Concurrent and prospective associations between family socioeconomic status, social support and salivary diurnal and hair cortisol in adolescence.

BACKGROUND: Exposure to socioeconomic adversity is hypothesized to impact hypothalamic-pituitary-adrenal (HPA) axis activity and cortisol secretion, but existing evidence is inconsistent. Yet, few studies have investigated this association using a developmental approach that considers potential protective contextual factors. This study examined the role of stability and changes in family socioeconomic status (SES) in the prediction of multiple cortisol indicators and tested whether social support moderated these associations. METHODS: Participants were part of a population-based sample of twin pairs recruited at birth. Family SES was assessed in early childhood (ages 0-5) and mid-adolescence (age 14). Social support was assessed at ages 14 and 19. Diurnal cortisol (n = 569) was measured at age 14 at awakening, 30 min later, in the afternoon and evening over four non-consecutive days. Hair cortisol concentration (HCC, n = 704) was measured at age 19. All data were collected before the pandemic and multilevel regression models were conducted to account for the nested data structure. RESULTS: Youth exposed to lower family SES levels in childhood and mid-adolescence had a flatter diurnal slope and higher HCC compared with those who experienced upward socioeconomic mobility in mid-adolescence. Contrastingly, mid-adolescence SES showed no association with the diurnal slope or HCC for youth from higher-SES households in early childhood. Moreover, youth raised in higher-SES families in early childhood had a higher CAR in mid-adolescence if they reported greater social support in mid-adolescence. Social support also moderated the SES-cortisol association in mid-adolescence, with higher-SES youth showing higher awakening cortisol secretion when reporting more social support. CONCLUSIONS: Our findings support the hypothesis that early socioeconomic adversity sensitizes HPA axis activity to later socioeconomic disadvantage, which may bear consequences for socioemotional and behavioral functioning.

The potential beneficial effects of Lactobacillus plantarum GM11 on rats with chronic unpredictable mild stress- induced depression.

OBJECTIVE: The main purpose of the present study was to assess the beneficial effect of Lactobacillus plantarum GM11 (LacP GM11), screened from Sichuan traditional fermented food, in depressive rats induced by chronic unpredictable mild stress (CUMS). METHODS: Male SPF SD rats were randomly assigned to 3 groups: the control group, CUMS group and CUMS + LacP GM11 group (n = 10). The rats in the CUMS and LacP GM11 groups received CUMS stimulation for 42 d. The behavioral tests and levels of monoamine neurotransmitter, glucocorticoid hormone and brain-derived neurotrophic factor (BDNF) in the serum and hippocampus were measured. The effects of LacP GM11 on the mRNA and protein expression of BDNF and cAMP response element binding protein (CREB) in the hippocampus were also investigated. RESULTS: After supplementation for 21 d, LacP GM11 was associated with alleviation of depressive-like behavior, not anxiety-like behavior, in depressive rats. LacP GM11 increased the levels of 5-hydroxytryptamine (5-HT) and BDNF and decreased the level of cortisol (CORT) in the serum and hippocampus in depressed rats. In addition, treatment with LacP GM11 also increased the mRNA and protein expression of BDNF and CREB in the hippocampus. CONCLUSIONS: This work has revealed that LacP GM11 has potential beneficial effects on depression. This effect might be related to alleviating monoamine neurotransmitter deficiency, HPA axis hyperfunction and CREB-BDNF signaling pathway downregulation. This study demonstrates that LacP GM11 could be a potential therapeutic approach to treat depression and other mental health problems.

Ginsenosides modulate hypothalamic-pituitary-adrenal function by inhibiting FKBP51 on glucocorticoid receptor to ameliorate depression in mice exposed to chronic unpredictable mild stress.

Depression, which affects millions of individuals worldwide, is associated with glucocorticoid (GC) impairment, with the FKBP51 protein playing a pivotal role. Ginsenosides, extracted from the root of Panax ginseng C.A. Mey, have demonstrated the potential to mitigate depression associated with GC dysregulation. This study evaluated the therapeutic efficacy of ethanol extract of P. ginseng (PG) in treating depression and its underlying FKBP51-linked mechanism. Using chronic unpredictable stress, a depression model was developed in Kunming mice to test the efficacy of PG by observing changes in behaviors and protein expression in depressed mice. The mechanism of action was investigated through transfection with HEK293T cells. Depressed mice treated with PG demonstrated notable improvements: the rate of weight loss was reduced, sucrose preference and open-field activity were enhanced, and the rate of apoptosis in hippocampal cells was decreased. Additionally, the HPA axis function appeared to be restored. These physiological adjustments coincided with an increase in GR levels and a decrease in FKBP51 levels. Altogether, these results suggested that PG treatment effectively alleviates depressive symptoms in mice. PG also moderated FKBP51-GR interaction, lessening FKBP51's restraint on GR nuclear entry. This modulation may enhance the sensitivity of the GR response, reinforcing the negative feedback regulation of the HPA axis and thereby reducing depressive symptoms in mice. These findings highlight the potential of PG as a promising curative treatment for depression, providing a basis for the development of innovative treatments targeting the FKBP51-GR pathway.

Pregestational Prediabetes Induces Maternal Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysregulation and Results in Adverse Foetal Outcomes.

Maternal type 2 diabetes mellitus (T2DM) has been shown to result in foetal programming of the hypothalamic-pituitary-adrenal (HPA) axis, leading to adverse foetal outcomes. T2DM is preceded by prediabetes and shares similar pathophysiological complications. However, no studies have investigated the effects of maternal prediabetes on foetal HPA axis function and postnatal offspring development. Hence, this study investigated the effects of pregestational prediabetes on maternal HPA axis function and postnatal offspring development. Pre-diabetic (PD) and non-pre-diabetic (NPD) female Sprague Dawley rats were mated with non-prediabetic males. After gestation, male pups born from the PD and NPD groups were collected. Markers of HPA axis function, adrenocorticotropin hormone (ACTH) and corticosterone, were measured in all dams and pups. Glucose tolerance, insulin and gene expressions of mineralocorticoid (MR) and glucocorticoid (GR) receptors were further measured in all pups at birth and their developmental milestones. The results demonstrated increased basal concentrations of ACTH and corticosterone in the dams from the PD group by comparison to NPD. Furthermore, the results show an increase basal ACTH and corticosterone concentrations, disturbed MR and GR gene expression, glucose intolerance and insulin resistance assessed via the Homeostasis Model Assessment (HOMA) indices in the pups born from the PD group compared to NPD group at all developmental milestones. These observations reveal that pregestational prediabetes is associated with maternal dysregulation of the HPA axis, impacting offspring HPA axis development along with impaired glucose handling.

Dissimilar Changes in Serum Cortisol after Epileptic and Psychogenic Non-Epileptic Seizures: A Promising Biomarker in the Differential Diagnosis of Paroxysmal Events?

The hypothalamic-pituitary-adrenal axis is known to be involved in the pathogenesis of epilepsy and psychiatric disorders. Epileptic seizures (ESs) and psychogenic non-epileptic seizures (PNESs) are frequently differentially misdiagnosed. This study aimed to evaluate changes in serum cortisol and prolactin levels after ESs and PNESs as possible differential diagnostic biomarkers. Patients over 18 years with ESs (n = 29) and PNESs with motor manifestations (n = 45), captured on video-EEG monitoring, were included. Serum cortisol and prolactin levels as well as hemograms were assessed in blood samples taken at admission, during the first hour after the seizure, and after 6, 12, and 24 h. Cortisol and prolactine response were evident in the ES group (but not the PNES group) as an acute significant increase within the first hour after seizure. The occurrence of seizures in patients with ESs and PNESs demonstrated different circadian patterns. ROC analysis confirmed the accuracy of discrimination between paroxysmal events based on cortisol response: the AUC equals 0.865, with a prediction accuracy at the cutoff point of 376.5 nmol/L 0.811 (sensitivity 86.7%, specificity 72.4%). Thus, assessments of acute serum cortisol response to a paroxysmal event may be regarded as a simple, fast, and minimally invasive laboratory test contributing to differential diagnosis of ESs and PNESs.

Glucocorticoid treatment during COVID-19 infection: does it affect the incidence of long COVID?

BACKGROUND: Long COVID (LC) is a frequent complication of COVID infection. It usually results in cognitive impairment, myalgia, headache and fatigue. No effective treatment has been found yet. We aimed to explore the effect of glucocorticoid (GC) treatment during COVID-19 infection on the later development of LC. METHODS: We examined electronic health records from Clalit Health Services for documentation of COVID-19, GC treatment, and LC frequency. Background diagnoses, demographic data, hospitalization rates, and the use of anti-COVID drugs were recorded. RESULTS: 1,322,599 cases of COVID-19 infection met the inclusion criteria; 13,530 patients (1.02%) received GC treatment. 149,272 patients, 11.29% of COVID-19 patients were diagnosed with LC. Age and female gender were prognostic risk factors for LC (OR 1.06 for age, OR 1.4 for female gender; p value < 0.0001). Background psychiatric diagnoses, migraine, backache and irritable bowel syndrome were predisposing conditions for LC (OR 2.7, p value < .0001). Higher BMI was associated with a greater probability of LC (OR of 1.25 for obese population). COVID patients who received GC were diagnosed with LC more frequently: 2294 cases (16.95%) compared to 146,978 cases (11.23%) in the non-GC group; (adjusted OR of 1.28 ± 0.07, 95% CI, p < 0.0001). CONCLUSIONS: GC treatment during COVID-19 is correlated with the development of LC. In vivo and animal models may be used to explore the mechanism of this correlation. Future directions include prospective studies as well.

Childhood maltreatment disrupts HPA-axis activity under basal and stress conditions in a dose-response relationship in children and adolescents.

BACKGROUND: This study investigates the impact of childhood maltreatment (CM) on hypothalamic-pituitary-adrenal (HPA)-axis functioning and on anxiety perception. Moreover, the influence of CM severity and frequency was also explored. METHODS: In total, 187 participants aged 7-17 were assessed for CM history using validated questionnaires and ad hoc interviews to be classified according to the criteria of the Tool for Assessing the Severity of Situations in which Children are Vulnerable (TASSCV). Psychopathology was ascertained using the K-SADS-PL5. To assess HPA-axis functioning, salivary cortisol samples were collected throughout a normal day and during an acute psychosocial stressor, the Trier Social Stress Test for children (TSST-C). Subjective anxiety was evaluated using STAI/-C. RESULTS: Youth with a CM history had higher overall diurnal cortisol levels (p = 0.001), blunted cortisol response to acute psychosocial stress (p = 0.002) and greater perceived anxiety (p = 0.003), than those without CM. Specifically, participants exposed to moderate/severe or often/frequent CM showed the greater diurnal cortisol output (pseverity = 0.002; pfrequency = 0.003), and blunted cortisol response during the TSST-C (pseverity = 0.006; pfrequency = 0.008). Meanwhile, youth with low CM severity/frequency exhibited a similar cortisol response to those without CM. However, perceived anxiety was higher in those exposed to CM (p < 0.001), regardless of its severity/frequency. CONCLUSIONS: Disturbances in HPA-axis functioning are already evident early after CM exposure, while psychological and physiological responses to an acute stressor are dissociated in youth exposed to CM. The dose-response relationship described in this paper highlights the need to comprehensively evaluate CM so that vulnerable children can be identified and assigned to proper interventions.

Subiculum-BNST structural connectivity in humans and macaques.

Invasive tract-tracing studies in rodents implicate a direct connection between the subiculum and bed nucleus of the stria terminalis (BNST) as a key component of neural pathways mediating hippocampal regulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis. A clear characterisation of the connections linking the subiculum and BNST in humans and non-human primates is lacking. To address this, we first delineated the projections from the subiculum to the BNST using anterograde tracers injected into macaque monkeys, revealing evidence for a monosynaptic subiculum-BNST projection involving the fornix. Second, we used in vivo diffusion MRI tractography in macaques and humans to demonstrate substantial subiculum complex connectivity to the BNST in both species. This connection was primarily carried by the fornix, with additional connectivity via the amygdala, consistent with rodent anatomy. Third, utilising the twin-based nature of our human sample, we found that microstructural properties of these tracts were moderately heritable (h2 ∼ 0.5). In a final analysis, we found no evidence of any significant association between subiculum complex-BNST tract microstructure and indices of perceived stress/dispositional negativity and alcohol use, derived from principal component analysis decomposition of self-report data. Our findings address a key translational gap in our knowledge of the neurocircuitry regulating stress.

Therapeutic Anti-Depressant Potential of Microbial GABA Produced by Lactobacillus rhamnosus Strains for GABAergic Signaling Restoration and Inhibition of Addiction-Induced HPA Axis Hyperactivity.

The role of the microbiota-gut-brain (MGB) axis in mood regulation and depression treatment has gained attention in recent years, as evidenced by the growing number of animal and human studies that have reported the anti-depressive and associated gamma-aminobutyric acid-ergic (GABAergic) effects of probiotics developed from Lactobacillus rhamnosus bacterial strains in the gut microbiome. The depressive states attenuated by these probiotics in patients suffering from clinical depression also characterize the severe and relapse-inducing withdrawal phase of the addiction cycle, which has been found to arise from the intoxication-enabled hyperregulation of the hypothalamic-pituitary-adrenal (HPA) axis, the body's major stress response system, and a corresponding attenuation of its main inhibitory system, the gamma-aminobutyric acid (GABA) signaling system. Therefore, the use of probiotics in the treatment of general cases of depression provides hope for a novel therapeutic approach to withdrawal depression remediation. This review discusses potential therapeutic avenues by which probiotic application of Lactobacillus rhamnosus strains can be used to restore the central GABAergic activity responsible for attenuating the depression-inducing HPA axis hyperactivity in addiction withdrawal. Also, information is provided on brain GABAergic signaling from other known GABA-producing strains of gut microbiota.

Do different types of stress differentially alter behavioural and neurobiological outcomes associated with depression in rodent models? A systematic review.

Cataloguing the effects of different types of stress on behaviour and physiology in rodent models has not been comprehensively attempted. Here, we systematically review whether chronic exposure to physical stress, psychosocial stress, or both types of stress can induce different behavioural and neurobiological outcomes in male and female rodents. We found that physical stress consistently increased depressive-like behaviour, impaired social interaction and decreased body weight, while psychosocial stress consistently increased both anxiety- and depressive-like behaviour, impaired social interaction and learning and memory, increased HPA axis activity, peripheral inflammation and microglial activation, and decreased hippocampal neurogenesis in male rodents. Moreover, we found that the combined effect of both stress types resulted in a more severe pathological state defined by increased anxiety- and depressive-like behaviour, impaired social interaction and learning and memory, increased HPA axis activity and central inflammation, and reduced hippocampal neurogenesis and neural plasticity in male rodents. Phenotypes for females were less consistent, irrespective of the type of stress exposure, on account of the limited number of studies using females. This review highlights that the type of stress may indeed matter and will help animal researchers to more appropriately choose a stress/depression model that fits their research purposes.

The Characterization of Sex Differences in Hypoglycemia-Induced Activation of HPA Axis on the Transcriptomic Level.

Activation of the hypothalamic-pituitary-adrenal (HPA) axis using an insulin tolerance test (ITT) is a medical diagnostic procedure that is frequently used in humans to assess the HPA and growth-hormone (GH) axes. Whether sex differences exist in the response to ITT stress is unknown. Thus, investigations into the analysis of transcripts during activation of the HPA axis in response to hypoglycemia have revealed the underlying influences of sex in signaling pathways that stimulate the HPA axis. We assessed four time points of ITT application in Balb/c mice. After insulin injection, expression levels of 192 microRNAs and 41 mRNAs associated with the HPA, GH and hypothalamic-pituitary-gonadal (HPG) axes were determined by real-time RT-PCR in the hypothalamus, pituitary and adrenal tissues, as well as blood samples (Raw data accession: https://drive.google.com/drive/folders/10qI00NAtjxOepcNKxSJnQbJeBFa6zgHK?usp=sharing ). Although the ITT is commonly used as a gold standard for evaluating the HPA axis, we found completely different responses between males and females with respect to activation of the HPA axis. While activation of several transcripts in the hypothalamus and pituitary was observed after performing the ITT in males within 10 min, females responded via the pituitary and adrenal immediately and durably over 40 min. Additionally, we found that microRNA alterations precede mRNA responses in the HPA axis. Furthermore, robust changes in the levels of several transcripts including Avpr1b and Avpr2 observed at all time points strongly suggest that transcriptional control of these genes occurs mostly via differential signaling in pituitary and blood between males and females. Male and female HPA axis responses to ITT involve a number of sophisticated regulatory signaling pathways of miRNAs and mRNAs. Our results highlight the first robust markers in several layers of HPA, HPG and GH axis involved in ITT/hypoglycemia stress-induced dynamics.

Assessment of the combined effects of chromium and benzene on the rat neuroendocrine and immune systems.

This study assessed the hypothalamic-pituitary-adrenocortical (HPA) axis and lymphoid organs (thymus, spleen, and bone marrow) of Wistar rats treated with a mixture of chromium and benzene. Animals were assessed at three time-points (45, 90 and 135 days) following oral mixture exposure. The hypothalamus-pituitary system was examined in light and electron microscopy. Lymphoid organs underwent a morphological assessment and the immunophenotype of splenocytes was characterized immunohistochemically using monoclonal antibodies. Splenocytes cytokine production of was determined by ELISA after Con-A stimulation. Combined exposure to chromium and benzene in average doses of 20 mg Cr (VI)/kg body weight/day and 0.6 ml benzene/kg body weight/day impaired the responsiveness of the central compartment of the HPA axis, as evidenced by functional activation of the secretory activity of the hypothalamus and pituitary gland, which was not followed by a sufficient extrusion of nonapeptides at the neurohypophysis and hypothalamic median eminence. Chromium and benzene exposure reduced the thymus mass, thymocytes count, and caused a number of structural and functional changes indicative of transient thymus involution. In the spleen, exposure to both chemicals resulted in lymphoreticular hyperplasia and plasma cell-macrophage transformation (also observed in lymph nodes). Apoptosis of thymocytes and lymphocytes was also observed in T-zones of the spleen. Notably, the effects were similar to those observed earlier for the single agents, under the same experimental conditions, without evidence of additivity.

Associations between maternal awakening salivary cortisol levels in mid-pregnancy and adverse birth outcomes.

PURPOSE: Elevated levels of maternal cortisol have been hypothesized as the intermediate process between symptoms of depression and psychosocial stress during pregnancy and adverse birth outcomes. Therefore, we examined associations between cortisol levels in the second trimester of pregnancy and risks of three common birth outcomes in a nested case-control study. METHODS: This study was embedded in the PRIDE Study (n = 3,019), from which we selected all cases with preterm birth (n = 64), low birth weight (n = 49), and small-for-gestational age (SGA; n = 65), and 260 randomly selected controls, among the participants who provided a single awakening saliva sample in approximately gestational week 19 in 2012-2016. Multivariable linear and logistic regression was performed to assess the associations between continuous and categorized cortisol levels and the selected outcomes. RESULTS: We did not observe any associations between maternal cortisol levels and preterm birth and low birth weight. However, high cortisol levels (≥ 90th percentile) seemed to be associated with SGA (adjusted odds ratio 2.1, 95% confidence interval 0.9-4.8), in particular among girls (adjusted odds ratio 3.7, 95% confidence interval 1.1-11.9, based on eight exposed cases) in an exploratory analysis. CONCLUSION: The results of this study showed no suggestions of associations between maternal awakening cortisol levels in mid-pregnancy and adverse birth outcomes, except for an increased risk of SGA.

Cancer and stress: NextGen strategies.

Chronic stress is well-known to cause physiological distress that leads to body balance perturbations by altering signaling pathways in the neuroendocrine and sympathetic nervous systems. This increases allostatic load, which is the cost of physiological fluctuations that are required to cope with psychological challenges as well as changes in the physical environment. Recent studies have enriched our knowledge about the role of chronic stress in disease development, especially carcinogenesis. Stress stimulates the hypothalamic-pituitaryadrenal (HPA) axis and the sympathetic nervous system (SNS), resulting in an abnormal release of hormones. These activate signaling pathways that elevate expression of downstream oncogenes. This occurs by activation of specific receptors that promote numerous cancer biological processes, including proliferation, genomic instability, angiogenesis, metastasis, immune evasion and metabolic disorders. Moreover, accumulating evidence has revealed that ß-adrenergic receptor (ADRB) antagonists and downstream target inhibitors exhibit remarkable anti-tumor effects. Psychosomatic behavioral interventions (PBI) and traditional Chinese medicine (TCM) also effectively relieve the impact of stress in cancer patients. In this review, we discuss recent advances in the underlying mechanisms that are responsible for stress in promoting malignancies. Collectively, these data provide approaches for NextGen pharmacological therapies, PBI and TCM to reduce the burden of tumorigenesis.

Annual regulation of adrenocortical function in migrant and resident subspecies of white-crowned sparrow.

Corticosterone affects physiology and behavior both during normal daily processes but also in response to environmental challenges and is known to mediate life history trade-offs. Many studies have investigated patterns of corticosterone production at targeted times of year, while ignoring underlying annual profiles. We aimed to understand the annual regulation of hypothalamic-pituitary-adrenal (HPA) axis function of both migrant (Zonotrichia leucophrys gambelii; n = 926) and resident (Z. l. nutalli; n = 688) subspecies of white-crowned sparrow and how it is influenced by environmental conditions - wind, precipitation, and temperature. We predicted that more dramatic seasonal changes in baseline and stress-induced corticosterone would occur in migrants to precisely time the onset of breeding and cope with environmental extremes on their arctic breeding grounds, while changes in residents would be muted as they experience a more forgiving breeding schedule and comparatively benign environmental conditions in coastal California. During the course of a year, the harshest conditions were experienced the summer breeding grounds for migrants, at which point they had higher corticosterone levels compared to residents. For residents, the winter months coincided with harshest conditions at which point they had higher corticosterone levels than migrants. For both subspecies, corticosterone tended to rise as environmental conditions became colder and windier. We found that the annual maxima in stress-induced corticosterone occurred prior to egg lay for all birds except resident females. Migrants had much higher baseline and acute stress-induced corticosterone during breeding compared to residents; where in a harsher environment the timing of the onset of reproduction is more critical because the breeding season is shorter. Interestingly, molt was the only stage within the annual cycle in which subspecies differences were absent suggesting that a requisite reduction in corticosterone may have to be met for feather growth. These data suggest that modulation of the HPA axis is largely driven by environmental factors, social cues, and their potential interactions with a genetic program.

Epilepsy Associated Depression: An Update on Current Scenario, Suggested Mechanisms, and Opportunities.

Depression is one of the most frequent psychiatric comorbidities associated with epilepsy having a major impact on the patient's quality of life. Several screening tools are available to identify and follow up psychiatric disorders in epilepsy. Out of various psychiatric disorders, people with epilepsy (PWE) are at greater risk of developing depression. This bidirectional relationship further hinders pharmacotherapy of comorbid depression in PWE as some antiepileptic drugs (AEDs) worsen associated depression and coadministration of existing antidepressants (ADs) to alleviate comorbid depression has been reported to worsen seizures. Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) are first choice of ADs and are considered safe in PWE, but there are no high-quality evidences. Similar to observations in people with depression, PWE also showed pharmacoresistant to available SSRI/SNRIs, which further complicates the disease prognosis. Randomized double-blind placebo-controlled clinical trials are necessary to report efficacy and safety of available ADs in PWE. We should also move beyond ADs, and therefore, we reviewed common pathological mechanisms such as neuroinflammation, dysregulated hypothalamus pituitary adrenal (HPA) axis, altered neurogenesis, and altered tryptophan metabolism responsible for coexistent relationship of epilepsy and depression. Based on these common pertinent pathways involved in the genesis of epilepsy and depression, we suggested novel targets and therapeutic approaches for safe management of comorbid depression in epilepsy.

Assessing the role of ghrelin and the enzyme ghrelin O-acyltransferase (GOAT) system in food reward, food motivation, and binge eating behavior.

The peripheral peptide hormone ghrelin is a powerful stimulator of food intake, which leads to body weight gain and adiposity in both rodents and humans. The hormone, thus, increases the vulnerability to obesity and binge eating behavior. Several studies have revealed that ghrelin's functions are due to its interaction with the growth hormone secretagogue receptor type 1a (GHSR1a) in the hypothalamic area; besides, ghrelin also promotes the reinforcing properties of hedonic food, acting at extra-hypothalamic sites and interacting with dopaminergic, cannabinoid, opioid, and orexin signaling. The hormone is primarily present in two forms in the plasma and the enzyme ghrelin O-acyltransferase (GOAT) allows the acylation reaction which causes the transformation of des-acyl-ghrelin (DAG) to the active form acyl-ghrelin (AG). DAG has been demonstrated to show antagonist properties; it is metabolically active, and counteracts the effects of AG on glucose metabolism and lipolysis, and reduces food consumption, body weight, and hedonic feeding response. Both peptides seem to influence the hypothalamic-pituitary-adrenal (HPA) axis and the corticosterone/cortisol level that drive the urge to eat under stressful conditions. These findings suggest that DAG and inhibition of GOAT may be targets for obesity and bingeing-related eating disorders and that AG/DAG ratio may be an important potential biomarker to assess the risk of developing maladaptive eating behaviors.

Acute restraint stress does not alter corticosteroid receptors or 11ß-hydroxysteroid dehydrogenase gene expression at hypothalamic-pituitary-adrenal axis regulatory sites in captive male white-crowned sparrows (Zonotrichia leucophrys gambelii).

Capture-restraint is often used to investigate the acute hypothalamic-pituitary-adrenal axis (HPA) response to stress in wild and captive animals through the production of glucocorticoids. Although this approach is useful for understanding changes in glucocorticoids, it overlooks potential changes in the complex regulatory systems associated with the glucocorticoid response, including genomic receptors, steroid metabolizing enzymes, carrier proteins, and downstream target proteins (e.g. gonadotropin-inhibitory hormone; GnIH). The present study in captive male white-crowned sparrows (Zonotrichia leucophrys) tests the hypothesis that corticosteroid receptors (mineralocorticoid - MR and glucocorticoid - GR), 11ß-hydroxysteroid dehydrogenase 1 (11ßHSD1) and 2 (11ßHSD2), corticosteroid binding globulin (CBG), and GnIH undergo rapid changes in expression to mediate the glucocorticoid response to acute stress. To determine dynamic changes in gene mRNA expression in the hippocampus, hypothalamus, pituitary gland, and liver, birds were sampled within 3 min of entering the room and after 10, 30, and 60 min of capture restraint stress in a cloth bag. Restraint stress handling increased CBG and decreased GnIH mRNA expression in the liver and hypothalamus, respectively. MR, GR, 11ßHSD1, and 11ßHSD2 mRNA expression in the brain, pituitary gland, and liver did not change. No correlations were found between gene expression and baseline or stress-induced plasma corticosterone levels. No rapid changes of MR, GR, 11ßHSD1, and 11ßHSD2 mRNA expression during a standardized acute restraint protocol suggests that tissue level sensitivity may remain constant during acute stressors. However, the observed rise in CBG mRNA expression could act to facilitate transport to target tissues or buffer the rise in circulating glucocorticoids. Further studies on tissue specific sensitivity are warranted.

The neurophysiological embedding of child maltreatment.

Maltreatment adversely impacts the development of children across a host of domains. One way in which maltreatment may exert its deleterious effects is by becoming embedded in the activity of neurophysiological systems that regulate metabolic function. This paper reviews the literature regarding the association between childhood maltreatment and the activity of three systems: the parasympathetic nervous system, the sympathetic nervous system, and the hypothalamic-pituitary-adrenal axis. A particular emphasis is placed on the extent to which the literature supports a common account of activity across these systems under conditions of homeostasis and stress. The paper concludes with an outline of directions for future research and the implications of the literature for policy and practice.

Dopaminergic afferents from midbrain to dorsolateral bed nucleus of stria terminalis inhibit release and expression of corticotropin-releasing hormone in paraventricular nucleus.

Dopaminergic (DAergic) neurons of the midbrain ventral tegmental area (VTA) are known to regulate the hypothalamic-pituitary-adrenal (HPA) axis but have no direct projections to the paraventricular nucleus (PVN) of the hypothalamus. This study investigated whether VTA DAergic afferents modulate glutamatergic transmission-dependent GABAergic neurons in dorsolateral bed nucleus of stria terminalis (dlBNST) to affect the activity of the HPA-axis. Herein, we demonstrate that systemic administration of the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or the VTA-injection of 1-methyl-4-phenylpyridinium ion (MPP+) in male mice (MPTP-mice and MPP+mice) caused a decline of tyrosine hydroxylase positive (TH+) cells in VTA with a reduction in TH+fibers in the dlBNST. MPTP-mice and MPP+mice displayed a clear increase in serum levels of corticosterone (CORT) and adrenocorticotropic hormone, corticotropin-releasing hormone (CRH) expression, and CRH neuron activity in PVN. The presynaptic glutamate release, glutamatergic synaptic transmission and induction of long-term potentiation in dlBNST of MPTP-mice were suppressed, and these effects were rescued by a D1-like DAergic receptor (D1R) agonist and mimicked in control dlBNST by blockade of D1R. MPTP-mice exhibited low expression of glutamic acid decarboxylase and dysfunction of the excitatory-dependent GABAergic circuit in dlBNST, and these effects were recovered by the administration of D1R agonist. Furthermore, either dlBNST-injection of D1R agonist or PVN-injection of GABAA receptor (GABAA R) agonist could correct the increased secretion and expression of CRH in MPTP-mice. The results indicate that the DAergic afferents from VTA enhance excitatory-dependent activation of GABAergic neurons in dlBNST, which suppress the activity of the HPA-axis.