Prenatal serotonin reuptake inhibitor antidepressant exposure, SLC6A4 genetic variations, and cortisol activity in 6-year-old children of depressed mothers: A cohort study.

Prenatal exposure to maternal depression and serotonin reuptake inhibitor (SRI) antidepressants both affect the development of the hypothalamic-pituitary-adrenal (HPA) system, possibly via the neurotransmitter serotonin (5HT). In a community cohort, we investigated the impact of two factors that shape prenatal 5HT signaling (prenatal SRI [pSRI] exposure and child SLC6A4 genotype) on HPA activity at age 6 years. Generalized estimating equation (GEE) models were used to study associations between cortisol reactivity, pSRI exposure, and child SLC6A4 genotype, controlling for maternal depression, child age, and sex (48 pSRI exposed, 74 nonexposed). Salivary cortisol levels were obtained at five time points during a laboratory stress challenge: arrival at the laboratory, following two sequential developmental assessments, and then 20 and 40 min following the onset of a stress-inducing cognitive/social task. Cortisol decreased from arrival across both developmental assessments, and then increased across both time points following the stress challenge in both groups. pSRI-exposed children had lower cortisol levels across all time points. In a separate GEE model, we observed a lower cortisol stress response among children with LG /S alleles compared with children with La/La alleles, and this was particularly evident among children of mothers reporting greater third trimester depressed mood. Our findings suggest that pSRI exposure and a genetic factor associated with modulating 5HT signaling shaped HPA reactivity to a laboratory stress challenge at school age.

Prevalence and risk factors for hypothalamus-pituitary-adrenal axis suppression in infants receiving glucocorticoid eye drops after ocular surgery.

PURPOSE: To examine the prevalence and risk factors for hypothalamus-pituitary-adrenal axis suppression (HPA axis suppression) in infants receiving glucocorticoid (GC) eye drops after ocular surgery. METHODS: This was a clinical observational cohort study. Children under the age of two receiving GC eye drops after cataract or glaucoma surgery between 1 January 2017 and 31 December 2021 were included at one centre. Medical history and results of the adrenocorticotropic hormone (ACTH) stimulation tests were obtained through patient charts. RESULTS: Forty-nine infants were included in the study. Ten out of 22 patients (45.5%) tested during treatment and two out of 27 patients (7.4%) tested after treatment cessation were diagnosed with HPA axis suppression. The duration of HPA axis suppression extended beyond 3 months in 8 out of 12 patients. Logistic regression showed that infants with HPA axis suppression had received a higher GC dose/body weight/day before the first ACTH test (p < 0.001). There was a 79% (95% CI:1.28;2.50) increase in the odds of having HPA axis suppression for a 0.01 mg GC increase/kg/day corresponding to an additional daily eye drop for an infant weighing 5 kg. There was an association between HPA axis suppression and number of days from surgery to test (p = 0.003), age at surgery (p = 0.035) and cumulated GC dose (p = 0.005). Three infants with HPA axis suppression had affected growth and one had Cushing-like features, but there were no cases of Addisonian crisis. CONCLUSION: Infants are at risk of having hypothalamus-pituitary-adrenal axis suppression if they receive a high daily glucocorticoid dose per weight by topical ocular administration. Infants receiving glucocorticoids after ocular surgery should be monitored clinically or by ACTH testing.

Suppression of adult cytogenesis in the rat brain leads to sex-differentiated disruption of the HPA axis activity.

OBJECTIVES: The action of stress hormones, mainly glucocorticoids, starts and coordinates the systemic response to stressful events. The HPA axis activity is predicated on information processing and modulation by upstream centres, such as the hippocampus where adult-born neurons (hABN) have been reported to be an important component in the processing and integration of new information. Still, it remains unclear whether and how hABN regulates HPA axis activity and CORT production, particularly when considering sex differences. MATERIALS AND METHODS: Using both sexes of a transgenic rat model of cytogenesis ablation (GFAP-Tk rat model), we examined the endocrinological and behavioural effects of disrupting the generation of new astrocytes and neurons within the hippocampal dentate gyrus (DG). RESULTS: Our results show that GFAP-Tk male rats present a heightened acute stress response. In contrast, GFAP-Tk female rats have increased corticosterone secretion at nadir, a heightened, yet delayed, response to an acute stress stimulus, accompanied by neuronal hypertrophy in the basal lateral amygdala and increased expression of the glucocorticoid receptors in the ventral DG. CONCLUSIONS: Our results reveal that hABN regulation of the HPA axis response is sex-differentiated.

Impact of Hydrocortisone and of CRH Infusion on the Hypothalamus-Pituitary-Adrenocortical Axis of Septic Male Mice.

PURPOSE: Sepsis is hallmarked by high plasma cortisol/corticosterone (CORT), low adrenocorticotropic hormone (ACTH), and high pro-opiomelanocortin (POMC). While corticotropin-releasing hormone-(CRH) and arginine-vasopressin (AVP)-driven pituitary POMC expression remains active, POMC processing into ACTH becomes impaired. Low ACTH is accompanied by loss of adrenocortical structure, although steroidogenic enzymes remain expressed. We hypothesized that treatment of sepsis with hydrocortisone (HC) aggravates this phenotype whereas CRH infusion safeguards ACTH-driven adrenocortical structure. METHODS: In a fluid-resuscitated, antibiotics-treated mouse model of prolonged sepsis, we compared the effects of HC and CRH infusion with placebo on plasma ACTH, POMC, and CORT; on markers of hypothalamic CRH and AVP signaling and pituitary POMC processing; and on the adrenocortical structure and markers of steroidogenesis. In adrenal explants, we studied the steroidogenic capacity of POMC. RESULTS: During sepsis, HC further suppressed plasma ACTH, but not POMC, predominantly by suppressing sepsis-activated CRH/AVP-signaling pathways. In contrast, in CRH-treated sepsis, plasma ACTH was normalized following restoration of pituitary POMC processing. The sepsis-induced rise in markers of adrenocortical steroidogenesis was unaltered by CRH and suppressed partially by HC, which also increased adrenal markers of inflammation. Ex vivo stimulation of adrenal explants with POMC increased CORT as effectively as an equimolar dose of ACTH. CONCLUSIONS: Treatment of sepsis with HC impaired integrity and function of the hypothalamic-pituitary-adrenal axis at the level of the pituitary and the adrenal cortex while CRH restored pituitary POMC processing without affecting the adrenal cortex. Sepsis-induced high-circulating POMC may be responsible for ongoing adrenocortical steroidogenesis despite low ACTH.

Glucocorticoid Production in Lymphoid Organs: Acute Effects of Lipopolysaccharide in Neonatal and Adult Mice.

Glucocorticoids (GCs) are critical modulators of the immune system. The hypothalamic-pituitary-adrenal (HPA) axis regulates circulating GC levels and is stimulated by endotoxins. Lymphoid organs also produce GCs; however, it is not known how lymphoid GC levels are regulated in response to endotoxins. We assessed whether an acute challenge of lipopolysaccharide (LPS) increases lymphoid levels of progesterone and GCs, and expression of steroidogenic enzymes and key HPA axis components (eg, corticotropin-releasing hormone [CRH], adrenocorticotropic hormone [ACTH]). We administered LPS (50 µg/kg intraperitoneally) or vehicle control to male and female C57BL/6J neonatal (postnatal day [PND] 5) and adult (PND90) mice and collected blood, bone marrow, thymus, and spleen 4 hours later. We measured progesterone, 11-deoxycorticosterone, corticosterone, and 11-dehydrocorticosterone via liquid chromatography-tandem mass spectrometry. We measured gene expression of key steroidogenic enzymes (Cyp11b1, Hsd11b1, and Hsd11b2) and HPA axis components (Crh, Crhr1, Pomc, and Mc2r) via quantitative polymerase chain reaction. At PND5, LPS induced greater increases in steroid levels in lymphoid organs than in blood. In contrast, at PND90, LPS induced greater increases in steroid levels in blood than in lymphoid organs. Steroidogenic enzyme transcripts were present in all lymphoid organs, and LPS altered steroidogenic enzyme expression predominantly in the spleen. Lastly, we detected transcripts of key HPA axis components in all lymphoid organs, and there was an effect of LPS in the spleen. Taken together, these data suggest that LPS regulates GC production by lymphoid organs, similar to its effects on the adrenal glands, and the effects of LPS might be mediated by local expression of CRH and ACTH.

The Type of Fat in the Diet Influences Regulatory Aminopeptidases of the Renin-Angiotensin System and Stress in the Hypothalamic-Pituitary-Adrenal Axis in Adult Wistar Rats.

(1) Background: Prolonged feeding with a high-fat diet (HFD) acts as a stressor by activating the functions of the hypothalamic-pituitary-adrenal gland (HPA) stress axis, accompanied of hypertension by inducing the renin-angiotensin-aldosterone system. Angiotensinases enzymes are regulatory aminopeptidases of angiotensin metabolism, which together with the dipeptidyl peptidase IV (DPP-IV), pyroglutamyl- and tyrosyl-aminopeptidase (pGluAP, TyrAP), participate in cognitive, stress, metabolic and cardiovascular functions. These functions appear to be modulated by the type of fat used in the diet. (2) Methods: To analyze a possible coordinated response of aminopeptidases, their activities were simultaneously determined in the hypothalamus, adenohypophysis and adrenal gland of adult male rats fed diets enriched with monounsaturated (standard diet (S diet) supplemented with 20% virgin olive oil; VOO diet) or saturated fatty acids (diet S supplemented with 20% butter and 0.1% cholesterol; Bch diet). Aminopeptidase activities were measured by fluorimetry using 2-Naphthylamine as substrates. (3) Results: the hypothalamus did not show differences in any of the experimental diets. In the pituitary, the Bch diet stimulated the renin-angiotensin system (RAS) by increasing certain angiotensinase activities (alanyl-, arginyl- and cystinyl-aminopeptidase) with respect to the S and VOO diets. DPP-IV activity was increased with the Bch diet, and TyrAP activity decrease with the VOO diet, having both a crucial role on stress and eating behavior. In the adrenal gland, both HFDs showed an increase in angiotensinase aspartyl-aminopeptidase. The interrelation of angiotensinases activities in the tissues were depending on the type of diet. In addition, correlations were shown between angiotensinases and aminopeptidases that regulate stress and eating behavior. (4) Conclusions: Taken together, these results support that the source of fat in the diet affects several peptidases activities in the HPA axis, which could be related to alterations in RAS, stress and feeding behavior.

HPA axis dysregulation is associated with differential methylation of CpG-sites in related genes.

DNA methylation shifts in Hypothalamic-pituitary-adrenal (HPA) axis related genes is reported in psychiatric disorders including hypersexual disorder. This study, comprising 20 dexamethasone suppression test (DST) non-suppressors and 73 controls, examined the association between the HPA axis dysregulation, shifts in DNA methylation of HPA axis related genes and importantly, gene expression. Individuals with cortisol level ≥ 138 nmol/l, after the low dose (0.5 mg) dexamethasone suppression test (DST) were classified as non-suppressors. Genome-wide methylation pattern, measured in whole blood using the EPIC BeadChip, investigated CpG sites located within 2000 bp of the transcriptional start site of key HPA axis genes, i.e.: CRH, CRHBP, CRHR-1, CRHR-2, FKBP5 and NR3C1. Regression models including DNA methylation M-values and the binary outcome (DST non-suppression status) were performed. Gene transcripts with an abundance of differentially methylated CpG sites were identified with binomial tests. Pearson correlations and robust linear regressions were performed between CpG methylation and gene expression in two independent cohorts. Six of 76 CpG sites were significantly hypermethylated in DST non-suppressors (nominal P < 0.05), associated with genes CRH, CRHR1, CRHR2, FKBP5 and NR3C1. NR3C1 transcript AJ877169 showed statistically significant abundance of probes differentially methylated by DST non-suppression status and correlated with DST cortisol levels. Further, methylation levels of cg07733851 and cg27122725 were positively correlated with gene expression levels of the NR3C1 gene. Methylation levels of cg08636224 (FKBP5) correlated with baseline cortisol and gene expression. Our findings revealed that DNA methylation shifts are involved in the altered mechanism of the HPA axis suggesting that new epigenetic targets should be considered behind psychiatric disorders.

Effect of Constant Illumination on the Function of the Hypothalamic-Pituitary-Adrenal Axis in Nonhuman Primates.

We studied the effect of constant illumination on the effects of administration of arginine vasopressin (AVP), one of the most important regulators of the key adaptive hypothalamic-pituitary-adrenal (HPA) axis under basal conditions and during stress, as well as on the circadian rhythm of activity of HPA axis and the pineal gland in laboratory primates. In young adult female rhesus monkeys exposed to constant illumination for 7 weeks, the rise in the concentration of ACTH and cortisol in response to administration of AVP was markedly reduced in comparison with both the basal period and with the control group of animals. In addition, a destructive effect of constant lighting on circadian rhythm of cortisol secretion was observed in the absence of significant circadian changes in melatonin secretion. The inhibitory effect of constant illumination on the function of the HPA axis under basal conditions and under conditions of its activation can reduce the body's adaptive abilities.

Rationale of a lower dexamethasone dose in prenatal congenital adrenal hyperplasia therapy based on pharmacokinetic modelling.

CONTEXT: Prenatal dexamethasone therapy is used in female foetuses with congenital adrenal hyperplasia to suppress androgen excess and prevent virilisation of the external genitalia. The traditional dexamethasone dose of 20 µg/kg/day has been used since decades without examination in clinical trials and is thus still considered experimental. OBJECTIVE: As the traditional dexamethasone dose potentially causes adverse effects in treated mothers and foetuses, we aimed to provide a rationale of a reduced dexamethasone dose in prenatal congenital adrenal hyperplasia therapy based on a pharmacokinetics-based modelling and simulation framework. METHODS: Based on a published dexamethasone dataset, a nonlinear mixed-effects model was developed describing maternal dexamethasone pharmacokinetics. In stochastic simulations (n = 1000), a typical pregnant population (n = 124) was split into two dosing arms receiving either the traditional 20 µg/kg/day dexamethasone dose or reduced doses between 5 and 10 µg/kg/day. Target maternal dexamethasone concentrations, identified from the literature, served as a threshold to be exceeded by 90% of mothers at a steady state to ensure foetal hypothalamic-pituitary-adrenal axis suppression. RESULTS: A two-compartment dexamethasone pharmacokinetic model was developed and subsequently evaluated to be fit for purpose. The simulations, including a sensitivity analysis regarding the assumed foetal:maternal dexamethasone concentration ratio, resulted in 7.5 µg/kg/day to be the minimum effective dose and thus our suggested dose. CONCLUSIONS: We conclude that the traditional dexamethasone dose is three-fold higher than needed, possibly causing harm in treated foetuses and mothers. The clinical relevance and appropriateness of our recommended dose should be tested in a prospective clinical trial.

A GLP-1 Receptor Agonist Inhibits Aldosterone Release in Healthy Volunteers.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are antidiabetic drugs with effects beyond antihyperglycemic action. The aim of the study was to examine whether a single dose of exenatide could be used as a stimulation test for the pituitary-adrenal axis. We carried out a single-group, open-label pilot clinical trial in an ambulatory setting. Ten healthy volunteers of both sexes with body weight>65 kg and age between 18-50 years were recruited. After fasting for 12 hours the subjects received 10 µg of exenatide solution subcutaneously. Blood samples were taken before the administration of exenatide and up to 150 minutes thereafter. The primary outcome was the maximal level of cortisol after the administration of exenatide. Single administration of exenatide 10 µg resulted in a modest increase in ACTH and cortisol levels, as compared to untreated values, and a decrease in blood glucose levels. Remarkably, a robust suppression of both renin and aldosterone levels occurred. We showed that acute administration of exenatide in a full therapeutic dose modestly stimulates the hypothalamic-pituitary-adrenal axis but inhibits the renin-aldosterone system. Further research is warranted to confirm this finding in the placebo-controlled study.

Elucidating the Possible Role of FoxO in Depression.

Forkhead box-O (FoxO) transcriptional factors perform essential functions in several physiological and biological processes. Recent studies have shown that FoxO is implicated in the pathophysiology of depression. Changes in the upstream mediators of FoxOs including brain-derived neurotrophic factor (BDNF) and protein kinase B have been associated with depressive disorder and the antidepressant agents are known to alter the phosphorylation of FoxOs. Moreover, FoxOs might be regulated by serotonin or noradrenaline signaling and the hypothalamic-pituitary-adrenal (HPA)-axis,both of them are associated with the development of the depressive disorder. FoxO also regulates neural morphology, synaptogenesis, and neurogenesis in the hippocampus, which accounts for the pathogenesis of the depressive disorder. The current article underlined the potential functions of FoxOs in the etiology of depressive disorder and formulate few essential proposals for further investigation. The review also proposes that FoxO and its signal pathway might establish possible therapeutic mediators for the management of depressive disorder.

Loss of vagal integrity disrupts immune components of the microbiota-gut-brain axis and inhibits the effect of Lactobacillus rhamnosus on behavior and the corticosterone stress response.

The vagus nerve is one of the major signalling components between the gut microbiota and brain. However, the exact relationship between gut-brain signaling along the vagus and the effects of gut microbes on brain function and behaviour is unclear. In particular, the relationship between the vagus nerve and immune signaling, that also appears to play a critical role in microbiota-gut-brain communication, has not been delineated. The aim of the present study was to determine the effect of subdiaphragmatic vagotomy on peripheral and central immune changes associated with the anxiolytic actions of L.rhamnosus. Male mice underwent vagotomy or sham surgery, followed by administration of L.rhamnosus for 14 days. L.rhamnosus administration following sham surgery resulted in reduced anxiety-like behaviour, and an attenuation of the hypothalamic-pituitary-adrenal axis (HPA axis), as indicated by reduced plasma corticosterone after acute restraint stress. These effects were associated with an increase in splenic T regulatory cells and a decrease in activated microglia in the hippocampus. The anxiolytic effects, HPA modulation and increase in T regulatory cells were prevented by vagotomy, whereas vagotomy alone led to a significant increase in activated microglia in the hippocampus that was not altered with L.rhamnosus treatment. Thus, both microbe induced and constitutive vagal signaling influences critical immune components of the microbiota-gut-brain axis. These findings suggest that, rather than acting as a direct neural link to the central nervous system, the role of the vagus nerve in gut-microbe to brain signalling is as an integral component of a bi-directional neuroimmunoendocrine pathway.

Transcriptomic study of the mechanism by which the Kai Yu Zhong Yu recipe improves oocyte quality in a stressed mouse model.

ETHNOPHARMACOLOGICAL RELEVANCE: The Kai Yu Zhong Yu recipe (KYZY) is a classic herbal formula in traditional Chinese medicine (TCM) that has been used to treat infertility associated with psychological stress for more than three hundred years. AIM OF THE STUDY: Psychological stress has major impacts on fertility, with variable outcomes depending on the nature, strength, and duration of the stress. Stress can directly disturb ovulation, oocyte quality, maturation, and embryo development. The aim of this study is to investigate the molecular mechanism by which KYZY improves oocyte developmental potential under psychological stress. MATERIALS AND METHODS: ICR female mice aged 4-5 weeks were randomly divided into five groups: control, stressed in the chronic unpredictable stress model (CUSM), and stressed plus KYZY treatment at 38.2 g/kg (KYZYH), 19.1 g/kg (KYZYM), or 9.6 g/kg (KYZYL). Ovary function was assessed by measuring serum levels of estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and anti-Müllerian hormone (AMH). Oocyte quality was evaluated in terms of reactive oxygen species (ROS) levels, apoptotic DNA fragmentation, and mitochondria distribution. We used RNA sequencing (RNAseq) to identify differentially expressed genes (DEGs) between groups and then further analyzed the DEGs for gene ontology (GO) term enrichment and protein-protein interactions. RESULTS: Mice in the stressed group had reduced serum E2, LH, and FSH as well as increased ROS levels, increased apoptosis, and disturbed mitochondria distribution in oocytes. Treatment with KYZY at all three doses reversed or ameliorated these negative effects of stress. DEG analysis identified 187 common genes between the two comparisons (stressed vs. control and KYZYM vs. stressed), 33 of which were annotated with six gene ontology (GO)'s biological process (BP) terms: cell differentiation, apoptosis, ATP synthesis, protein homo-oligomerization, neuron migration, and negative regulation of peptidase activity. Protein-protein interaction network analysis of DEGs identified key hub genes. Notably, the genes Atp5o and Cyc1 were both involved in the ATP synthesis and among the top three hub genes, suggesting that regulation of oocyte mitochondrial electron transport and ATP synthesis is important in the response to stress and also is a possible mechanism of action for KYZY. CONCLUSIONS: KYZY was effective in ameliorating the adverse effects of stress on oocyte competence, possibly by targeting the mitochondrial respiratory chain and ATP synthase.

Vagus nerve stimulation suppresses corticotropin-releasing factor-induced adrenocorticotropic hormone release in rats.

Adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome is characterized by hypothalamus-pituitary-adrenal axis dysfunction. As the neuroendocrinological axis has been shown to react under the regulation of the central nerve system through the corticotropin-releasing factor (CRF) releasing from the hypothalamic paraventricular nucleus. Whether one of the neuromodulation therapies, vagus nerve stimulation, is able to treat this neuroendocrinological disorder remains unknown. In this study, we explored the effects of vagus nerve stimulation (VNS) on CRF-induced serum ACTH level change in normal rats. After the vagus nerve electrode placement, the ACTH and corticosterone levels were measured multiple times before and after the administration of CRF (2 µg/kg) in switched-ON and -OFF groups, respectively, compared to the control group. Our results showed that 2 h continuous stimulation on the vagus nerve inhibited CRF-induced ACTH release up to 1 h compared with the control group, while the corticosterone level was not influenced. The vagus nerve might be a potential therapeutic target in the treatment of ACTH-dependent Cushing's syndrome disorders involving hypothalamus-pituitary-adrenal axis dysfunction.

HIV-1 Tat Protein Promotes Neuroendocrine Dysfunction Concurrent with the Potentiation of Oxycodone's Psychomotor Effects in Female Mice.

Human immunodeficiency virus (HIV) is associated with neuroendocrine dysfunction which may contribute to co-morbid stress-sensitive disorders. The hypothalamic-pituitary-adrenal (HPA) or -gonadal (HPG) axes are perturbed in up to 50% of HIV patients. The mechanisms are not known, but we have found the HIV-1 trans-activator of transcription (Tat) protein to recapitulate the clinical phenotype in male mice. We hypothesized that HPA and/or HPG dysregulation contributes to Tat-mediated interactions with oxycodone, an opioid often prescribed to HIV patients, in females. Female mice that conditionally-expressed the Tat1-86 protein [Tat(+) mice] or their counterparts that did not [Tat(-) control mice] were exposed to forced swim stress (or not) and behaviorally-assessed for motor and anxiety-like behavior. Some mice had glucocorticoid receptors (GR) or corticotropin-releasing factor receptors (CRF-R) pharmacologically inhibited. Some mice were ovariectomized (OVX). As seen previously in males, Tat elevated basal corticosterone levels and potentiated oxycodone's psychomotor activity in females. Unlike males, females did not demonstrate adrenal insufficiency and oxycodone potentiation was not regulated by GRs or CRF-Rs. Rather OVX attenuated Tat/oxycodone interactions. Either Tat or oxycodone increased anxiety-like behavior and their combination increased hypothalamic allopregnanolone. OVX increased basal hypothalamic allopregnanolone and obviated Tat or oxycodone-mediated fluctuations. Together, these data provide further evidence for Tat-mediated dysregulation of the HPA axis and reveal the importance of HPG axis regulation in females. HPA/HPG disruption may contribute vulnerability to affective and substance use disorders.

Melatonin Administration Accelerates Puberty Onset in Mice by Promoting FSH Synthesis.

Although melatonin has been extensively studied in animal reproduction, the mechanism of melatonin in puberty remains elusive. This study was designed to explore the effect of intraperitoneal administration of melatonin on puberty onset in female mice. The injection of melatonin into postnatal days 10 mice at a dose of 15 mg/kg accelerated the puberty onset in mice. Mechanistically, there was no difference in physical growth and serum Leptin levels after melatonin administration. Meanwhile, the serum levels of reproductive hormones involved in hypothalamic-pituitary-ovarian axis, such as FSH and estrogen level in serum were increased. The mRNA levels of GnRH and GnRHr were not affected by melatonin, while the expressions of FSHß in pituitary and Cyp19a1 in ovary were significantly up-regulated. In addition, melatonin still promoted FSH synthesis after ovariectomy. Furthermore, the enhanced activity of ERK1/2 signaling verified that the expression of FSHß increased in pituitary. We confirmed that melatonin promoted the FSH synthesis in pituitary, thereby increased serum estrogen levels and ultimately accelerated puberty onset. However, these effects of melatonin may be pharmacological due to the high dose. This study would help us to understand the functions of melatonin in pubertal regulation comprehensively.

The combination of fluoxetine and environmental enrichment reduces postpartum stress-related behaviors through the oxytocinergic system and HPA axis in mice.

Gestational stress can increase postpartum depression in women. To treat maternal depression, fluoxetine (FLX) is most commonly prescribed. While FLX may be effective for the mother, at high doses it may have adverse effects on the fetus. As environmental enrichment (EE) can reduce maternal stress effects, we hypothesized that a subthreshold dose of FLX increases the impact of EE to reduce anxiety and depression-like behavior in postpartum dams exposed to gestational stress. We evaluated this hypothesis in mice and to assess underlying mechanisms we additionally measured hypothalamic-pituitary-adrenal (HPA) axis function and brain levels of the hormone oxytocin, which are thought to be implicated in postpartum depression. Gestational stress increased anxiety- and depression-like behavior in postpartum dams. This was accompanied by an increase in HPA axis function and a decrease in whole-brain oxytocin levels in dams. A combination of FLX and EE remediated the behavioral, HPA axis and oxytocin changes induced by gestational stress. Central administration of an oxytocin receptor antagonist prevented the remediating effect of FLX + EE, indicating that brain oxytocin contributes to the effect of FLX + EE. These findings suggest that oxytocin is causally involved in FLX + EE mediated remediation of postpartum stress-related behaviors, and HPA axis function in postpartum dams.

Effects of hydrocortisone and yohimbine on selective attention to emotional cues.

INTRODUCTION: Facial expressions contain important affective information, and selective attention to facial expression provides an advantage in the face of loss, stress and danger. In addition, the sympathetic nervous system and hypothalamus-pituitary-adrenal axis mediate the organism's response to loss and danger. Here, we aimed at investigating the influence of sympathetic nervous system and hypothalamus-pituitary-adrenal axis activation on selective attention to affective facial stimuli. METHODS AND MATERIALS: One hundred-and-four healthy men between 18-35 years old (mean (standard deviation) age: 24.1 (3.5) years) participated in the study. We used a randomised, double-blind, placebo-controlled design. Participants received either: (a) yohimbine, (b) hydrocortisone, (c) yohimbine and hydrocortisone or (d) placebo only and participated in a dot-probe task with sad, happy and neutral faces. We collected salivary samples to measure cortisol and alpha amylase activity in addition to measurements of blood pressure and heart rate. Salivary cortisol served as correlate of hypothalamus-pituitary-adrenal axis activation and salivary alpha amylase activity, blood pressure and heart rate as correlates of sympathetic nervous system activation. Measurements were carried out before and after drug administration. RESULTS: We did not find a main effect or interaction effect of hydrocortisone or yohimbine administration on selective attention to happy faces. However, we found an interaction of yohimbine and hydrocortisone on selective attention to sad faces. Post-hoc t-test revealed an attentional bias away from sad stimuli and towards neutral faces in the hydrocortisone-only group. DISCUSSION: Only hydrocortisone administration led to an attentional bias away from sad faces. Future studies should investigate these effects in major depression disorder, as this disorder is characterised by glucocorticoid resistance and increased processing of sad stimuli.

The Volatile Oil of Zanthoxylum bungeanum Pericarp Improved the Hypothalamic-Pituitary-Adrenal Axis and Gut Microbiota to Attenuate Chronic Unpredictable Stress-Induced Anxiety Behavior in Rats.

BACKGROUND: Anxiety disorders (ADs) are the most prevalent mental disorders worldwide. Stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis and dysbiosis of gut microbiota seem to contribute to the onset of ADs. This study was designed to investigate the ameliorative effect of volatile oil of Zanthoxylum bungeanum (VOZB) on chronic unpredictable stress (CUS) induced anxiety behavior, as well as the altered HPA axis and gut microbiota. METHODS: Experimental rats were exposed to the CUS for 14 consecutive days. Meanwhile, VOZB was administered at doses of 50, 100 and 200 mg/kg/day for 14 days. The anxiety behavior was evaluated by elevated plus-maze (EPM) and open field (OF). The protein expressions and mRNA levels of corticotropin-releasing hormone (CRH) and glucocorticoid receptor (GR) in hypothalamus was determined, as well the hormone levels of HPA axis in serum. Furthermore, gut microbiota was detected by16S rRNA gene sequencing. The chemical constituents of VOZB were identified by GC-MS analysis. RESULTS: VOZB treatment (100 and 200 mg/kg/day) increased the ratio of open-arm entries and time in EPM test, as well as the central zone entries and time in OF test. Moreover, VOZB treatment reduced the protein expressions and mRNA levels of CRH, but elevated those of GR in hypothalamus. Similarly, the hormone levels of the HPA axis in serum were decreased by VOZB treatment. Besides, VOZB treatment restored the CUS-induced dysbiosis of gut microbiota, raising the Sobs and Chao indexes, inhibiting Lachnospiraceae, but facilitating Bacteroidales_S24-7_group, Lactobacillaceae, and Prevotellaceae. Additionally, Sobs and Chao indexes were negatively correlated to the serum corticosterone and CRH levels. CONCLUSION: VOZB showed an ameliorative effect on CUS-induced anxiety behavior, potentially via inhibiting activation of the HPA axis and restoring the dysbiosis of gut microbiota, thus improving the stress-induced abnormality of the microbiota-gut-brain axis.

Total glycosides from stems of Cistanche tubulosa alleviate depression-like behaviors: bidirectional interaction of the phytochemicals and gut microbiota.

BACKGROUND: As the most frequently used kidney-yang tonifying herb in traditional Chinese medicine, dried succulent stems of Cistanche tubulosa (Schenk) Wight (CT) have been shown to be effective in the treatment of depression. However, the antidepressant components and their underlying mechanism remain unclear. PURPOSE: To explore the active components of CT against depression, as well as the potential mechanisms. STUDY DESIGN AND METHODS: Behavioral despair tests were used to assess the antidepressant activities of polysaccharides, oligosaccharides and different glycoside-enriched fractions separated from CT, as well as the typical gut microbiota metabolites including 3-hydroxyphenylpropionic acid (3-HPP) and hydroxytyrosol (HT). Furthermore, the effects of bioactive fractions and metabolites on chronic unpredictable mild stress (CUMS) model were explored with multiple pharmacodynamics and biochemical analyses. Changes in colonic histology and the intestinal barrier were observed by staining and immunohistochemical analysis. Gut microbial features and tryptophan-kynurenine metabolism were explored using 16S rRNA sequencing and western-blotting, respectively. RESULTS: Total glycosides (TG) dramatically alleviated depression-like behaviors compared to different separated fractions, reflecting in the synergistic effects of phenylethanoid and iridoid glycosides on the hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, severe neuro- and peripheral inflammation, and deficiencies in 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor in the hippocampus. Moreover, TG mitigated low-grade inflammation in the colon and intestinal barrier disruption, and the abundances of several bacterial genera highly correlated with the HPA axis and inflammation in CUMS rats. Consistently, the expression of indoleamine 2, 3-dioxygenase 1 (IDO1) in the colon was significantly reduced after TG administration, accompanied by the suppression of tryptophan-kynurenine metabolism. On the other hand, HT also exerted a marked antidepressant effect by ameliorating HPA axis function, pro-inflammatory cytokine release, and tryptophan-kynurenine metabolism, while it was unable to largely adjust the disordered gut microbiota in the same manner as TG. Surprisingly, superior to fluoxetine, TG and HT could further improve dysfunction of the hypothalamic-pituitary-gonadal axis and abnormal cyclic nucleotide metabolism. CONCLUSION: TG are primarily responsible for the antidepressant activity of CT; its effect might be achieved through the bidirectional interaction of the phytochemicals and gut microbiota, and reflect the advantage of CT in the treatment of depression.