The diagnostic yield of inferior petrosal sinus sampling in Cushing syndrome in the era of ovine CRH shortage.

PURPOSE: The ovine corticotropin-releasing hormone (oCRH) stimulation test has been routinely used in the diagnostic work-up of ACTH-dependent Cushing syndrome (CS). With oCRH currently being out-of-stock in Europe, we aimed at evaluating the diagnostic performance of inferior petrosal sinus sampling (IPSS) without oCRH stimulation. METHODS: We compared the values of 40 patients with ACTH-dependent CS and negative MRI findings in whom ACTH was measured before and after oCRH stimulation. RESULTS: The ratio of central-to-peripheral ACTH measurement (IPS:P) before the combined 3, 5, and 10 min of oCRH stimulation yielded diminished sensitivity (85% vs. 97%), alongside markedly decreased specificity (57% vs. 71%), as well as reduced positive and negative predictive values (90% vs. 94% and 44% vs. 83%), respectively. CONCLUSIONS: With the current drug shortages in Europe, ACTH measurements without oCRH stimulation in IPSS cannot be recommended. Thus, we call for desmopressin or the commercially available human CRH as a potential alternative in the confirmation of ACTH excess by IPSS in equivocal MRI findings.

Role of CRH in colitis and colitis-associated cancer: a combinative result of central and peripheral effects?

Corticotropin-releasing factor family peptides (CRF peptides) comprise corticotropin releasing hormone (CRH), urocortin (UCN1), UCN2 and UCN3. CRH is first isolated in the brain and later with UCNs found in many peripheral cells/tissues including the colon. CRH and UCNs function via the two types of receptors, CRF1 and CRF2, with CRH mainly acting on CRF1, UCN1 on both CRF1 &CRF2 and UCN2-3 on CRF2. Compiling evidence shows that CRH participates in inflammation and cancers via both indirect central effects related to stress response and direct peripheral influence. CRH, as a stress-response mediator, plays a significant central role in promoting the development of colitis involving colon motility, immunity and gut flora, while a few anti-colitis results of central CRH are also reported. Moreover, CRH is found to directly influence the motility and immune/inflammatory cells in the colon. Likewise, CRH is believed to be greatly related to tumorigenesis of many kinds of cancers including colon cancer via the central action during chronic stress while the peripheral effects on colitis-associated-colon cancer (CAC) are also proved. We and others observe that CRH/CRF1 plays a significant peripheral role in the development of colitis and CAC in that CRF1 deficiency dramatically suppresses the colon inflammation and CAC. However, up to date, there still exist not many relevant experimental data on this topic, and there seems to be no absolute clearcut between the central and direct peripheral effects of CRH in colitis and colon cancer. Taken together, CRH, as a critical factor in stress and immunity, may participate in colitis and CAC as a centrally active molecule; meanwhile, CRH has direct peripheral effects regulating the development of colitis and CAC, both of which will be summarized in this review.

Efficacy of Shu-yi-ning-chang decoction on IBS-D: Modulating Nr4a3 pathway to reduce visceral hypersensitivity.

AIM OF THE STUDY: To evaluate the therapeutic effect of SYNC in diarrhea irritable bowel syndrome (IBS-D) and explore its underlying mechanism through transcriptomic sequencing (RNA-Seq). MATERIALS AND METHODS: A rat model of IBS-D was constructed to elucidate the effects of SYNC. Abdominal withdrawal reflex (AWR), fecal water content (FWC), and recording body weight were calculated to assess visceral sensitivity in rats. Histopathological changes in the colon and alterations in mast cell (MC) count were determined. Immunohistochemistry was employed to assess mast cell tryptase (MCT) expression in rat colons. Serum levels of corticotropin-releasing Hormone (CRH), interleukin-6 (IL-6), calcitonin gene-related peptide (CGRP), and 5-hydroxytryptamine (5-HT) were quantified using ELISA. RNA-Seq of colon tissue was performed, followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Western blot analysis was conducted to quantify the expression levels of key proteins in the Nr4a3 pathway in the colon and hypothalamus tissues of rats. RESULTS: SYNC alleviated visceral hypersensitivity and mood disorders in rats with IBS-D. Moreover, it was positively correlated with its dosage and the observed effects, such as the enhancement of the colon's mucosal lining condition and reduction in the number and activation of MCs within the model group. SYNC reduced the expression levels of factors related to the brain-gut axis and inflammatory markers in the bloodstream. RNA-Seq analysis indicated that SYNC down-regulated the expression of Nr4a3 and PI3K. These SYNC-targeted genes primarily played roles in immune regulation and inflammatory responses, correlating with the modulation of Nr4a3 and the PI3K/AKT pathway. Western blot analysis further confirmed SYNC's influence on inflammation-related MC activation by downregulating key proteins in the Nr4a3/PI3K pathway. CONCLUSIONS: SYNC inhibited mast cell activation and attenuated visceral hypersensitivity in the colon tissues of IBS-D rats. These effects were mediated by the Nr4a3/PI3K signaling pathway.

AKAP150-anchored PKA regulates synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the mouse lateral habenula.

The scaffolding A-kinase anchoring protein 150 (AKAP150) is critically involved in kinase and phosphatase regulation of synaptic transmission/plasticity, and neuronal excitability. Emerging evidence also suggests that AKAP150 signaling may play a key role in brain's processing of rewarding/aversive experiences, however its role in the lateral habenula (LHb, as an important brain reward circuitry) is completely unknown. Using whole cell patch clamp recordings in LHb of male wildtype and ΔPKA knockin mice (with deficiency in AKAP-anchoring of PKA), here we show that the genetic disruption of PKA anchoring to AKAP150 significantly reduces AMPA receptor-mediated glutamatergic transmission and prevents the induction of presynaptic endocannabinoid-mediated long-term depression in LHb neurons. Moreover, ΔPKA mutation potentiates GABAA receptor-mediated inhibitory transmission while increasing LHb intrinsic excitability through suppression of medium afterhyperpolarizations. ΔPKA mutation-induced suppression of medium afterhyperpolarizations also blunts the synaptic and neuroexcitatory actions of the stress neuromodulator, corticotropin releasing factor (CRF), in mouse LHb. Altogether, our data suggest that AKAP150 complex signaling plays a critical role in regulation of AMPA and GABAA receptor synaptic strength, glutamatergic plasticity and CRF neuromodulation possibly through AMPA receptor and potassium channel trafficking and endocannabinoid signaling within the LHb.

Placental corticotrophin-releasing hormone trajectories in pregnancy: Associations with postpartum depressive symptoms.

OBJECTIVE: Depressive symptoms following birth are common and can have adverse effects for mothers, children, and families. Changes in hypothalamic-pituitary-adrenal (HPA) axis regulation during pregnancy may be implicated in the development of postpartum depressive symptoms, particularly changes in placental corticotropinreleasing hormone (pCRH). However, few studies have tested how dynamic pCRH changes over pregnancy relate to postpartum depressive symptoms. This preregistered investigation tests associations of both pCRH levels and changes from early to late pregnancy with postpartum depressive symptoms. METHODS: The sample consists of 173 women studied in early, mid, and late pregnancy who later reported on depressive symptoms with the Edinburgh Postpartum Depression Scale during interviews at 1, 6 and 12 months postpartum. Blood samples were collected at each prenatal timepoint and assayed for pCRH using radioimmunoassay. Latent growth curve analysis was employed to identify distinct trajectories of pCRH during pregnancy. RESULTS: We identified three prenatal pCRH trajectories labeled as typical, flat, and accelerated. Each trajectory showed exponential increases in pCRH levels over the course of gestation but differed in overall levels and rates of change. pCRH levels were not associated with postpartum depressive symptoms. However, women with accelerated pCRH trajectories reported marginally higher depressive symptoms one month postpartum. Primary analysis models adjusted for marital status, income, prepregnancy BMI, parity, prenatal depressive symptoms, and gestational age. CONCLUSIONS: These findings add to our understanding of dynamic changes to maternal HPA axis regulation during pregnancy and contribute to growing evidence on how pCRH changes relate to the development of postpartum depressive symptoms.

Early life nutrient restriction affects hypothalamic-pituitary-interrenal axis gene expression in a diet type-specific manner.

Stressful experiences in early life can alter phenotypic expression later in life. For instance, in vertebrates, early life nutrient restriction can modify later life activity of the hypothalamic-pituitary-adrenal/interrenal axis (the HPI in amphibians), including the up- and downstream regulatory components of glucocorticoid signaling. Early life nutrient restriction can also influence later life behavior and metabolism (e.g., fat accumulation). Yet, less is known about whether nutrient stress-induced carryover effects on HPA/HPI axis regulation can vary across environmental contexts, such as the type of diet on which nutrient restriction occurs. Here, we experimentally address this question using the plains spadefoot toad (Spea bombifrons), whose larvae develop in ephemeral habitats that impose intense competition over access to two qualitatively distinct diet types: detritus and live shrimp prey. Consistent with diet type-specific carryover effects of early life nutrient restriction on later life HPI axis regulation, we found that temporary nutrient restriction at the larval stage reduced juvenile (i.e., post-metamorphic) brain gene expression of an upstream glucocorticoid regulator (corticotropin-releasing hormone) and two downstream regulators (glucocorticoid and mineralocorticoid receptors) only on the shrimp diet. These patterns are consistent with known diet type-specific effects of larval nutrient restriction on juvenile corticosterone and behavior. Additionally, larval nutrient restriction increased juvenile body fat levels. Our study indicates that HPA/HPI axis regulatory responses to nutrient restriction can vary remarkably across diet types. Such diet type-specific regulation of the HPA/HPI axis might provide a basis for developmental or evolutionary decoupling of stress-induced carryover effects.

Influence of copper source and dietary inclusion level on growth performance of weaned pigs and expression of trace element related genes in the small intestine.

Copper is routinely supplemented to weanling pig diets at concentrations above nutritional requirements to enhance growth performance. We hypothesised that this effect depends on the source of Cu and its dietary concentration. We tested this in weaned pigs (26 d of age) over a 35-d period using a 2 × 3 factorial arrangement with two Cu-sources (CuSO4 and Cu2O, monovalent copper oxide, CoRouge®) and three supplementary dietary Cu-levels (15, 80 and 160 mg Cu/kg) as respective factors. Increasing Cu level linearly increased (P < 0.001) final BW and daily gain. These effects tended (P = 0.09) to be greater with Cu2O than CuSO4. Feed conversion ratio decreased linearly (P < 0.001) with increasing dietary Cu content, independent of Cu source. Plasma Cu, Zn and Fe levels were unaffected, whereas liver Cu content increased quadratically (P < 0.001) with increasing dietary Cu content, with a larger increase (P < 0.001) with CuSO4 than Cu2O. Bile Cu content increased quadratically (P = 0.025) with increasing Cu content, irrespective of Cu source. RT-qPCR analysis revealed that increasing Cu content quadratically (P = 0.009) increased duodenal but not ileal metallothionein 1A (MT1A) mRNA, with greater effect (P = 0.010) of CuSO4. Regardless of the Cu source, increasing Cu dose linearly increased (P = 0.006) duodenal DMT1/SLC11A2 mRNA but decreased ZIP4/SLC39A4 mRNA in duodenum (P < 0.001) and ileum (P < 0.005). ZnT10/SLC30A10 mRNA was significantly (P = 0.021) and numerically (P = 0.061) greater with Cu2O compared to CuSO4, in duodenum and ileum, respectively. Copper content quadratically modulated duodenal but not ileal transferrin receptor (P = 0.029) and ferric reductase CYBRD1 mRNA (P = 0.022). In hypothalamus, high Cu dose (P = 0.024) and Cu2O as source (P = 0.028) reduced corticotropin-releasing hormone (CRH) mRNA. Low versus high CuSO4 increased corticotropin-releasing hormone receptor (CRHR2) mRNA, while low Cu2O had the opposite effect (P = 0.009). In conclusion, incremental Cu intake enhanced growth performance, with a tendency for a greater effect of Cu2O. The lower increase in duodenal MT1A mRNA and liver Cu content indicates that less Cu from Cu2O was absorbed by gut and sequestered in liver. Thus, high Cu absorption is not essential for its growth-promoting effect and dietary Cu may affect intestinal Fe and Zn absorption via the active, transcellular route. The effects on hypothalamic CRH and CRHR2 expression indicate a role for the hypothalamus in mediating the effects of Cu on growth performance.

[Effect of Zuogui Jiangtang Jieyu Formula on intestinal flora and short-chain fatty acid metabolism in rats with diabetes mellitus complicated with depression].

This study aimed to investigate the regulatory effects of Zuogui Jiangtang Jieyu Formula(ZJJ) on the intestinal flora, short chain fatty acids(SCFAs), and neuroinflammation in rats with diabetes mellitus complicated depression(DD). The DD model was established in rats and model rats were randomly divided into a model group, a positive drug(metformin + fluoxetine) group, a ZJJ low-dose group, and a ZJJ high-dose group, with eight rats in each group. Another eight rats were assigned to the blank group. Subsequently, depressive-like behavior test was conducted on the rats, and cerebrospinal fluid samples were collected to measure pro-inflammatory cytokines [interleukin-1ß(IL-1ß), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α)]. Blood serum samples were collected to measure proteins related to the hypothalamic-pituitary-adrenal axis(HPA axis), including corticotropin-releasing hormone(CRH), adrenocorticotropic hormone(ACTH), and cortisol(CORT), as well as glucose metabolism. Gut contents were collected from each group for 16S rRNA sequencing analysis of intestinal flora and SCFAs sequencing. The results indicated that ZJJ not only improved glucose metabolism in DD rats(P<0.01) but also alleviated depressive-like behavior(P<0.05) and HPA axis hyperactivity(P<0.05 or P<0.01). Besides, it also improved the neuroinflammatory response in the brain, as evidenced by a significant reduction in pro-inflammatory cytokines in cerebrospinal fluid(P<0.05 or P<0.01). Additionally, ZJJ improved the intestinal flora, causing the intestinal flora in DD rats to resemble that of the blank group, characterized by an increased Firmicutes abundance. ZJJ significantly increased the levels of SCFAs(acetic acid, butyric acid, valeric acid, and isovaleric acid)(P<0.01). Therefore, it is deduced that ZJJ can effectively ameliorate intestinal flora dysbiosis, regulate SCFAs, and thereby improve both glucose metabolism disturbances and depressive-like behavior in DD.

Characterisation of biomarkers of intestinal barrier function in response to a high fat/high carbohydrate meal and corticotropin releasing hormone.

BACKGROUND: Variation of circulating concentrations of putative biomarkers of intestinal barrier function over the day and after acute physiological interventions are poorly documented on humans. This study aimed to examine the stability and pharmacokinetics of changes in plasma concentrations of intestinal Fatty-acid -binding -protein (IFABP), Lipopolysaccharide-binging-protein (LBP), soluble CD14, and Syndecan-1 after acute stress and high fat-high-carbohydrate meal. METHODS: In a single-blinded, cross-over, randomised study, healthy volunteers received on separate days corticotropin-releasing hormone (CRH, 100 µg) or normal saline (as placebo) intravenously in random order, then a HFHC meal. Participants were allowed low caloric food. Markers of intestinal barrier function were measured at set timed intervals from 30 minutes before to 24 hours after interventions. RESULTS: 10 participants (50% female) completed all three arms of the study. IFABP decreased by median 3.6 (IQR 1.4-10)% from -30 minutes to zero time (p = 0.001) and further reduced by 25 (20-52)% at 24 hours (p = 0.01) on the low caloric diet, but did not change in response to the meal. Syndecan-1, LBP and sCD14 were stable over a 24-hour period and not affected acutely by food intake. LBP levels 2 hours after CRH reduced by 0.61 (-0.95 to 0.05) µg/ml compared with 0.16 (-0.3 to 0.5) µg/ml post placebo injection (p = 0.05), but other markers did not change. CONCLUSION: Concentrations of IFABP, but not other markers, are unstable over 24 hours and should be measured fasting. A HFHC meal does not change intestinal permeability. Transient reduction of LPB after CRH confirms acute barrier dysfunction during stress.

Larger hypothalamic subfield volumes in patients with chronic insomnia disorder and relationships to levels of corticotropin-releasing hormone.

The hypothalamus is a well-established core structure in the sleep-wake cycle. While previous studies have not consistently found whole hypothalamus volume changes in chronic insomnia disorder (CID), differences may exist at the smaller substructural level of the hypothalamic nuclei. The study aimed to investigate the differences in total and subfield hypothalamic volumes, between CID patients and healthy controls (HCs) in vivo, through an advanced deep learning-based automated segmentation tool. A total of 150 patients with CID and 155 demographically matched HCs underwent T1-weighted structural magnetic resonance scanning. We utilized FreeSurfer v7.2 for automated segmentation of the hypothalamus and its five nuclei. Additionally, correlation and causal mediation analyses were performed to investigate the association between hypothalamic volume changes, insomnia symptom severity, and hypothalamus-pituitary-adrenal (HPA) axis-related blood biomarkers. CID patients exhibited larger volumes in the right anterior inferior, left anterior superior, and left posterior subunits of the hypothalamus compared to HCs. Moreover, we observed a positive association between blood corticotropin-releasing hormone (CRH) levels and insomnia severity, with anterior inferior hypothalamus (a-iHyp) hypertrophy mediating this relationship. In conclusion, we found significant volume increases in several hypothalamic subfield regions in CID patients, highlighting the central role of the HPA axis in the pathophysiology of insomnia.

Sex-specific associations between placental corticotropin releasing hormone and problem behaviors in childhood.

Placental corticotropin-releasing hormone (pCRH) is a neuroactive peptide produced in high concentrations in mid-late pregnancy, during key periods of fetal brain development. Some evidence suggests that higher pCRH exposure during gestation is associated with adverse neurodevelopment, particularly in female offspring. In 858 mother-child dyads from the sociodemographically diverse CANDLE cohort (Memphis, TN), we examined: (1) the slope of pCRH rise in mid-late pregnancy and (2) estimated pCRH at delivery as a measure of cumulative prenatal exposure. When children were 4 years-old, mothers reported on problem behaviors using the Child Behavior Checklist (CBCL) and cognitive performance was assessed by trained psychologists using the Stanford-Binet Intelligence Scales. We fitted linear regression models examining pCRH in relation to behavioral and cognitive performance measures, adjusting for covariates. Using interaction models, we evaluated whether associations differed by fetal sex, breastfeeding, and postnatal neighborhood opportunity. In the full cohort, log-transformed pCRH measures were not associated with outcomes; however, we observed sex differences in some models (interaction p-values≤0.01). In male offspring, an interquartile (IQR) increase in pCRH slope (but not estimated pCRH at delivery), was positively associated with raw Total (ß=3.06, 95%CI: 0.40, 5.72), Internalizing (ß=0.89, 95%CI: 0.03, 1.76), and Externalizing (ß=1.25, 95%CI: 0.27, 2.22) Problem scores, whereas, in females, all associations were negative (Total Problems: ß=-1.99, 95%CI: -3.89, -0.09; Internalizing: ß=-0.82, 95%CI: -1.42, -0.23; Externalizing: ß=-0.56, 95%CI: -1.34, 0.22). No associations with cognitive performance were observed nor did we observe moderation by breastfeeding or postnatal neighborhood opportunity. Our results provide further evidence that prenatal pCRH exposure may impact subsequent child behavior in sex-specific ways, however in contrast to prior studies suggesting adverse impacts in females, steeper mid-gestation pCRH rise was associated with more problem behaviors in males, but fewer in females.

The Lack of TRPA1 Ion Channel Does Not Affect the Chronic Stress-Induced Activation of the Locus Ceruleus.

We have previously proven the involvement of transient receptor potential ankyrin 1 (TRPA1) in stress adaptation. A lack of TRPA1 affects both urocortin 1 (member of the corticotropin-releasing hormone (CRH) family) content of the Edinger-Westphal nucleus. The noradrenergic locus ceruleus (LC) is also an important player in mood control. We aimed at investigating whether the TRPA1 is expressed in the LC, and to test if the response to chronic variable mild stress (CVMS) is affected by a lack of TRPA1. The TRPA1 expression was examined via RNAscope in situ hybridization. We investigated TRPA1 knockout and wildtype mice using the CVMS model of depression. Tyrosine hydroxylase (TH) and FOSB double immunofluorescence were used to test the functional neuromorphological changes in the LC. No TRPA1 expression was detected in the LC. The TH content was not affected by CVMS exposure. The CVMS-induced FOSB immunosignal did not co-localize with the TH neurons. TRPA1 is not expressed in the LC. A lack of functional TRPA1 receptor neither directly nor indirectly affects the TH content of LC neurons under CVMS.

Neurobiology of Stress-Induced Nicotine Relapse.

Tobacco smoking is the leading cause of preventable death and disease. Although there are some FAD-approved medicines for controlling smoking, the relapse rate remains very high. Among the factors that could induce nicotine relapse, stress might be the most important one. In the last decades, preclinical studies have generated many new findings that lead to a better understanding of stress-induced relapse of nicotine-seeking. Several molecules such as α3ß4 nicotinic acetylcholine receptor, α2-adrenergic receptors, cannabinoid receptor 1, trace amine-associated receptor 1, and neuropeptide systems (corticotropin-releasing factor and its receptors, dynorphine and kappa opioid receptor) have been linked to stress-induced nicotine relapse. In this review, we discuss recent advances in the neurobiology, treatment targets, and potential therapeutics of stress-induced nicotine relapse. We also discuss some factors that may influence stress-induced nicotine relapse and that should be considered in future studies. In the final section, a perspective on some research directions is provided. Further investigation on the neurobiology of stress-induced nicotine relapse will shed light on the development of new medicines for controlling smoking and will help us understand the interactions between the stress and reward systems in the brain.

Pharmacological Manipulation of Corticotropin-Releasing Factor Receptors in the Anterior and Posterior Subregions of the Insular Cortex Differently Affects Anxiety-Like Behaviors in the Elevated Plus Maze in Rats.

Neuroimaging data in humans and neurobiological studies in rodents have suggested an involvement of the insular cortex (IC) in anxiety manifestations. However, the local neurochemical mechanisms involved are still poorly understood. Corticotropin-releasing factor (CRF) neurotransmission has been described as a prominent neurochemical mechanism involved in the expression of anxiety-like behaviors, but the brain sites related are poorly understood. Additionally, several findings indicate that control of physiological and behavioral responses by the IC occurs in a site-specific manner along its rostrocaudal axis. Thus, this study is aimed at evaluating the effect of CRF receptor agonism and antagonism within the anterior and posterior subregions of the IC in controlling anxiety-related behaviors in the elevated plus maze (EPM). For this, independent groups (six groups) of animals received bilateral microinjections of vehicle, the selective CRF1 receptor antagonist CP376395, or CRF into either the anterior or posterior subregions of the IC. Ten minutes later, the behavior in the EPM was evaluated for five minutes. Treatment of the anterior IC with CP376395, but not with CRF, increased the time and number of entries into the open arms of the EPM. CRF, but not the CRF1 receptor antagonist, microinjected into the posterior IC also increased exploration of the EPM open arms. Taken together, these data indicate that CRFergic neurotransmission in the anterior IC is involved in the expression of anxiety-related behaviors in the EPM. This neurochemical mechanism does not seem to be activated within the posterior IC during exposure to the EPM, but the effects caused by CRF microinjection indicate that activation of CRF receptors in this IC subregion might evoke anxiolytic-like effects.

Two Adverse Early Life Events Induce Differential Changes in Brain CRH and Serotonin Systems in Rats along with Hyperphagia and Depression.

BACKGROUND: Different types of stress inflicted in early stages of life elevate the risk, among adult animals and humans, to develop disturbed emotional-associated behaviors, such as hyperphagia or depression. Early-life stressed (ELS) adults present hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis, which is a risk factor associated with mood disorders. However, the prevalence of hyperphagia (17%) and depression (50%) is variable among adults that experienced ELS, suggesting that the nature, intensity, and chronicity of the stress determines the specific behavioral alteration that those individuals develop. METHODS: We analyzed corticosterone serum levels, Crh, GR, Crhr1 genes expression in the hypothalamic paraventricular nucleus, amygdala, and hippocampus due to their regulatory role on HPA axis in adult rats that experienced maternal separation (MS) or limited nesting material (LNM) stress; as well as the serotonergic system activity in the same regions given its association with the corticotropin-releasing hormone (CRH) pathway functioning and with the hyperphagia and depression development. RESULTS: Alterations in dams' maternal care provoked an unresponsive or hyper-responsive HPA axis function to an acute stress in MS and LNM adults, respectively. The differential changes in amygdala and hippocampal CRH system seemed compensating alterations to the hypothalamic desensitized glucocorticoids receptor (GR) in MS or hypersensitive in LNM. However, both adult animals developed hyperphagia and depression-like behavior when subjected to the forced-swimming test, which helps to understand that both hypo and hypercortisolemic patients present those disorders. CONCLUSION: Different ELS types induce neuroendocrine, brain CRH and 5-hydroxytriptamine (5-HT) systems' alterations that may interact converging to develop similar maladaptive behaviors.

Role of corticotropin-releasing factor neurotransmission in the lateral hypothalamus on baroreflex impairment evoked by chronic variable stress in rats.

Despite the importance of physiological responses to stress in a short-term, chronically these adjustments may be harmful and lead to diseases, including cardiovascular diseases. The lateral hypothalamus (LH) has been reported to be involved in expression of physiological and behavioral responses to stress, but the local neurochemical mechanisms involved are not completely described. The corticotropin-releasing factor (CRF) neurotransmission is a prominent brain neurochemical system implicated in the physiological and behavioral changes induced by aversive threats. Furthermore, chronic exposure to aversive situations affects the CRF neurotransmission in brain regions involved in stress responses. Therefore, in this study, we evaluated the influence of CRF neurotransmission in the LH on changes in cardiovascular function and baroreflex activity induced by chronic variable stress (CVS). We identified that CVS enhanced baseline arterial pressure and impaired baroreflex function, which were followed by increased expression of CRF2, but not CRF1, receptor expression within the LH. Local microinjection of either CRF1 or CRF2 receptor antagonist within the LH inhibited the baroreflex impairment caused by CVS, but without affecting the mild hypertension. Taken together, the findings documented in this study suggest that LH CRF neurotransmission participates in the baroreflex impairment related to chronic stress exposure.

Psychological stress induces hair regenerative disorders through corticotropin-releasing hormone-mediated autophagy inhibition.

Psychosocial stress is increasing, causing a growing number of people to suffer from hair loss. Stress-related corticotropin-releasing hormone (CRH) is associated with hair loss, but the mechanism by which hair follicles respond to stress and CRH remain poorly understood. The aim of the study is to elucidate the association between CRH and stress-related hair regenerative disorders, and reveal the potential pathological mechanisms. A chronic unpredictable stress mouse model and a chronic social defeat stress mouse model were used to examine the role of CRH and stress-related hair regrowth. Chronic unpredictable stress and chronic social defeat stress increased the expression of CRH and CRH receptors (CRHRs), and contributed to the onset of hair-cycle abnormalities. Psychoemotional stress and stress-related CRH blocked hair follicle regrowth, which could be restored by astressin, a CRHR antagonist. Long-term exposure to either chronic unpredictable stress or CRH induced a decrease in autophagy, which could be partially rescued by astressin. Activating CRHR, by stress or CRH administration, decreased autophagy via the mTOR-ULK1 signaling pathway to mediate hair regenerative disorders, which could be partially reversed through enhancing autophagy by administration of brefeldin A. These findings indicate that CRH-mediated autophagy inhibition play an important role in stress-induced hair regenerative disorders. CRH regulates the local hypothalamic-pituitary-adrenal axis of hair follicles, but also plays an independent pathogenic role in stress-related hair regenerative disorders through CRH-mediated autophagy inhibition. This work contributes to the present understanding of hair loss and suggests that enhancing autophagy may have a therapeutic effect on stress-induced hair loss.

Hypothalamic CRF neurons facilitate brain reward function.

Aversive stimuli activate corticotropin-releasing factor (CRF)-expressing neurons in the paraventricular nucleus of hypothalamus (PVNCRF neurons) and other brain stress systems to facilitate avoidance behaviors. Appetitive stimuli also engage the brain stress systems, but their contributions to reward-related behaviors are less well understood. Here, we show that mice work vigorously to optically activate PVNCRF neurons in an operant chamber, indicating a reinforcing nature of these neurons. The reinforcing property of these neurons is not mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis. We found that PVNCRF neurons send direct projections to the ventral tegmental area (VTA), and selective activation of these projections induced robust self-stimulation behaviors, without activation of the HPA axis. Similar to the PVNCRF cell bodies, self-stimulation of PVNCRF-VTA projection was dramatically attenuated by systemic pretreatment of CRF receptor 1 or dopamine D1 receptor (D1R) antagonist and augmented by corticosterone synthesis inhibitor metyrapone, but not altered by dopamine D2 receptor (D2R) antagonist. Furthermore, we found that activation of PVNCRF-VTA projections increased c-Fos expression in the VTA dopamine neurons and rapidly triggered dopamine release in the nucleus accumbens (NAc), and microinfusion of D1R or D2R antagonist into the NAc decreased the self-stimulation of these projections. Together, our findings reveal an unappreciated role of PVNCRF neurons and their VTA projections in driving reward-related behaviors, independent of their core neuroendocrine functions. As activation of PVNCRF neurons is the final common path for many stress systems, our study suggests a novel mechanism underlying the positive reinforcing effect of stressful stimuli.

Neuroscience of reward: Paradoxical roles for corticotrophin-releasing factor.

The brain has long been known to control stress and reward through complex and interconnected circuitry. A new study now reveals a group of hypothalamic neurons that paradoxically mediate both reward and aversion.

Blood mRNA expression levels of glucocorticoid receptors and FKBP5 are associated with depressive disorder and altered HPA axis.

BACKGROUND: While depression has been associated with alterations in the hypothalamic-pituitary adrenal (HPA) axis function, there is still controversy regarding the nature and extent of the dysfunction, such as in the debate about hypercortisolism vs. hypocortisolism. It may therefore be necessary to understand whether and how HPA axis function in depression is linked to mRNA expression of key genes regulating this system. METHODS: We studied 163 depressed outpatients, most of whom were chronically ill, and 181 healthy controls. Blood mRNA expression levels of NR3C1 (including GRα, GRß, and GR-P isoforms), FKBP4, and FKBP5 were measured at baseline. HPA axis feedback sensitivity was measured by the dexamethasone (Dex)/corticotropin-releasing hormone (CRH) test. The association between mRNA expression levels and HPA axis feedback sensitivity was examined. RESULTS: Compared to controls, patients showed significantly higher expression of GRα and lower expression of FKBP5, and higher post-Dex cortisol levels, even after controlling for age and sex. FKBP5 expression was significantly positively correlated with cortisol levels in patients, while GRα expression was significantly negatively correlated with cortisol levels in controls. LIMITATIONS: Most patients were taking psychotropic medications. The large number of correlation tests may have caused type I errors. CONCLUSIONS: The tripartite relationship between depression, mRNA expression of GR and FKBP5, and HPA axis function suggests that the altered gene expression affects HPA axis dysregulation and, as a result, impacts the development and/or illness course of depressive disorder. The combination of increased GRα expression and decreased FKBP5 expression may serve as a biomarker for chronic depression.