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Background: Red ginseng (RG) alleviates psychiatric disorders. Fermented red ginseng (fRG) alleviates stress-induced gut inflammation. Gut dysbiosis causes psychiatric disorders with gut inflammation. To understand the gut microbiota-mediated action mechanism of RG and fRG against anxiety/depression (AD), we investigated the effects of RG, fRG, ginsenoside Rd, and 20(S)-β-D-glucopyranosyl protopanaxadiol (CK) on gut microbiota dysbiosis-induced AD and colitis in mice., Methods: Mice with AD and colitis were prepared by exposing to immobilization stress (IS) or transplanting the feces of patients with ulcerative colitis and depression (UCDF). AD-like behaviors were measured in the elevated plus maze, light/dark transition, forced swimming, and tail suspension tests., Results: Oral gavage of UCDF increased AD-like behaviors and induced neuroinflammation, gastrointestinal inflammation, and gut microbiota fluctuation in mice. Oral administration of fRG or RG treatment reduced UCDF-induced AD-like behaviors, hippocampal and hypothalamic IL-6 expression, and blood corticosterone level, whereas UCDF-suppressed hippocampal BDNF + NeuN + cell population and dopamine and hypothalamic serotonin levels increased. Furthermore, their treatments suppressed UCDF-induced colonic inflammation and partially restored UCDF-induced gut microbiota fluctuation. Oral administration of fRG, RG, Rd, or CK also decreased IS-induced AD-like behaviors, blood IL-6 and corticosterone and colonic IL-6 and TNF-α levels, and gut dysbiosis, while IS-suppressed hypothalamic dopamine and serotonin levels increased., Conclusion: Oral gavage of UCDF caused AD, neuroinflammation, and gastrointestinal inflammation in mice. fRG mitigated AD and colitis in UCDF-exposed mice by the regulation of the microbiota-gut-brain axis and IS-exposed mice by the regulation of the hypothalamic-pituitary-adrenal axis., Competing Interests: The authors declare no conflict of interest., (© 2022 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

Purpose: To investigate the association between the 2 acute phase proteins, C-reactive protein (CRP) and pentraxin 3 (PTX3) with central serous chorioretinopathy (CSCR), as PTX3 is a glucocorticoid-induced protein., Design: Cross-sectional multicenter study., Participants: Patients with CSCR compared with age- and sex-matched healthy participants., Methods: Patients with CSCR from 3 centers in Europe were included in the study. The clinical form of CSCR was recorded. Blood samples from patients with CSCR and healthy participants were sampled, and high-sensitivity CRP and PTX3 levels were measured in the serum., Main Outcome Measures: C-reactive protein and PTX3 serum level comparison between patients with CSCR with age- and sex-matched healthy participants., Results: Although CRP levels were higher in patients with CSCR (n = 216) than in age- and sex-matched controls (n = 130) (2.2 ± 3.2 mg/l vs. 1.5 mg/l ± 1.4, respectively, P  = 0.037), PTX3 levels were lower in patients with CSCR (10.5 ± 19.9 pg/ml vs. 87.4 ± 73.2 pg/ml, respectively, P < 0.001). There was no significant difference in CRP or PTX3 levels between patients with acute/recurrent and chronic CSCR., Conclusions: In patients with CSCR, high CRP and low PTX3 levels suggest a form of low-grade systemic inflammation together with a lack of glucocorticoid pathway activation, raising new hypotheses on the pathophysiology of CSCR., Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article., (© 2023 Published by Elsevier Inc. on behalf of American Academy of Ophthalmology.)

Background: Gut microbiome and inflammatory bowel disease (IBD) are implicated in the development of depression, but the effect of their interactions on the risk of depression remains unclear. We aim to analyze the effect of interactions between gut microbiome and IBD on the risk of depression, and explore candidate genes involving the interactions., Methods: Using the individual genotype and depression traits data from the UK Biobank, we calculated the polygenetic risk scores (PRS) of 114 gut microbiome, ulcerative colitis (UC), Crohn's disease (CD), and total IBD (CD + UC) respectively. The effects of interactions between gut microbiome and IBD on depression were assessed through a linear regression model. Moreover, for observed significant interactions between gut microbiome PRS and IBD PRS, PLINK software was used to test pair-wise single nucleotide polymorphisms (SNPs) interaction of corresponding gut microbiome PRS and IBD PRS on depression., Results: We found 64 candidate interactions between gut microbiome and IBD on four phenotypes of depression, such as F&#95;Lachnospiraceae (RNT)  × (CD + UC) for patient health questionnaire-9 (PHQ-9) score ( P  = 1.48 × 10 -3 ), F&#95;Veillonellaceae (HB)  × UC for self-reported depression ( P  = 2.83 × 10 -3 ) and P&#95;Firmicutes (RNT)  × CD for age at first episode of depression ( P  = 8.50 × 10 -3 ). We observed interactions of gut-microbiome-associated SNPs × IBD-associated SNPs, such as G&#95;Alloprevotella (HB) -associated rs147650986 ( GPM6A ) × IBD-associated rs114471990 ( QRICH1 ) ( P  = 2.26 × 10 -4 )., Conclusion: Our results support the effects of interactions between gut microbiome and IBD on depression risk, and reported several novel candidate genes for depression., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background & Aims: Efruxifermin has shown clinical efficacy in patients with non-alcoholic steatohepatitis (NASH) and F1-F3 fibrosis. The primary objective of the BALANCED Cohort C was to assess the safety and tolerability of efruxifermin in patients with compensated NASH cirrhosis., Methods: Patients with NASH and stage 4 fibrosis (n = 30) were randomized 2:1 to receive efruxifermin 50 mg (n = 20) or placebo (n = 10) once-weekly for 16 weeks. The primary endpoint was safety and tolerability of efruxifermin. Secondary and exploratory endpoints included evaluation of non-invasive markers of liver injury and fibrosis, glucose and lipid metabolism, and changes in histology in a subset of patients who consented to end-of-study liver biopsy., Results: Efruxifermin was safe and well-tolerated; most adverse events (AEs) were grade 1 (n = 7, 23.3%) or grade 2 (n = 19, 63.3%). The most frequent AEs were gastrointestinal, including transient, mild to moderate diarrhea, and/or nausea. Significant improvements were noted in key markers of liver injury (alanine aminotransferase) and glucose and lipid metabolism. Sixteen-week treatment with efruxifermin was associated with significant reductions in non-invasive markers of fibrosis including Pro-C3 (least squares mean change from baseline [LSMCFB] -9 μg/L efruxifermin vs.  -3.4 μg/L placebo; p  = 0.0130) and ELF score (-0.4 efruxifermin vs.  +0.4 placebo; p  = 0.0036), with a trend towards reduced liver stiffness (LSMCFB -5.7 kPa efruxifermin vs.  -1.1 kPa placebo; n.s.). Of 12 efruxifermin-treated patients with liver biopsy after 16 weeks, 4 (33%) achieved fibrosis improvement of at least one stage without worsening of NASH, while an additional 3 (25%) achieved resolution of NASH, compared to 0 of 5 placebo-treated patients., Conclusions: Efruxifermin appeared safe and well-tolerated with encouraging improvements in markers of liver injury, fibrosis, and glucose and lipid metabolism following 16 weeks of treatment, warranting confirmation in larger and longer term studies., Lay Summary: Cirrhosis resulting from non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease, represents a major unmet medical need. Currently there are no approved drugs for the treatment of NASH. This proof-of-concept randomized, double-blind clinical trial demonstrated the potential therapeutic benefit of efruxifermin treatment compared to placebo in patients with cirrhosis due to NASH., Clinical Trial Number: NCT03976401., Competing Interests: Stephen A. Harrison holds a leadership or fiduciary role at, advises, consults for, receives grants or contracts from Northsea Therapeutics. He advises, consults for, receives grants or contracts, support for attending meetings and/or travel from Madrigal Pharmaceuticals, Inc. He advises, consults for, and receives grants or contracts from Akero Therapeutics, Inc. He advises, consults for, and receives grants or contracts from Axcella Health, Inc., Cymabay Therapeutics, Inc., Galectin Therapeutics, Inc., Hepion Pharmaceuticals, Inc., Hightide Therapeutics, Inc., Intercept Pharmaceuticals, Inc., Metacrine Inc., NGM Biopharmaceuticals Inc., Genfit Corp, Novo Nordisk, Poxel, Sagimet Biosciences. He advises and receives grants or contracts from Gilead Sciences, Inc., Galmed Research & Dev. LTD., and Novartis Pharmaceuticals Corp. He consults for and receives grants or contracts from Viking Therapeutics, Inc. and Enyo Pharma S.A. He advises and consults for Altimmune, Echosens North America Inc. Foresite Labs, LLC, HistoIndex PTE LTD, Medpace Inc., Prometic, Pharma SMT LTD, Ridgeline and Sonic Incytes Medical Corp, Terns Inc. He advises for 89bio, Arrowhead, Chronwell, CiVi, Indalo, PathAI, and Theratechnologies. He consults for AgomAB, Alentis Therapeutics AG, Alimentiv, Inc, Boston Pharmaceuticals, B Riley FBR Inc. BVF Partners LP, Cohbar, Inc. Canfite, Corcept Therapeutics, Inc, Fibronostics, Fortress Biotech, Inc GNS, Inipharm, Ionis, Kowa Research Institute, Microba, Nutrasource, Perspectum Diagnostics, and Piper Sandler. He receives grants or contracts from Cirius Therapeutics, Inc., and CiVi Biopharma Inc. He holds stock or stock options at Akero Therapeutics, Inc., Chronwell Inc., Cirius Therapeutics, Inc, Galectin Therapeutics, Inc., Genfit Corp, Hepion Pharmaceuticals Inc., HistoIndex PTE LTD, Metacrine Inc., NGM Biopharmaceuticals., Northsea Therapeutics B.V, and Sonic Incytes Medical Corp. Peter J. Ruane: none. Bradley Freilich: none. Guy Neff has received payment or honoraria from Intercept Pharmaceuticals. Rashmee Patil has received grants to institution from 89 Bio, AltImmune, Boehringer Ingelheim, Bristol Myers Squibb, Corcept Therapeutics, Fibronostics, Galectin Therapeutics, Genentech, Gilead, Helio Health, Hepagene, Madrigal Pharmaceuticals, NGMBio, NorthSea Therapeutics, Poxel, Sagimet Biosciences, and Viking Therapeutics. He consults for Intercept Pharmaceuticals. Cynthia Behling has received payment via Pacific Rim Pathology for liver biopsy scoring. She has received grants as a co-investigator under N100 K U01 DK61734. She has received honoraria for lectures from Pfizer and Alimentev. She is a co-chair on NASH CRN Pathology Committee. Chen Hu: none. Reshma Shringarpure, Brittany de Temple, Erica Fong, Erik J. Tillman, Timothy Rolph, Andrew Cheng, and Kitty Yale are employees of Akero Therapeutics and own stock and/or stock options of Akero Therapeutics. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

Research over the past few decades has established a role for the endocannabinoid system in contributing to the neural and endocrine responses to stress exposure. The two endocannabinoid ligands, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), both play roles in regulating the stress response and both exhibit dynamic changes in response to stress exposure. Most of this previous research, however, was conducted in male rodents. Given that, especially in rodents, the stress response is influenced by sex, an understanding of how these dynamic responses of endocannabinoids in response to stress is influenced by sex could provide insight into sex differences of the acute stress response. We exposed adult, Sprague Dawley rats to different commonly utilized acute stress modalities, specifically restraint, swim and foot shock stress. Thirty minutes following stress onset, we excised the amygdala, hippocampus and medial prefrontal cortex, corticolimbic brain regions involved in the stress response, to measure endocannabinoid levels. When AEA levels were altered in response to restraint and swim stress, they were reduced, whereas exposure to foot shock stress led to an increase in the amygdala. 2-AG levels, when they were altered by stress exposure were only increased, specifically in males in the amygdala following swim stress, and in the hippocampus and medial prefrontal cortex overall following foot shock stress. This increase in 2-AG levels following stress only in males was the only sex difference found in stress-induced changes in endocannabinoid levels. There were no consistent sex differences observed. Collectively, these data contribute to our further understanding of the interactions between stress and endocannabinoid function., Competing Interests: The authors declare no conflict of interest. Our funding acknowledgement statement can be found above, and funding agencies had no influence on the design, execution or publishing of this work., (© 2022 The Authors.)

Background: Postpartum depression is a mood disorder that affects about 9-20% of women after child birth. Reports suggest that gestational iron deficiency can cause a deficit in behavioral, cognitive and affective functions and can precipitate depressive symptoms in mothers during the postpartum period. The present study examined the effect of iron supplementation on depressive behavior during postpartum period in a rat model., Method: Female Sprague-Dawley rats were crossed. Pregnant rats received iron, fluoxetine, desferrioxamine or vehicle throughout the period of gestation. During the postpartum period, mothers from all groups were taken through the open field test (OFT), forced swim test (FST), novelty-induced hypophagia (NIH) and sacrificed for histological examination of the brains., Results: Results showed that rats treated with iron-chelating agent, desferrioxamine, and vehicle during gestation exhibited increased immobility scores in the FST, increased latency to feed and reduced feeding in the NIH with corresponding decreased number of neurons and dendritic branches in the cortex of the brain. These depression-related effects were attenuated by perinatal iron supplementation which showed decreased immobility scores in the FST comparable to rats treated with fluoxetine, a clinically effective antidepressant. Iron treatment also decreased latency to feeding while increasing feeding behavior in the NIH. Iron-treated dams had a higher number of neurons with dendritic connections in the frontal cortex compared to vehicle- and desferrioxamine-treated groups., Conclusion: The results suggest that, iron supplementation during gestation exerts an antidepressant-like effect in postpartum Sprague-Dawley rats, attenuates neuronal loss associated with depression and increases dendritic spine density., (© 2022 The Authors.)

Ciliary neurotrophic factor (CNTF) is produced by astrocytes which have been implicated in regulating stress responses. We found that CNTF in the medial amygdala (MeA) promotes despair or passive coping, i.e., immobility in an acute forced swim stress, in female mice, while having no effect in males. Neutralizing CNTF antibody injected into the MeA of wildtype females reduced activation of downstream STAT3 (Y705) 24 and 48 h later. In concert, the antibody reduced immobility in the swim test in females and only after MeA injection, but not when injected in the central or basolateral amygdala. Antibody injected into the male MeA did not affect immobility. These data reveal a unique role of CNTF in female MeA in promoting despair or passive coping behavior. Moreover, 4 weeks of chronic unpredictable stress (CUS) increased immobility in the swim test and reduced sucrose preference in wildtype CNTF+/+, but not CNTF-/- littermate, females. Following CUS, 10 min of restraint stress increased plasma corticosterone levels only in CNTF+/+ females. In males, the CUS effects were present in both genotypes. Further, CUS increased CNTF expression in the MeA of female, but not male, mice. CUS did not alter CNTF in the female hippocampus, hypothalamus and bed nucleus of stria terminalis. This suggests that MeA CNTF has a female-specific role in promoting CUS-induced despair or passive coping, behavioral anhedonia and neuroendocrine responses. Compared to CNTF+/+ mice, CNTF-/- mice did not show differences in CUS-induced anxiety-like behavior and sensorimotor gating function as measured by elevated T-Maze, open field and pre-pulse inhibition of the acoustic startle response. Together, this study reveals a novel CNTF-mediated female-specific mechanism in stress responses and points to opportunities for developing treatments for stress-related disorders in women., Competing Interests: The authors declare no competing financial interests or potential conflicts of interest., (© 2022 The Authors.)

Natural variations in maternal care in the rat influence the development of neuronal systems that regulate endocrine and behavioral responses to stress. Thus, as adults, rats that received higher levels of maternal licking/grooming (LG) in infancy are less ‘fearful’ in response to novelty, compared with adult offspring of Low LG mothers. The present study examined the influence of maternal care on behavioral and neuronal responses to a more specific, localizable form of threat using an electrified probe in the shock-probe burying test. Even under these conditions, adult offspring of High LG mothers displayed lower levels of fear reactivity (i.e. less shock-induced freezing and probe burying) throughout the test than did offspring of Low LG mothers. These differences in fearfulness were associated with differential patterns of cFos immunoreactivity (cFos-IR), 120 min following test exposure. Relative to control rats exposed to a non-electrified probe, cFos-IR was increased in the offspring of High LG mothers exposed to an electrified probe in the dentate gyrus, ventral subiculum, lateral and medial septum, nucleus accumbens and the dorsal periaqueductal gray. Shock-exposed offspring of Low LG dams displayed a very different pattern of neuronal activation characterized by both increases (area CA1of the ventral hippocampus and the inferior colliculus) and decreases (paraventricular nucleus of the hypothalamus and the ventrolateral periaqueductal gray) in cFos-IR compared with the no-shock controls. Together these results suggest that maternal care serves to ‘program’ neuronal circuits that modulate fear-related responding in the rat resulting in qualitatively different neuronal responses to stress. [Copyright &y& Elsevier]

11β-hydroxysteroid dehydrogenases (11β-HSDs) catalyse the interconversion of active cortisol and inert cortisone. Two isozymes have been discovered, each with unique properties and powerful biological roles. 11β-HSD2 potently inactivates cortisol, protecting key tissues. By contrast, 11β-HSD1 regenerates cortisol, amplifying its actions in liver, fat and brain. Overexpression of this isozyme may contribute to the pathogenesis of the metabolic syndrome. Its inhibition is a potential therapeutic target for both metabolic and glucocorticoid-associated CNS disorders. [Copyright &y& Elsevier]

The bed nucleus of the stria terminalis (BNST) is believed to be a critical relay between the central nucleus of the amygdala (CE) and the paraventricular nucleus of the hypothalamus in the control of hypothalamic–pituitary–adrenal (HPA) responses elicited by conditioned fear stimuli. If correct, lesions of CE or BNST should block expression of HPA responses elicited by either a specific conditioned fear cue or a conditioned context. To test this, rats were subjected to cued (tone) or contextual classical fear conditioning. Two days later, electrolytic or sham lesions were placed in CE or BNST. After 5 days, the rats were tested for both behavioral (freezing) and neuroendocrine (corticosterone) responses to tone or contextual cues. CE lesions attenuated conditioned freezing and corticosterone responses to both tone and context. In contrast, BNST lesions attenuated these responses to contextual but not tone stimuli. These results suggest CE is indeed an essential output of the amygdala for the expression of conditioned fear responses, including HPA responses, regardless of the nature of the conditioned stimulus. However, because lesions of BNST only affected behavioral and endocrine responses to contextual stimuli, the results do not support the notion that BNST is critical for HPA responses elicited by conditioned fear stimuli in general. Instead, the BNST may be essential specifically for contextual conditioned fear responses, including both behavioral and HPA responses, by virtue of its connections with the hippocampus, a structure essential to contextual conditioning. The results are also not consistent with the hypothesis that BNST is only involved in unconditioned aspects of fear and anxiety. [Copyright &y& Elsevier]

Depressive patients with psychotic features demonstrate distinct biological abnormalities in the hypothalamic–pituitary–adrenal axis (HPA), dopaminergic activity, electroencephalogram sleep profiles and measures of serotonergic function when compared to nonpsychotic depressive patients. However, very few functional neuroimaging studies were specifically designed for studying the effects of psychotic features on neuroimaging findings in depressed patients. The objective of the present study was to compare brain Single Photon Emission Tomography (SPECT) images in a group of unmedicated depressive patients with and without psychotic features. Twenty-eight patients who fully met DSM-IV criteria for major depressive disorder (MDD, 12 had psychotic features) were included in the study. They were compared with 16 control subjects matched for age, gender and education. Both psychotic and nonpsychotic depressed patients showed significantly lower regional cerebral blood flow (rCBF) values in the left and right superior frontal cortex, and left anterior cingulate cortex compared to those of controls. In comparison with depressive patients without psychotic features (DwoPF), depressive patients with psychotic features (DwPF) showed significantly lower rCBF perfusion ratios in left parietal cortex, left cerebellum but had higher rCBF perfusion ratio in the left inferior frontal cortex and caudate nucleus. The present study showed that DwPF have a different rCBF pattern compared to patients without psychotic features. Abnormalities involving inferior frontal cortex, striatum and cerebellum may play an important role in the generation of psychotic symptoms in depression. [Copyright &y& Elsevier]

This study was designed to compare growth hormone, cortisol and prolactin responses to physical exercise in depressed patients and healthy comparison subjects. Patients fulfilled the DSM-IV diagnostic criteria for current major depressive disorder; subjective depressive symptoms were rated with Montgomery-Åsberg Depression Rating Scale (MÅDRS) immediately before the experiment. Growth hormone, cortisol and prolactin were measured before and immediately after physiologically stressful bicycle cardiopulmonary exercise test. After exercise, there were three additional hormone measurements, with 30-min intervals. No significant difference was found in baseline growth hormone, cortisol or prolactin levels between patients and the control group. Plasma growth hormone and cortisol levels increased significantly during physical exercise in both patients and controls and returned to baseline in 90 min. There was no significant difference in growth hormone or cortisol responses to physical exercise between the two groups. However, prolactin levels increased only in the depressed patients group during the exercise. We hypothesize that acute exercise may have a stronger effect on serotonin (5-HT) release in depressed patients, which is reflected in increased plasma prolactin concentration. [Copyright &y& Elsevier]

The notion that stress can induce chronic tinnitus, or increase its intensity, is predominant in the literature on tinnitus. However, there is little empirical support for this claim, since previous studies rely merely on subjective reports. In the present study, we used an objective physiological measure of stress (i.e., basal secretion of the stress hormone cortisol), in order to assess the relationship between tinnitus and stress. We hypothesized that tinnitus, a permanent internal sound, should behave as a stressor and should be accompanied by chronically elevated cortisol levels in individuals with severe tinnitus. In addition, we hypothesized that suffering from severe tinnitus should generalize to an intolerance towards external sounds. Two groups each comprised of 18 participants (with and without tinnitus) matched on education and health status participated in the study. Tinnitus severity, as assessed by tinnitus-related distress, was high in half of the tinnitus participants, and low in the other half. Basal cortisol levels were measured using saliva samples (five saliva samples per day for 3 days within a week) taken in the participant’s natural environment. Intolerance to external sounds was assessed psychometrically. The high tinnitus-related distress group had chronic cortisol levels greater than both the low tinnitus-related distress and control groups, and also displayed greater intolerance to external sounds. The low tinnitus-related distress and control groups did not differ from each other on either of these measures. Our study thus provides the first physiological and empirical evidence of a link between intolerance to both internal (tinnitus) and external sounds in persons with tinnitus, and is compatible with the clinical observation that severe tinnitus is associated with high stress levels. [Copyright &y& Elsevier]

Stress activates the hypothalamic–pituitary–adrenal (HPA) axis through release of corticotropin releasing factor (CRF), leading to production of glucocorticoids that down regulate immune responses. However, acute stress via CRF also has pro-inflammatory effects. We previously showed that acute stress increases rat blood–brain barrier (BBB) permeability, an effect involving brain mast cells and CRF, as it was absent in W/Wv mast cell-deficient mice and was blocked by the CRF-receptor antagonist, Antalarmin. We investigated if CRF could also have a direct action on brain microvessel endothelial cells (BMEC) isolated from rat and bovine brain. BMEC were cultured and identified by electron microscopy. Western blot analysis of cultured BMEC identified CRF receptor protein; stimulation with CRF, or it structural analogue urocortin (Ucn) showed that the receptor is functionally coupled to adenylate cyclase as it increased cyclic AMP (cAMP) levels by 2-fold. These findings suggest that CRF could affect BMEC structure or function, as reported for increased cAMP levels by other studies. It is, therefore, possible that CRF may directly regulate BBB permeability, in addition to any effect mediated via brain mast cells. [Copyright &y& Elsevier]

The brain noradrenergic system is activated by stress, modulating the activity of forebrain regions involved in behavioral and neuroendocrine responses to stress. In this study, we characterized brain noradrenergic reactivity to acute immobilization stress in three rat strains that differ in their neuroendocrine stress response: the inbred Lewis (Lew) and Wistar–Kyoto (WKY) rats, and outbred Sprague–Dawley (SD) rats. Noradrenergic reactivity was assessed by measuring tyrosine hydroxylase mRNA expression in locus coeruleus, and norepinephrine release in the lateral bed nucleus of the stria terminalis. Behavioral measures of arousal and acute stress responsivity included locomotion in a novel environment, fear-potentiated startle, and stress-induced reductions in social interaction and open-arm exploration on the elevated-plus maze. Neuroendocrine responses were assessed by plasma adrenocorticotropic hormone. Compared to SD, adrenocorticotropic hormone responses of Lew rats were blunted, whereas those of WKY were enhanced. The behavioral effects of stress were similar in Lew and SD rats, despite baseline differences. Lew had similar elevations of tyrosine hydroxylase mRNA, and initially greater norepinephrine release in the lateral bed nucleus of the stria terminalis during stress, although both noradrenergic responses returned toward baseline more rapidly than in SD rats. WKY rats showed depressed baseline startle and lower baseline exploratory and social behavior than SD. However, unlike the Lew or SD rats, WKY exhibited a lack both of fear potentiation of the startle response and of stress-induced reductions in exploratory and social behavior, indicating attenuated stress responsivity. Acute noradrenergic reactivity to stress, measured by either tyrosine hydroxylase mRNA levels or norepinephrine release, was also attenuated in WKY rats. Thus, reduced arousal and behavioral responsivity in WKY rats may be related to deficient brain noradrenergic reactivity. This deficit may alter their ability to cope with stress, resulting in the exaggerated neuroendocrine responses and increased susceptibility to stress-related pathology exhibited by this strain. [Copyright &y& Elsevier]

The extra-hypothalamic actions of corticotropin-releasing hormone (CRH) have been accorded an important role in coordinating responses to stressors and contributing to the consequences of drug abuse. Recent proposals suggest that CRH actions in the bed nucleus of the stria terminalis coordinate responses to tonic/unpredictable stressors whereas these actions in the central nucleus of the amygdala coordinate responses to phasic/predictable stressors. We used in situ hybridization histochemistry and site-specific microinjections of a CRH receptor antagonist to study the role of CRH in opiate withdrawal.Rats undergoing opiate withdrawal displayed clear behavioral and autonomic changes accompanied by hyperalgesia and increased plasma corticosterone. In situ hybridization of CRH mRNA revealed significant increases in the central nucleus of the amygdala but not in the bed nucleus of the stria terminalis among rats either chronically pre-treated with morphine, given an injection of naloxone, or both (precipitated withdrawal). An increase of CRH mRNA in the paraventricular nucleus of the hypothalamus was specific to rats undergoing withdrawal. Intracerebroventricular microinjection of the CRH receptor antagonist, αhCRH9–41, reduced the severity of opiate withdrawal. Microinjections of αhCRH9–41 into the central nucleus of the amygdala also reduced the severity of withdrawal whereas bed nucleus of the stria terminalis microinjections of αhCRH9–41 were without effect.These experiments provide evidence for a role of amygdala, but not bed nucleus of the stria terminalis, CRH in opiate dependence. We propose a specific role for down-regulation of opiate receptor signaling in increased expression of the CRH gene in the amygdala. Moreover, we suggest that the roles accorded to CRH in the bed nucleus of the stria terminalis versus amygdala in coordinating responses to stressors may need to be reconsidered to distinguish between external and internal/interoceptive stressors. [Copyright &y& Elsevier]

We have previously shown that a single exposure of adult rats to a severe emotional stressor such as immobilization is able to exert a long-term desensitization of the response of the hypothalamic–pituitary–adrenal (HPA) axis to the same stimulus when applied days to weeks later. Surprisingly, the intensity of the effect increased with time elapsed between the two exposures, suggesting that we are dealing with a new type of stress-associated phenomenon. Taking into account the clinical importance of tolerance to endotoxin, in the present study we assessed whether a single exposure to an immunological stressor such as lipopolysaccharide can induce effects similar to those of immobilization. Rats injected with lipopolysaccharide (1 mg/kg) showed a reduction of the response of the corticotropin-releasing factor mRNA in the paraventricular nucleus of the hypothalamus after a new lipopolysaccharide injection 4, but not 2 weeks later. In an additional experiment using a different blood sampling procedure, adrenocorticotropin hormone, corticosterone and tumor necrosis factor-α responses were reduced approximately to the same extent by previous experience with lipopolysaccharide either 1 or 4 weeks before.Our data suggest that a previous single exposure to lipopolysaccharide induces a long-lasting tolerance of the HPA axis that likely involves some kind of learning-like brain plasticity. [Copyright &y& Elsevier]

Nitric oxide (NO) is a neurosignaling molecule that appears to play a significant role in learning and memory. This molecule has also been implicated in neurotoxicity due to its oxidative properties. Previous experiments from our laboratories have demonstrated elevated hippocampal and cortical neuronal nitric oxide synthase (NOS) mRNA levels in aged cognitively unimpaired and impaired Long–Evans rats, which could represent either increased neuronal NOS activity thereby leading to NO-mediated neurotoxicity, or a compensatory response by aged neurones to maintain physiological nitric oxide output. The current study measured the protein expression and activity levels of neuronal and inducible NOS in young adult (6 months) and aged (24–26 months) Long–Evans rats by means of western blotting and NOS activity assay. Aged animals were assigned as either cognitively unimpaired or aged with moderate cognitive impairments based on their performances in the Morris water maze behavioural task. Our results showed that hippocampal and cortical neuronal NOS expressions were significantly decreased in aged animals. These aged animals also exhibited increased hippocampal and cortical inducible NOS expressions. Between the two aged animal groups, cognitively impaired rats showed significantly lower hippocampal and cortical neuronal but higher hippocampal inducible NOS expressions. Young adult rats exhibited significantly higher hippocampal and cortical NOS activities than the aged animals. Aged animals with cognitive deficits showed significantly lower hippocampal NOS activity than cognitively unimpaired aged rats.Our data indicate that aging is associated with a decline in neuronal but elevated inducible NOS functioning in brain areas involved in learning and memory. These phenomena could contribute to the cognitive deficits observed in a sub-population of aged animals. [Copyright &y& Elsevier]

The brain noradrenergic system is activated by stress, and modulates the activity of forebrain regions involved in behavioral and neuroendocrine responses to stress, such as the lateral bed nucleus of the stria terminalis (BSTL). This region of the limbic forebrain receives dense noradrenergic innervation, and has been implicated in both anxiety and regulation of the hypothalamic–pituitary–adrenal axis. We hypothesized that stress-induced release of norepinephrine in the BSTL modulates anxiety-like behavioral responses to stress and activation of the hypothalamic–pituitary–adrenal stress axis.Using microdialysis, we showed that release of norepinephrine was increased in the BSTL of male Sprague–Dawley rats during immobilization stress. In the next experiment, we then microinjected noradrenergic antagonists into the BSTL immediately prior to acute immobilization stress to examine noradrenergic modulation of behavioral stress reactivity. Either the α1-receptor antagonist benoxathian, or a cocktail of β1- and β2-receptor antagonists (betaxolol+ICI 118,551) blocked the anxiety-like reduction in open-arm exploration on the elevated plus-maze, but not the reduction in social behavior induced in the social interaction test. In a third experiment, benoxathian reduced plasma levels of adrenocorticotropic hormone following stress, but β-receptor antagonists had no effect.From these results we suggest that stress-induced norepinephrine release acts on both α1- and β-receptors in the BSTL to facilitate anxiety-like behavioral responses on the plus-maze but not the social interaction test, and modulates hypothalamic–pituitary–adrenal axis activation via α1-receptors only. Together with previous results in which adrenergic antagonists in central amygdala attenuated behavioral responses on the social interaction test but not the plus-maze, these observations suggest the two behavioral tests measure different dimensions of stress reactivity, and that norepinephrine facilitates different components of the stress response by region- and receptor-specific mechanisms. [Copyright &y& Elsevier]

Background: The effects of halobetasol propionate (HBP) lotion 0.05% on the hypothalamic-pituitary-adrenal (HPA) axis have not been previously evaluated in adolescents., Objective: To examine the effect of HBP on HPA axis suppression in patients aged <17 years with plaque psoriasis., Methods: In this phase 4, open-label, multicenter study, patients aged 12 to 16 years 11 months with stable plaque psoriasis covering ≥10% of their body surface area were enrolled. The patients applied an HBP lotion twice daily for up to 2 weeks. The cosyntropin stimulation test was used to determine cortisol levels at the time of screening and at the end of the study to evaluate HPA axis response. The additional endpoints included adverse events, disease severity (measured using Investigator Global Assessment score), and percent body surface area affected., Results: Sixteen patients were enrolled and included in the safety population; 14 were included in the evaluable population. One patient exhibited an abnormal HPA axis response (16.2 μg/dL) at the end of the study; the response returned to normal at the 6-month follow-up visit. By the end of the study, the Investigator Global Assessment score improved by ≥1 point in most patients; moreover, the percent body surface area affected decreased from 11.5% to 2.8%. One mild adverse event was possibly related to the HBP lotion; however, it resolved and did not cause study discontinuation., Limitations: Small sample size., Conclusion: The HBP lotion 0.05% appeared efficacious and well tolerated in patients as young as 12 years old., Competing Interests: Dr Laquer has served on advisory boards for Almirall, Celgene, LEO Pharmaceuticals, Novartis, and Pfizer. Author Nguyen has served on advisory boards and as a consultant for Celgene; Foamix; IntraDerm Pharmaceuticals; LEO Pharmaceuticals; Mayne; Novartis; Pfizer; Sanofi Regeneron; and Sun Pharmaceutical Industries, Inc; as a speaker for Amgen; Celgene; Eli Lilly; Encore Pharmaceuticals; Janssen; LEO Pharmaceuticals; Mayne; Novartis; Sun Pharmaceutical Industries, Inc; and UCB. Dr Squittieri is an employee of Sun Pharmaceutical Industries, Inc. Dr Nguyen has served as a consultant for AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Corrona, Eli Lilly, Janssen, Novartis, Pfizer, Sanofi Regeneron, and UCB; as an investigator for AbbVie, Amgen, Bristol-Myers Squibb, Biogen, Eli Lilly, GlaxoSmithKline, Merck, Novartis, Pfizer, and Sanofi Regeneron; and as a speaker for AbbVie; Almirall; Amgen; Celgene; Eli Lilly; Novartis; Pfizer; Sanofi Regeneron; and Sun Pharmaceutical Industries, Inc., (© 2021 by the American Academy of Dermatology, Inc. Published by Elsevier Inc.)

Exercise can reduce the incidence of stress-related mental diseases, such as depression and anxiety. Control group was neither exposed to CVMS nor TRE (noCVMS/noTRE). Females were tested and levels of serum17-beta-oestradiol (E 2 ), estrogen receptors α immunoreactive neurons (ERα-IRs), estrogen receptors β immunoreactive neurons (ERβ-IRs) and oxytocin immunoreactive neurons (OT-IRs) were measured. The results showed there's increased anxiety-like behaviors for mice from CVMS/noTRE, CVMS/higher speed TRE (CVMS/HTRE) and noCVMS/HTRE groups when they were put in open field and elevated maze tests. They had lower serum E 2 levels than mice from CVMS/low-moderate speed TRE (CVMS/LMTRE), noCVMS/LMTRE and noCVMS/noTRE groups. The three groups of CVMS/noTRE, CVMS/HTRE and noCVMS/HTRE mice had more ERα-IRs and less ERβ-IRs in the medial preoptic area (mPOA), bed nucleus of the stria terminalis (BNST) and medial amygdala (MeA), hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON). The number of OT-IRs in PVN and SON of CVMS/noTRE, CVMS/HTRE and noCVMS/HTRE mice was also lower than that of mice from CVMS/LMTRE, noCVMS/LMTRE and noCVMS/noTRE groups. Interestingly, CVMS/LMTRE and noCVMS/LMTRE mice were similar to noCVMS/noTRE mice in that they did not show anxiety, while CVMS/HTRE and noCVMS/HTRE mice did not, which were similar to the mice in CVMS/noTRE. We propose that LMTRE instead of HTRE changes the serum concentration of E 2 . ERβ/ERα ratio and OT level in the brain may be responsible for the decrease in anxiety-like behavior in female mice exposed to anxiety-inducing stress conditions., Competing Interests: The authors declare no competing financial interests., (© 2021 Published by Elsevier Ltd on behalf of International Brain Research Organization.)

Background: Adrenal insufficiency (AI) may cause psychiatric symptoms. We evaluated the correlation between the hypothalamic-pituitary-adrenal axis (HPA) function in patients with mental illness who complained of postprandial symptoms in addition to fatigue., Methods: We recruited 16 patients with mental illness who complained of postprandial symptoms in addition to fatigue for the evaluation of the HPA axis function using a rapid adrenocorticotropin (ACTH) test with Cortrosyn®, (250 μg), a corticotropin-releasing hormone (CRH) test, and an insulin tolerance test (ITT). The ITT results were adopted if the nadir blood glucose level was <2.2 mm/L. Patients with showed a peak cortisol level of <496.6 nmol/L (18 μg/dL) in the ITT were diagnosed with AI and the results were compared with the results of the rapid ACTH and CRH tests. The patients' clinical characteristics were evaluated., Results: Twelve of 16 patients met the criteria for the adoption of the ITT. A peak cortisol level of <496.6 nmol/L was detected by the rapid ACTH test in three patients, by the CRH test in ten patients, and by the ITT in all twelve patients. Six of the above 12 patients used exogenous steroids due to the comorbidities such as bronchial asthma., Conclusions: Twelve of the patients who complained of postprandial symptoms in addition to fatigue met the diagnostic criteria for AI. AI is often latent and more frequent in patients with mental illness. It is therefore necessary to inquire about exogenous steroid use for comorbidities when managing such patients., (© 2021 The Authors.)

Background & Aims: Hepatic enzymes play a major role in the metabolic elimination of cortisol, and reduced rates of cortisol clearance have been consistently observed in patients with chronic liver disease. It is less clear whether there are concomitant abnormalities of adrenocortical function in patients with cirrhosis. In the present study, we sought to assess adrenocortical function in patients with cirrhosis using measures of free cortisol appearance and elimination rates that are independent of serum concentrations of cortisol binding proteins., Methods: Post hoc analysis used computer-assisted numerical and modelling methods with serial total and free cortisol concentration data to obtain rates of free cortisol appearance and elimination. Rate parameters were obtained in 114 patients with chronic liver disease, including Child-Pugh (CP) ≤8 (n = 53) and CP >8 (n = 61)., Results: Maximal cortisol secretion rate (CSR max ) was significantly decreased ( p  = 0.01) in patients with cirrhosis with CP >8 (0.28 nM/s; 95% CI 0.24-0.34) compared with those with CP ≤8 (0.39 nM/s; 95% CI 0.33-0.46), and CSR max was negatively correlated with CP score (r = -0.19, p  = 0.01). Free cortisol elimination rate was significantly ( p  = 0.04) decreased in the CP >8 group (0.16 ± 0.20 min -1 ) compared with that in the CP ≤8 group (0.21 ± 0.21 min -1 ), and free cortisol elimination rates were negatively correlated with CP score (r = -0.23, p  = 0.01). A significant correlation between CSR max and free cortisol elimination rate (r = 0.88, p <0.001) was observed., Conclusions: CSR max and free cortisol elimination rates were significantly reduced according to severity of cirrhosis. In contrast to stimulated total cortisol concentrations, CSR max estimates were independent of cortisol-binding protein concentrations. Results provide additional evidence of subnormal adrenocortical function in patients with cirrhosis., Lay Summary: We applied numerical analytic methods to characterise adrenocortical function in patients with varying stages of chronic liver disease. We found that patients with more severe cirrhosis have decreased rate of free cortisol elimination and decreased maximal cortisol secretion rate, which is a measure of adrenocortical function. In contrast to conventional measures of adrenocortical function, those obtained using numerical methods were not affected by variation in corticosteroid binding globulin and albumin concentrations. We conclude that patients with cirrhosis demonstrate measurable abnormalities of adrenocortical function, evidence of which supports aspects of the hepatoadrenal syndrome hypothesis., Competing Interests: The authors have no conflicts of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details.

Translational animal models for studying post-traumatic stress disorder (PTSD) are valuable for elucidating the poorly understood neurobiology of this neuropsychiatric disorder. These models should encompass crucial features, including persistence of PTSD-like phenotypes triggered after exposure to a single traumatic event, trauma susceptibility/resilience and predictive validity. Here we propose a novel arousal-based individual screening (AIS) model that recapitulates all these features. The AIS model was designed by coupling the traumatization (24 h restraint) of C57BL/6 J mice with a novel individual screening. This screening consists of z-normalization of post-trauma changes in startle reactivity, which is a measure of arousal depending on neural circuits conserved across mammals. Through the AIS model, we identified susceptible mice showing long-lasting hyperarousal (up to 56 days post-trauma), and resilient mice showing normal arousal. Susceptible mice further showed persistent PTSD-like phenotypes including exaggerated fear reactivity and avoidance of trauma-related cue (up to 75 days post-trauma), increased avoidance-like behavior and social/cognitive impairment. Conversely, resilient mice adopted active coping strategies, behaving like control mice. We further uncovered novel transcriptional signatures driven by PTSD-related genes as well as dysfunction of hypothalamic-pituitary-adrenal axis, which corroborated the segregation in susceptible/resilient subpopulations obtained through the AIS model and correlated with trauma susceptibility/resilience. Impaired hippocampal synaptic plasticity was also observed in susceptible mice. Finally, chronic treatment with paroxetine ameliorated the PTSD-like phenotypes of susceptible mice. These findings indicate that the AIS model might be a new translational animal model for the study of crucial features of PTSD. It might shed light on the unclear PTSD neurobiology and identify new pharmacological targets for this difficult-to-treat disorder., (© 2020 The Authors.)