11ß-Hydroxysteroid dehydrogenase and the brain: Not (yet) lost in translation.

11-beta-hydroxysteroid dehydrogenases (11ß-HSDs) catalyse the conversion of active 11-hydroxy glucocorticoids (cortisol, corticosterone) and their inert 11-keto forms (cortisone, 11-dehydrocorticosterone). They were first reported in the body and brain 70 years ago, but only recently have they become of interest. 11ß-HSD2 is a dehydrogenase, potently inactivating glucocorticoids. In the kidney, 11ß-HSD2 generates the aldosterone-specificity of intrinsically non-selective mineralocorticoid receptors. 11ß-HSD2 also protects the developing foetal brain and body from premature glucocorticoid exposure, which otherwise engenders the programming of neuropsychiatric and cardio-metabolic disease risks. In the adult CNS, 11ß-HSD2 is confined to a part of the brain stem where it generates aldosterone-specific central control of salt appetite and perhaps blood pressure. 11ß-HSD1 is a reductase, amplifying active glucocorticoid levels within brain cells, notably in the cortex, hippocampus and amygdala, paralleling its metabolic functions in peripheral tissues. 11ß-HSD1 is elevated in the ageing rodent and, less certainly, human forebrain. Transgenic models show this rise contributes to age-related cognitive decline, at least in mice. 11ß-HSD1 inhibition robustly improves memory in healthy and pathological ageing rodent models and is showing initial promising results in phase II studies of healthy elderly people. Larger trials are needed to confirm and clarify the magnitude of effect and define target populations. The next decade will be crucial in determining how this tale ends - in new treatments or disappointment.

New View on the Impact of the Low-Frequency Electromagnetic Field (50 Hz) on Stress Responses: Hormesis Effect.

INTRODUCTION: Low-frequency electromagnetic field (50 Hz) (EMF) can modify crucial neuronal processes. Existing data indicate that exposure to EMF may represent a mild stressor and contribute to disturbances of the hypothalamic-pituitary-adrenal (HPA) axis. The important regulatory pathways controlling HPA axis activity include two types of corticosteroid receptors: mineralocorticoid receptors (MRs) and glucocorticoid receptors. They are particularly abundant in the hippocampus, a key locus of HPA axis feedback control. The research aimed at determining whether (1) EMF exhibits hormesis, it means bidirectional action depending on EMF intensity (1 or 7 mT) and (2) repeated EMF exposure changes stress response to subsequent stress factors. METHODS: The exposure (7 days, 1 h/day) of adult rats to EMF (1 mT and 7 mT) was repeated 3 times. HPA axis hormones and their receptors were analysed after each following exposure. Moreover, the impact of EMF exposure on hormonal and behavioural responses to subsequent stress factor - open-field test was evaluated. RESULTS: Our data suggest that exposure to EMF can establish a new "set-point" for HPA axis activity. The direction and dynamics of this process depend on the intensity of EMF and the number of exposures. EMF of 1 mT induced an adaptive stress response, but 7 mT EMF caused sensitization. Consequently, EMF changed the vulnerability of the organism to a subsequent stress factor. We have also shown the increase in MR mRNA abundance in the hippocampus of 1 mT EMF-exposed rats, which can represent the possible neuroprotective response and suggest therapeutic properties of EMFs.

11ß-Hydroxysteroid dehydrogenase 1 deficiency prevents PTSD-like memory in young adult mice.

Post-traumatic stress disorder (PTSD) is characterized by the co-existence of a persistent strong memory of the traumatic experience and amnesia for the peritraumatic context. Most animal models, however, fail to account for the contextual amnesia which is considered to play a critical role in the etiology of PTSD intrusive memories. It is also unclear how aging affects PTSD-like memory. Glucocorticoids alter the formation and retention of fear-associated memory. Here, we investigated whether a deficiency of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) (an intracellular glucocorticoid generating enzyme) and aging modulates fear conditioning and PTSD-like memory in mice. We first measured memory in 6 months and 24 months old 11ß-HSD1 deficient (HSD1 KO) and wildtype (WT) mice following paired tone-shock fear conditioning. Then, separate groups of mice were exposed to restraint stress immediately after unpaired tone-shock contextual fear conditioning. Compared with young controls, aged WT mice exhibited enhanced auditory cued fear memory, but contextual fear memory was not different. Contextual fear memory retention was attenuated in both young and aged HSD1 KO mice. In contrast, auditory cued fear memory was reduced 24 h after training only in aged HSD1 KO mice. When fear conditioned with stress, WT mice displayed PTSD-like memory (i.e., increased fear to tone not predictive of shock and reduced fear to 'aversive' conditioning context); this was unchanged with aging. In contrast, young HSD1 KO mice fear conditioned with stress showed normal fear memory (i.e., increased fear response to conditioning context), as observed in WT mice fear conditioned alone. While aged HSD1 KO mice fear conditioned with stress also displayed normal contextual fear memory, the fear response to the 'safe' tone remained. Thus, a deficiency of 11ß-HSD1 protects against both amnesia for the conditioning context and hypermnesia for a salient tone in young adult mice but only contextual amnesia is prevented in aged mice. These results suggest that brain 11ß-HSD1 generated glucocorticoids make a significant contribution to fear conditioning and PTSD-like memory. 11ß-HSD1 inhibition may be useful in prevention and/or treatment of PTSD.

Hair glucocorticoids are associated with childhood adversity, depressive symptoms and reduced global and lobar grey matter in Generation Scotland.

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been commonly reported in major depressive disorder (MDD), but with considerable heterogeneity of results; potentially due to the predominant use of acute measures of an inherently variable/phasic system. Chronic longer-term measures of HPA-axis activity have yet to be systematically examined in MDD, particularly in relation to brain phenotypes, and in the context of early-life/contemporaneous stress. Here, we utilise a temporally stable measure of cumulative HPA-axis function (hair glucocorticoids) to investigate associations between cortisol, cortisone and total glucocorticoids with concurrent measures of (i) lifetime-MDD case/control status and current symptom severity, (ii) early/current-life stress and (iii) structural neuroimaging phenotypes, in N = 993 individuals from Generation Scotland (mean age = 59.1 yrs). Increased levels of hair cortisol were significantly associated with reduced global and lobar brain volumes with reductions in the frontal, temporal and cingulate regions (ßrange = -0.057 to -0.104, all PFDR < 0.05). Increased levels of hair cortisone were significantly associated with MDD (lifetime-MDD status, current symptoms, and severity; ßrange = 0.071 to 0.115, all PFDR = < 0.05), with early-life adversity (ß = 0.083, P = 0.017), and with reduced global and regional brain volumes (global: ß = -0.059, P = 0.043; nucleus accumbens: ß = -0.075, PFDR = 0.044). Associations with total glucocorticoids followed a similar pattern to the cortisol findings. In this large community-based sample, elevated glucocorticoids were significantly associated with MDD, with early, but not later-life stress, and with reduced global and regional brain phenotypes. These findings provide important foundations for future mechanistic studies to formally explore causal relationships between early adversity, chronic rather than acute measures of glucocorticoids, and neurobiological associations relevant to the aetiology of MDD.

Effects of corticosterone within the hypothalamic arcuate nucleus on food intake and body weight in male rats.

OBJECTIVE: Obesity is a major cause of morbidity and mortality. Few weight-reducing medications are available, and these have limited efficacy. Cushing's Syndrome (caused by elevated glucocorticoid levels) and obesity have similar metabolic features. Though circulating glucocorticoid levels are not elevated in obesity, tissue-specific glucocorticoid levels have been implicated in the development of the metabolic phenotype of obesity. Tissue glucocorticoid levels are regulated by 11ß-hydroxysteroid dehydrogenase type1 (11ßHSD1), which increases the local concentration of active glucocorticoids by the production of corticosterone from 11-dehydrocorticosterone. 11ßHSD1 is expressed in the hypothalamic arcuate nucleus (ARC), a major weight and appetite-regulating centre, and therefore represents a target for novel anti-obesity therapeutic agents. Thus, we sought to investigate the effect of chronic alterations of ARC corticosterone levels (mediated by 11ßHSD1) on food intake and body weight in adult male rats. METHODS: Recombinant adeno-associated virus particles bearing sense 11ßHSD1 (rAAV-S11ßHSD1) and small interfering 11ßHSD1 (rAAV-si11ßHSD1), respectively, were stereotactically injected into the ARC (bilaterally) of adult male Wistar rats. rAAV-GFP was injected into control groups of male Wistar rats. Food intake and body weight were measured three times a week for 70 days. Terminal brain, plasma and intrascapular brown adipose tissue (iBAT) samples were taken for measurement of mRNA expression and hormone levels. RESULTS: Compared to controls, rAAV-S11ßHSD1 injection resulted in higher ARC corticosterone levels, hyperphagia and increased weight gain. Conversely, rAAV-si11ßHSD1 injection (compared to controls) resulted in lower ARC corticosterone levels, higher iBAT uncoupling protein-1 mRNA expression and less weight gain despite similar food intake. CONCLUSIONS: Therefore ARC corticosterone, regulated by 11ßHSD1, may play a role in food intake and body weight regulation. These data have important implications for the development of centrally-acting 11ßHSD1 inhibitors, which are currently being developed for the treatment of obesity, metabolic disorders, and other conditions.

Maternal Glucocorticoid Metabolism Across Pregnancy: A Potential Mechanism Underlying Fetal Glucocorticoid Exposure.

CONTEXT: Across pregnancy, maternal serum cortisol levels increase up to 3-fold. It is not known whether maternal peripheral cortisol metabolism and clearance change across pregnancy or influence fetal cortisol exposure and development. OBJECTIVES: The primary study objective was to compare maternal urinary glucocorticoid metabolites, as markers of cortisol metabolism and clearance, between the second and third trimester of pregnancy. Secondary objectives were to test associations of total maternal urinary glucocorticoid excretion, with maternal serum cortisol levels and offspring birth weight z score. DESIGN, PARTICIPANTS, AND SETTING: A total of 151 women with singleton pregnancies, recruited from prenatal clinic at the Pittsburgh site of the Measurement of Maternal Stress (MOMS) study, had 24-hour urine collections during both the second and third trimesters. RESULTS: Between the second and third trimester, total urinary glucocorticoid excretion increased (ratio of geometric means [RGM] 1.37, 95% CI 1.22-1.52, P < .001), and there was an increase in calculated 5ß-reductase compared to 5α-reductase activity (RGM 3.41, 95% CI 3.04-3.83, P < .001). During the third trimester total urinary glucocorticoid excretion and serum cortisol were negatively correlated (r = -0.179, P = .029). Mean total urinary glucocorticoid excretion across both trimesters and offspring birth weight z score were positively associated (ß = 0.314, P = .001). CONCLUSIONS: The estimated activity of maternal enzymes responsible for cortisol metabolism change between the second and third trimester of pregnancy. Additionally, maternal peripheral metabolism and clearance of cortisol may serve as a novel mechanism affecting fetal cortisol exposure and growth.

Face coverings and respiratory tract droplet dispersion.

Respiratory droplets are the primary transmission route for SARS-CoV-2, a principle which drives social distancing guidelines. Evidence suggests that virus transmission can be reduced by face coverings, but robust evidence for how mask usage might affect safe distancing parameters is lacking. Accordingly, we set out to quantify the effects of face coverings on respiratory tract droplet deposition. We tested an anatomically realistic manikin head which ejected fluorescent droplets of water and human volunteers, in speaking and coughing conditions without a face covering, or with a surgical mask or a single-layer cotton face covering. We quantified the number of droplets in flight using laser sheet illumination and UV-light for those that had landed at table height at up to 2 m. For human volunteers, expiratory droplets were caught on a microscope slide 5 cm from the mouth. Whether manikin or human, wearing a face covering decreased the number of projected droplets by less than 1000-fold. We estimated that a person standing 2 m from someone coughing without a mask is exposed to over 10 000 times more respiratory droplets than from someone standing 0.5 m away wearing a basic single-layer mask. Our results indicate that face coverings show consistent efficacy at blocking respiratory droplets and thus provide an opportunity to moderate social distancing policies. However, the methodologies we employed mostly detect larger (non-aerosol) sized droplets. If the aerosol transmission is later determined to be a significant driver of infection, then our findings may overestimate the effectiveness of face coverings.

Mining for Oxysterols in Cyp7b1-/- Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5.

Deficiency in cytochrome P450 (CYP) 7B1, also known as oxysterol 7α-hydroxylase, in humans leads to hereditary spastic paraplegia type 5 (SPG5) and in some cases in infants to liver disease. SPG5 is medically characterized by loss of motor neurons in the corticospinal tract. In an effort to gain a better understanding of the fundamental biochemistry of this disorder, we have extended our previous profiling of the oxysterol content of brain and plasma of Cyp7b1 knockout (-/-) mice to include, amongst other sterols, 25-hydroxylated cholesterol metabolites. Although brain cholesterol levels do not differ between wild-type (wt) and knockout mice, we find, using a charge-tagging methodology in combination with liquid chromatography-mass spectrometry (LC-MS) and multistage fragmentation (MSn), that there is a build-up of the CYP7B1 substrate 25-hydroxycholesterol (25-HC) in Cyp7b1-/- mouse brain and plasma. As reported earlier, levels of (25R)26-hydroxycholesterol (26-HC), 3ß-hydroxycholest-5-en-(25R)26-oic acid and 24S,25-epoxycholesterol (24S,25-EC) are similarly elevated in brain and plasma. Side-chain oxysterols including 25-HC, 26-HC and 24S,25-EC are known to bind to INSIG (insulin-induced gene) and inhibit the processing of SREBP-2 (sterol regulatory element-binding protein-2) to its active form as a master regulator of cholesterol biosynthesis. We suggest the concentration of cholesterol in brain of the Cyp7b1-/- mouse is maintained by balancing reduced metabolism, as a consequence of a loss in CYP7B1, with reduced biosynthesis. The Cyp7b1-/- mouse does not show a motor defect; whether the defect in humans is a consequence of less efficient homeostasis of cholesterol in brain has yet to be uncovered.

Predictors of Nephrolithiasis, Osteoporosis, and Mortality in Primary Hyperparathyroidism.

CONTEXT: Primary hyperparathyroidism (PHPT) has a prevalence of 0.86% and is associated with increased risk of nephrolithiasis and osteoporosis. PHPT may also be associated with increased risk of cardiovascular disease and mortality. OBJECTIVE: To identify risk factors for nephrolithiasis, osteoporosis, and mortality in PHPT. DESIGN: Retrospective cohort study. SETTING: University teaching hospital. PATIENTS: Presented with PHPT between 2006 and 2014 (n = 611). MAIN OUTCOME MEASURE: Assessment of nephrolithiasis, osteoporosis, and mortality. RESULTS: Of patients with PHPT, 13.9% had nephrolithiasis. Most had previously documented stone disease, and only 4.7% of asymptomatic patients who were screened for renal stones had calculi identified, not very dissimilar to the rate in the non-PHPT population. Younger age (P < 0.001) and male sex (P = 0.003) were the only independent predictors of nephrolithiasis. Of patients with dual-energy X-ray absorptiometry data, 48.4% had osteoporosis (223/461). Older age (P < 0.001), lower body mass index (P = 0.002), and lower creatinine (P = 0.006) were independently associated with a diagnosis of osteoporosis. Higher PTH was independently associated with lower z score at the hip (P = 0.009); otherwise, calcium and PTH were not associated with lower z scores. Mortality in PHPT was associated with older age (P < 0.008), social deprivation (P = 0.028), and adjusted calcium (P = 0.009) but not independently with PTH at diagnosis. CONCLUSIONS: Screening for nephrolithiasis has a low yield, particularly in lower risk patients. Osteoporosis is only minimally associated with biochemical indices of PHPT. Mortality is associated with higher calcium (and possibly vitamin D deficiency) but not PTH.

Cohort profile for the STratifying Resilience and Depression Longitudinally (STRADL) study: A depression-focused investigation of Generation Scotland, using detailed clinical, cognitive, and neuroimaging assessments.

STratifying Resilience and Depression Longitudinally (STRADL) is a population-based study built on the Generation Scotland: Scottish Family Health Study (GS:SFHS) resource. The aim of STRADL is to subtype major depressive disorder (MDD) on the basis of its aetiology, using detailed clinical, cognitive, and brain imaging assessments. The GS:SFHS provides an important opportunity to study complex gene-environment interactions, incorporating linkage to existing datasets and inclusion of early-life variables for two longitudinal birth cohorts. Specifically, data collection in STRADL included: socio-economic and lifestyle variables; physical measures; questionnaire data that assesses resilience, early-life adversity, personality, psychological health, and lifetime history of mood disorder; laboratory samples; cognitive tests; and brain magnetic resonance imaging. Some of the questionnaire and cognitive data were first assessed at the GS:SFHS baseline assessment between 2006-2011, thus providing longitudinal measures of depression and resilience. Similarly, routine NHS data and early-life variables are linked to STRADL data, further providing opportunities for longitudinal analysis. Recruitment has been completed and we consented and tested 1,188 participants.

Predicting outcomes and complications following radioiodine therapy in Graves' thyrotoxicosis.

OBJECTIVE: Radioiodine (RAI) is an effective treatment for Graves' thyrotoxicosis but is associated with a failure rate of 15% and may be a risk factor for thyroid eye disease (TED) and weight gain. We sought to examine predictors of RAI failure, weight gain, TED and patient satisfaction. DESIGN: Retrospective cohort study. PATIENTS: A total of 655 episodes of RAI in Graves' thyrotoxicosis patients (2006-2015). MEASUREMENTS: Biochemical assessment, including TFTs and thyrotropin receptor antibodies (TRAb), clinical features (eg, TED, weight and thionamide use) and patient questionnaire. RESULTS: The treatment failure rate was 17%. Failure was greater with higher fT4 (P = 0.002) and higher TRAb (P = 0.004). Failure rate was 42.2% when TRAb >40 U/L. Median weight gain was 3.2 kg in those with normal fT4 prior to RAI and 5.8 kg when fT4 was elevated (P < 0.001). New TED developed in 7.6% but was not associated with post-RAI dysthyroidism. Treatment satisfaction was generally high (median response 8/10). CONCLUSIONS: Treatment failure after RAI occurs in predictable groups and this should be reflected in the information provided to patients. Weight gain is common and may not entirely be explained by a return to pre-thyrotoxic baseline. We were unable to detect any significant impact of post-RAI dysthyroidism on weight gain, TED or thyroid symptoms in this large cohort.

Presentation, diagnostic assessment and surgical outcomes in primary hyperparathyroidism: a single centre's experience.

OBJECTIVE: Primary hyperparathyroidism (PHPT) is a common reason for referral to endocrinology but the evidence base guiding assessment is limited. We evaluated the clinical presentation, assessment and subsequent management in PHPT. DESIGN: Retrospective cohort study. PATIENTS: PHPT assessed between 2006 - 2014 (n = 611) in a university hospital. MEASUREMENTS: Symptoms, clinical features, biochemistry, neck radiology and surgical outcomes. RESULTS: Fatigue (23.8%), polyuria (15.6%) and polydipsia (14.9%) were associated with PHPT biochemistry. Bone fracture was present in 16.4% but was not associated with biochemistry. A history of nephrolithiasis (10.0%) was associated only with younger age (P = 0.006) and male gender (P = 0.037). Thiazide diuretic discontinuation was not associated with any subsequent change in calcium (P = 0.514). Urine calcium creatinine clearance ratio (CCCR) was <0.01 in 18.2% of patients with confirmed PHPT. Older age (P < 0.001) and lower PTH (P = 0.043) were associated with failure to locate an adenoma on ultrasound (44.0% of scans). When an adenoma was identified on ultrasound the lateralization was correct in 94.5%. Non-curative surgery occurred in 8.2% and was greater in those requiring more than one neck imaging modality (OR 2.42, P = 0.035). CONCLUSIONS: Clinical features associated with PHPT are not strongly related to biochemistry. Thiazide cessation does not appear to attenuate hypercalcaemia. PHPT remains the likeliest diagnosis in the presence of low CCCR. Ultrasound is highly discriminant when an adenoma is identified but surgical failure is more likely when more than one imaging modality is required.

Corrigendum: Genetic identification of thiosulfate sulfurtransferase as an adipocyte-expressed antidiabetic target in mice selected for leanness.

This corrects the article DOI: 10.1038/nm.4115.

Corrigendum: Dynamic Changes in DNA Methylation Occur during the First Year of Life in Preterm Infants.

[This corrects the article on p. 158 in vol. 7, PMID: 28018293.].

Midlife stress alters memory and mood-related behaviors in old age: Role of locally activated glucocorticoids.

Chronic exposure to stress during midlife associates with subsequent age-related cognitive decline and may increase the vulnerability to develop psychiatric conditions. Increased hypothalamic-pituitary-adrenal (HPA) axis activity has been implicated in pathogenesis though any causative role for glucocorticoids is unestablished. This study investigated the contribution of local glucocorticoid regeneration by the intracellular enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), in persisting midlife stress-induced behavioral effects in mice. Middle-aged (10 months old) 11ß-HSD1-deficient mice and wild-type congenic controls were randomly assigned to 28 days of chronic unpredictable stress or left undisturbed (non-stressed). All mice underwent behavioral testing at the end of the stress/non-stress period and again 6-7 months later. Chronic stress impaired spatial memory in middle-aged wild-type mice. The effects, involving a wide spectrum of behavioral modalities, persisted for 6-7 months after cessation of stress into early senescence. Enduring effects after midlife stress included impaired spatial memory, enhanced contextual fear memory, impaired fear extinction, heightened anxiety, depressive-like behavior, as well as reduced hippocampal glucocorticoid receptor mRNA expression. In contrast, 11ß-HSD1 deficient mice resisted both immediate and enduring effects of chronic stress, despite similar stress-induced increases in systemic glucocorticoid activity during midlife stress. In conclusion, chronic stress in midlife exerts persisting effects leading to cognitive and affective dysfunction in old age via mechanisms that depend, at least in part, on brain glucocorticoids generated locally by 11ß-HSD1. This finding supports selective 11ß-HSD1 inhibition as a novel therapeutic target to ameliorate the long-term consequences of stress-related psychiatric disorders in midlife.

11ß-hydroxysteroid dehydrogenase-1 deficiency alters brain energy metabolism in acute systemic inflammation.

Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11ß-hydroxysteroid dehydrogenase type-1 (11ß-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised that 11ß-HSD1 deficiency attenuates the brain cytokine response to inflammation. Because inflammation is associated with altered energy metabolism, we also examined the effects of 11ß-HSD1 deficiency upon hippocampal energy metabolism. Inflammation was induced in 11ß-HSD1 deficient (Hsd11b1Del/Del) and C57BL/6 control mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS reduced circulating neutrophil and monocyte numbers and increased plasma corticosterone levels equally in C57BL/6 and Hsd11b1Del/Del mice, suggesting a similar peripheral inflammatory response. However, the induction of pro-inflammatory cytokine mRNAs in the hippocampus was attenuated in Hsd11b1Del/Del mice. Principal component analysis of mRNA expression revealed a distinct metabolic response to LPS in hippocampus of Hsd11b1Del/Del mice. Expression of Pfkfb3 and Ldha, key contributors to the Warburg effect, showed greater induction in Hsd11b1Del/Del mice. Consistent with increased glycolytic flux, levels of 3-phosphoglyceraldehyde and dihydroxyacetone phosphate were reduced in hippocampus of LPS injected Hsd11b1Del/Del mice. Expression of Sdha and Sdhb, encoding subunits of succinate dehydrogenase/complex II that determines mitochondrial reserve respiratory capacity, was induced specifically in hippocampus of LPS injected Hsd11b1Del/Del mice, together with increased levels of its product, fumarate. These data suggest 11ß-HSD1 deficiency attenuates the hippocampal pro-inflammatory response to LPS, associated with increased capacity for aerobic glycolysis and mitochondrial ATP generation. This may provide better metabolic support and be neuroprotective during systemic inflammation or aging.

Macrophage 11ß-HSD-1 deficiency promotes inflammatory angiogenesis.

11ß-Hydroxysteroid dehydrogenase-1 (11ß-HSD1) predominantly converts inert glucocorticoids into active forms, thereby contributing to intracellular glucocorticoid levels. 11ß-HSD1 is dynamically regulated during inflammation, including in macrophages where it regulates phagocytic capacity. The resolution of inflammation in some disease models including inflammatory arthritis is impaired by 11ß-HSD1 deficiency or inhibition. However, 11ß-HSD1 deficiency/inhibition also promotes angiogenesis, which is beneficial in mouse models of surgical wound healing, myocardial infarction or obesity. The cell types responsible for the anti-inflammatory and anti-angiogenic roles of 11ß-HSD1 have not been characterised. Here, we generated Hsd11b1MKO mice with LysM-Cre mediated deletion of Hsd11b1 to investigate whether 11ß-HSD1 deficiency in myeloid phagocytes is pro-angiogenic and/or affects the resolution of inflammation. Resolution of inflammatory K/BxN-induced arthritis was impaired in Hsd11b1MKO mice to a similar extent as in mice globally deficient in 11ß-HSD1. This was associated with >2-fold elevation in levels of the endothelial marker Cdh5 mRNA, suggesting increased angiogenesis in joints of Hsd11b1MKO mice following arthritis. A pro-angiogenic phenotype was confirmed by measuring angiogenesis in subcutaneously implanted polyurethane sponges, in which Hsd11b1MKO mice showed 20% greater vessel density than their littermate controls, associated with higher expression of Cdh5 Thus, 11ß-HSD1 deficiency in myeloid phagocytes promotes angiogenesis. Targeting 11ß-HSD1 in macrophages may be beneficial in tissue repair.

Overexpression of Mineralocorticoid Receptors in the Mouse Forebrain Partly Alleviates the Effects of Chronic Early Life Stress on Spatial Memory, Neurogenesis and Synaptic Function in the Dentate Gyrus.

Evidence from human studies suggests that high expression of brain mineralocorticoid receptors (MR) may promote resilience against negative consequences of stress exposure, including childhood trauma. We examined, in mice, whether brain MR overexpression can alleviate the effects of chronic early life stress (ELS) on contextual memory formation under low and high stress conditions, and neurogenesis and synaptic function of dentate gyrus granular cells. Male mice were exposed to ELS by housing the dam with limited nesting and bedding material from postnatal day (PND) 2 to 9. We investigated the moderating role of MRs by using forebrain-specific transgenic MR overexpression (MR-tg) mice. Low-stress contextual (i.e., object relocation) memory formation was hampered by ELS in wildtype but not MR-tg mice. Anxiety like behavior and high-stress contextual (i.e., fear) memory formation were unaffected by ELS and/or MR expression level. At the cellular level, an interaction effect was observed between ELS and MR overexpression on the number of doublecortin-positive cells, with a significant difference between the wildtype ELS and MR-tg ELS groups. No interaction was found regarding Ki-67 and BrdU staining. A significant interaction between ELS and MR expression was further observed with regard to mEPSCs and mIPSC frequency. The ratio of evoked EPSC/IPSC or NMDA/AMPA responses was unaffected. Overall, these results suggest that ELS affects contextual memory formation under low stress conditions as well as neurogenesis and synaptic transmission in dentate granule cells, an effect that can be alleviated by MR-overexpression.