemented this with cultivation-independent 16S and ITS rRNA gene amplification and sequencing, pairing these results with host physiological and immune metrics, including body mass change, relative spleen mass and plasma corticosterone concentrations. We found significant effects of stress and captivity on the house sparrow microbiomes, with stress leading to an increased relative abundance of endotoxin-producing bacteria - a possible mechanism for the hyperinflammatory response observed in captive avians. While we found evidence that the microbiome community partially recovers after stress cessation, animals may lose key taxa, and the abundance of endotoxin-producing bacteria persists. Our results suggest an overall link between chronic stress, host immune system and the microbiome, with the loss of potentially beneficial taxa (e.g. lactic acid bacteria), and an increase in endotoxin-producing bacteria due to stress and captivity. Ultimately, consideration of the host's microbiome may be useful when evaluating the impact of stressors on individual and population health.

Transgenerational impact of topical steroid application on superoxide dismutase activities of hypothalamus-pituitary-adrenal axis in rats.

Topical steroids (TS) have been widely prescribed since the 1950s. This study investigated for the first time the transgenerational effects of TS on the antioxidant mechanism of the hypothalamus-pituitary-adrenal (HPA) axis, both in prenatal and infancy. Three generations (F1, F2, and F3) and prenatal group (P) were investigated in both sexes with two different time points; P45th and P75th day were accepted as puberty and early adulthood, respectively. Clobetasol propionate 0.05% was used as TS. Quantitative real-time PCR was performed to expressional analyses of Sod1, Sod2, and Sod3 genes in the HPA tissues. The Sod mRNA expression of the HPA belonging to P and F1 groups revealed similar results in both genders. The downregulation in the adrenal Sod level was determined in P and F1, F2, and F3 generations in both genders, especially in females (p < 0.05). The Sod activities in the pituitary of all groups were downregulated in female rats (p < 0.05). Interestingly, in male rats, Sod2 and Sod3 were not expressed in the pituitary compared with the control on the day P45, while Sod2 and Sod3 expressions were determined in all the groups on day P75. Sod1 overexpression was found in pituitary and hypothalamus of males in the F3 generation. This study showed that TS applied in infancy had a transgenerational adverse effect on antioxidant defense mechanisms, especially in the adrenal gland.

Heat-Stress Preconditioning Attenuates Behavioral Responses to Psychological Stress: The Role of HSP-70 in Modulating Stress Responses.

Exposure to high ambient temperature is a stressor that influences both biological and behavioral functions and has been previously shown to have an extensive impact on brain structure and function. Physiological, cellular and behavioral responses to heat-stress (HS) (40-41 °C, 2 h) were evaluated in adult male Sprague-Dawley rats. The effect of HS exposure before predator-scent stress (PSS) exposure (i.e., HS preconditioning) was examined. Finally, a possible mechanism of HS-preconditioning to PSS was investigated. Immunohistochemical analyses of chosen cellular markers were performed in the hippocampus and in the hypothalamic paraventricular nucleus (PVN). Plasma corticosterone levels were evaluated, and the behavioral assessment included the elevated plus-maze (EPM) and the acoustic startle response (ASR) paradigms. Endogenous levels of heat shock protein (HSP)-70 were manipulated using an amino acid (L-glutamine) and a pharmacological agent (Doxazosin). A single exposure to an acute HS resulted in decreased body mass (BM), increased body temperature and increased corticosterone levels. Additionally, extensive cellular, but not behavioral changes were noted. HS-preconditioning provided behavioral resiliency to anxiety-like behavior associated with PSS, possibly through the induction of HSP-70. Targeting of HSP-70 is an attractive strategy for stress-related psychopathology treatment.

Vasopressin V1B Receptor Antagonists as Potential Antidepressants.

Accumulating evidence shows that certain populations of depressed patients have impaired hypothalamus-pituitary-adrenal (HPA) axis function. Arginine-vasopressin (AVP) is one of the primary factors in HPA axis regulation under stress situations, and AVP and its receptor subtype (V1B receptor) play a pivotal role in HPA axis abnormalities observed in depression. Based on this hypothesis, several non-peptide V1B receptor antagonists have been synthesized, and the efficacies of some V1B receptor antagonists have been investigated in both animals and humans. V1B receptor antagonists exert antidepressant-like effects in several animal models at doses that attenuate the hyperactivity of the HPA axis, and some of their detailed mechanisms have been delineated. These results obtained in animal models were, at least partly, reproduced in clinical trials. At least 2 V1B receptor antagonists (TS-121 and ABT-436) showed tendencies to reduce the depression scores of patients with major depressive disorder at doses that attenuate HPA axis hyperactivity or block the pituitary V1B receptor. Importantly, TS-121 showed a clearer efficacy for patients with higher basal cortisol levels than for those with lower basal cortisol levels, which was consistent with the hypothesis that V1B receptor antagonists may be more effective for patients with HPA axis hyperactivity. Therefore, V1B receptor antagonists are promising approaches for the treatment of depression involving HPA axis impairment such as depression.

Reduced growth capacity of preimplantation mouse embryos in chronic unpredictable stress model.

Psychological stress can affect female reproduction by deteriorating oocyte quality, but the molecular mechanism is unclear. In this study, we used the chronic unpredictable stress model to study the effect of psychological stress on mouse oocyte competence during preimplantation stage, and RNA sequencing in single oocytes to analyze differential gene expression at the transcription level. Stress changed the serum levels of glucocorticoids and reduced oocyte developmental potential, depending on the strength of the stress. Strong stress (two stressors per day) reduced the fertilization rate and induced significant apoptosis in blastocysts. Moderate stress (one stressor per day) reduced the cleavage rate and blastocyst formation rate. Weak stress (one stressor every 2 days) did not have any significant negative effect on the fertilization, cleavage, and blastocyst formation. Hatching rate was not affected by stress, but stress retarded the development of the expanded blastocysts and inhibited the embryo development at early stages. Transcriptome analysis revealed that stress disturbed the expression of cell cycle regulators and apoptotic genes. The hub genes identified through protein-protein interaction analysis include Msln, Ceacam12, Psg16, Psg17, and Psg23, which are all carcinoembryonic or related genes involved in cell adhesion, proliferation, and migration. Thus, stress was inhibitory on fertilization and early embryo development in mice.