Corticosterone Levels In Mice Research Articles

Acute or Chronic Exposure to Corticosterone Promotes Wakefulness in Mice.

Elevated glucocorticoid levels triggered by stress potentially contribute to sleep disturbances in stress-induced depression. However, sleep changes in response to elevated corticosterone (CORT), the major glucocorticoid in rodents, remain unclear. Here, we investigated the effects of acute or chronic CORT administration on sleep using electroencephalogram (EEG) and electromyography (EMG) recordings in freely moving mice. Acute CORT exposure rapidly promoted wakefulness, marked by increased episodes and enhanced EEG delta power, while simultaneously suppressing rapid eye movement (REM) and non-rapid eye movement (NREM) sleep, with the latter marked by decreased mean duration and reduced delta power. Prolonged 28-day CORT exposure led to excessive wakefulness and REM sleep, characterized by higher episodes, and decreased NREM sleep, characterized by higher episodes and reduced mean duration. EEG theta activity during REM sleep and delta activity during NREM sleep were attenuated following 28-day CORT exposure. These effects persisted, except for REM sleep amounts, even 7 days after the drug withdrawal. Elevated plasma CORT levels and depressive phenotypes were identified and correlated with observed sleep changes during and after administration. Fos expression significantly increased in the lateral habenula, lateral hypothalamus, and ventral tegmental area following acute or chronic CORT treatment. Our findings demonstrate that CORT exposure enhanced wakefulness, suppressed and fragmented NREM sleep, and altered EEG activity across all stages. This study illuminates sleep alterations during short or extended periods of heightened CORT levels in mice, providing a neural link connecting insomnia and depression.

367-OR: E-cigarette Vaping Exposure Increases Adipose 11ß-HSD1 Expression and Disturbs Glucose Homeostasis in Mice

Electronic cigarette (E-cigs) use may increase the prediabetic risk, but the underlying mechanisms remain underexplored. Pre-receptor activation of glucocorticoids (GCs) via 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in adipose tissues has been identified as an important mediator of insulin resistance and type 2 diabetes. However, little is known about the effects of E-cig vaping on 11β-HSD1 and glucose homeostasis. To address this issue, we conducted animal model studies with mice exposed to aerosolized PBS, nicotine-free or nicotine-containing E-cigs, with concurrent exposure to either vehicle or the GC receptor (GR) antagonist RU486. We observed that exposure of E-cig vaping nicotine for 4 weeks increased 11β-HSD1 expression and induced lipase HSL and ATGL abundance within the adipose tissues with induction of hypercortisolemia in response to elevated plasma nicotine levels in mice compared with those of aerosolized E-cig vaping vehicle or PBS controls. Induction of adipose 11β-HSD1 was correlated with elevated the expression of hepatic gluconeogenic enzymes PEPCK and G6Pase and corresponded to the elevated fasting glucose levels. Moreover, E-cig vaping nicotine also increased glucose intolerance, but decreased the glucose-lowing effects of insulin and elevated plasma FFA levels in mice compared with PBS controls. However, E-cig vapor without nicotine did not affect these metabolic parameters. Furthermore, RU486 treatment attenuated E-cig vaping nicotine-induced adipose 11β-HSD1 and lipase expression. In addition, RU486 also attenuated the E-cig-mediated activation of hepatic PEPCK and G6Pase and decreased plasma FFA levels, but did not change the elevated plasma corticosterone levels in mice on E-cig vaping nicotine. These data indicate that E-cig vapor exposure harmfully affects glucose homeostasis and these effects may arise, in part, from aerosol nicotine-induced adipose 11β-HSD1 and GR expression. Disclosure J.Wang: None. T.Friedman: None. M.Jiang: None. Y.Liu: None. J.Liu: None. Y.Wang: None. S.C.J.Kim: None. E.Espinal: None. R.Yang: None. H.Zhong: None. X.M.Shao: None. K.Lutfy: None. Funding Tobacco-Related Disease Research Program (T31IR1603)

Fasting influences aquaporin expression, water transport and adipocyte metabolism in the peritoneal membrane.

The water channels aquaporin-1 (AQP1) and AQP7 are abundantly expressed in the peritoneal membrane. While AQP1 facilitates water transport during peritoneal dialysis (PD), the role of AQP7, which mediates glycerol transport during fasting, remains unknown. We investigated the distribution of AQP7 and AQP1 and used a mouse model of PD to investigate the role of AQP7 in the peritoneal membrane at baseline and after fasting. Single nucleus RNA-sequencing revealed that AQP7 was mostly detected in mature adipocytes, whereas AQP1 was essentially expressed in endothelial cells. Fasting induced significant decreases in whole body fat, plasma glucose, insulin and triglycerides, as well as higher plasma glycerol and corticosterone levels in mice, paralleled by major decreases in adipocyte size and levels of fatty acid synthase and leptin, and increased levels of hormone-sensitive lipase mRNAs in the peritoneum. Mechanistically, fasting upregulated the expression of AQP1 and AQP7 in the peritoneum, with increased ultrafiltration but no change in small solute transport. Studies based on Aqp1 and Aqp7 knockout mice and RU-486 inhibition demonstrated that the glucocorticoid induction of AQP1 mediates the increase in ultrafiltration whereas AQP7 regulates the size of adipocytes in the peritoneum. Fasting induces a coordinated regulation of lipolytic and lipogenic factors and aqua(glycero)porins in the peritoneum, driving structural and functional changes. These data yield novel information on the specific roles of aquaporins in the peritoneal membrane and indicate that fasting improves fluid removal in a mouse model of PD.

Anxiolytic Effect of Two Tobacco Essential Oils (Nicotiana tabacum Linn.) on Mice

Tobacco (Nicotiana tabacum Linn.) is a famous traditional herb used in folk medicine. The essential oils of tobacco have been demonstrated in modern studies to possess antioxidant, anti-inflammatory, and neuroprotective properties, while its anxiolytic effect has not been reported. The purpose of this study was to evaluate the anxiolytic effect of Yunnan tobacco essential oil (YTO) and Zimbabwe tobacco essential oil (ZTO) on mice. The constituents of YTO and ZTO were analyzed by GC/MS. The anxiolytic effect of YTO and ZTO (0.1%, 1%, and 10%, v/v) on male ICR mice was evaluated in the light–dark box test (LDB) and the elevated plus maze test (EPM) test via inhalation and transdermal administration. After the behavioral tests, salivary corticosterone levels in mice were measured. The behavioral analysis showed that the administration of both YTO and ZTO elevated the time that the mice spent in the light chamber in the LDB test compared to the untreated control. In the EPM test, YTO and ZTO increased the time spent in open arms and the number of entries into the open arms. In addition, both YTO and ZTO significantly decreased salivary corticosterone levels in mice (p ≤ 0.001). In summary, our results demonstrated that inhalation and transdermal administration of both YTO and ZTO showed anxiolytic effect on male ICR mice.

Microbiota regulate social behaviour via stress response neurons in the brain.

Social interactions among animals mediate essential behaviours, including mating, nurturing, and defence1,2. The gut microbiota contribute to social activity in mice3,4, but the gut-brain connections that regulate this complex behaviour and its underlying neural basis are unclear5,6. Here we show that the microbiome modulates neuronal activity in specific brain regions of male mice to regulate canonical stress responses and social behaviours. Social deviation in germ-free and antibiotic-treated mice is associated with elevated levels of the stress hormone corticosterone, which is primarily produced by activation of the hypothalamus-pituitary-adrenal (HPA) axis. Adrenalectomy, antagonism of glucocorticoid receptors, or pharmacological inhibition of corticosterone synthesis effectively corrects social deficits following microbiome depletion. Genetic ablation of glucocorticoid receptors in specific brain regions or chemogenetic inactivation of neurons in the paraventricular nucleus of the hypothalamus that produce corticotrophin-releasing hormone (CRH) reverse social impairments in antibiotic-treated mice. Conversely, specific activation of CRH-expressing neurons in the paraventricular nucleus induces social deficits in mice with a normal microbiome. Via microbiome profiling and in vivo selection, we identify a bacterial species, Enterococcus faecalis, that promotes social activity and reduces corticosterone levels in mice following social stress. These studies suggest that specific gut bacteria can restrain the activation of the HPA axis, and show that the microbiome can affect social behaviours through discrete neuronal circuits that mediate stress responses in the brain.

Effects of CRN04894, a Nonpeptide Orally Bioavailable ACTH Antagonist, on Corticosterone in Rodent Models of ACTH Excess

CRN04894 is an orally administered nonpeptide that is a potent and selective antagonist for adrenocorticotropic hormone (ACTH) acting at the melanocortin 2 receptor (MC2R) and is currently under development for the treatment of diseases of ACTH excess such as Cushing’s disease, congenital adrenal hyperplasia, and ectopic ACTH-secreting tumors. Cushing’s disease results from an adenoma derived from pituitary corticotropic cells that secrete excess ACTH, whereas ectopic ACTH syndrome arises from nonpituitary ACTH secreting tumors. Congenital adrenal hyperplasia is a genetic disease that results in cortisol deficiency leading to high levels of ACTH and adrenal androgens. Each of these indications is characterized by high ACTH levels that act on MC2R expressed in the adrenal cortex to drive pathological elevations of adrenally derived steroid hormones. CRN04894 blocks the action of ACTH at MC2R, providing a potential novel treatment for these diseases. Preclinical models of chronic hypercortisolemia include implantation of ACTH-secreting pituitary tumor cells in mice and continuous administration of ACTH via subcutaneously implanted osmotic pumps in rats. These models induce features consistent with human diseases of ACTH excess including hypercortisolemia and hypertrophy of the adrenal glands. We employed both rodent models to examine the pharmacodynamic effects of CRN04894 on corticosterone levels and adrenal gland morphology. In the mouse pituitary tumor model, subcutaneous inoculation of the ACTH-secreting mouse pituitary tumor cell line, AtT-20, into immunodeficient mice resulted in formation of tumors and increased plasma ACTH and corticosterone levels. Repeated daily oral administration of CRN04894 for 14 days dose-dependently and robustly suppressed plasma corticosterone levels in mice with AtT-20 tumors. In the rat model, subcutaneous implantation of osmotic pumps delivering ACTH resulted in increased corticosterone levels, reduction in body weight, and hypertrophy of the adrenal glands after 7 days. Daily oral administration of CRN04894 over 7 days dose-dependently suppressed corticosterone levels, mitigated the effect of ACTH excess on body weight, and rescued the adrenal gland hypertrophy. These findings provide evidence that CRN04894 functions as an effective ACTH antagonist at MC2R to suppress adrenal corticosterone secretion in both mouse and rat models of ACTH excess and hypercortisolemia, thus providing a strong rationale for its potential therapeutic utility in diseases of ACTH excess. This work was supported in part by an SBIR grant from the NIH awarded to Dr. Struthers (R43- DK115245)

Gum Arabic Modifies Glucocorticoid Metabolic Enzymes Gene Associated with Decreased Plasma Corticosterone Levels in Mice

Glucocorticoids (GCs), corticosterone in rodents and cortisol in humans are endogenous stress hormones that exert key...

Shi Xiao San ameliorates the development of adenomyosis in an ICR mouse model

The use of Shi Xiao San (SXS), composed of Pollen Typhae Angustifoliae and Faeces Trogopterori, can be traced back to the Song dynasty. Traditionally, SXS has been used to treat irregular menstruation, pelvic pain, progressive dysmenorrhea, and postpartum lochiorrhea. The management of adenomyosis (AM) is challenging and to the best of our knowledge there are currently no effective therapeutic strategies. Therefore, the aim of the present study was to investigate the effect of SXS on the development of adenomyosis in a mouse model. AM was induced in 60 neonatal female ICR mice by administering tamoxifen; 10 randomly selected mice were used for model identification via histopathological examination and 10 mice treated with the solvent alone were used as the normal controls. A total of sixty days after birth, the mice treated with AM were randomly divided into four groups and administered one of the following treatments: Low-dose SXS (55 mg/kg); high-dose SXS (110 mg/kg); danazol (1 mg/20 g body weight); or no treatment (model group); at the same time, the normal control group received no treatment. After 2 months of treatment, hotplate and tail-flick tests were used to assess the response to noxious thermal stimuli in the mice, and plasma samples were collected to measure corticosterone levels. Hematoxylin and eosin staining scores of myometrial infiltration and the number of AM nodules were evaluated. Furthermore, the expression of genes associated with AM-related pain was also analyzed. The results from the present study indicated that treatment with SXS decreased myometrial infiltration, alleviated generalized hyperalgesia, and lowered plasma corticosterone levels in mice with induced AM. These findings suggest that SXS effectively attenuated the development of AM, and may serve as a promising treatment approach for AM treatment.

3-(4-Chlorophenylselanyl)-1-methyl-1H-indole promotes recovery of neuropathic pain and depressive-like behavior induced by partial constriction of the sciatic nerve in mice

3-(4-Chlorophenylselanyl)-1-methyl-1H-indole (CMI) is an organoselenium compound that presents antioxidant activity, antinociceptive, anti-inflammatory and antidepressive-like effect in mice in previous studies conducted by our research group. In this study, we evaluate the anti-allodynic, anti-hyperalgesic and antidepressant-like effects of CMI on partial sciatic nerve ligation (PSNL) in male adult Swiss mice (25–35 g) as well as the involvement of oxidative stress in these effects. Mice underwent PSNL surgery and after 4 weeks they were treated with CMI (10 mg/kg, intragastric route [i.g.]) or vehicle. The treatment with CMI (10 mg/kg, i.g.) reversed the increased the percentage of response to Von-Frey Hair (VFH) stimulation, decreased the latency time to nociceptive response in the hot-plate test, increased immobility time in the forced swimming test (FST) and decreased groomings activity in the splash test, all induced by PSNL. Additionally, CMI also reversed increased the levels of reactive oxygen species (ROS) and lipid peroxidation in cortex and hippocampus and plasmatic levels of corticosterone in mice, induced by PSNL. Results demonstrate that CMI reversed behavioral and biochemical alterations in the dyad pain-depression induced by PSNL and possibly modulation of oxidative system.

Activation of amylin receptors attenuates alcohol-mediated behaviours in rodents.

Alcohol expresses its reinforcing properties by activating areas of the mesolimbic dopamine system, which consists of dopaminergic neurons projecting from the ventral tegmental area to the nucleus accumbens. The findings that reward induced by food and addictive drugs involve common mechanisms raise the possibility that gut–brain hormones, which control appetite, such as amylin, could be involved in reward regulation. Amylin decreases food intake, and despite its implication in the regulation of natural rewards, tenuous evidence support amylinergic mediation of artificial rewards, such as alcohol. Therefore, the present experiments were designed to investigate the effect of salmon calcitonin (sCT), an amylin receptor agonist and analogue of endogenous amylin, on various alcohol‐related behaviours in rodents. We showed that acute sCT administration attenuated the established effects of alcohol on the mesolimbic dopamine system, particularly alcohol‐induced locomotor stimulation and accumbal dopamine release. Using the conditioned place preference model, we demonstrated that repeated sCT administration prevented the expression of alcohol's rewarding properties and that acute sCT administration blocked the reward‐dependent memory consolidation. In addition, sCT pre‐treatment attenuated alcohol intake in low alcohol‐consuming rats, with a more evident decrease in high alcohol consumers in the intermittent alcohol access model. Lastly, sCT did not alter peanut butter intake, blood alcohol concentration and plasma corticosterone levels in mice. Taken together, the present data support that amylin signalling is involved in the expression of alcohol reinforcement and that amylin receptor agonists could be considered for the treatment of alcohol use disorder in humans.

Increasing adult hippocampal neurogenesis in mice after exposure to unpredictable chronic mild stress may counteract some of the effects of stress

Major depression is hypothesized to be associated with dysregulations of the hypothalamic–pituitary–adrenal (HPA) axis and impairments in adult hippocampal neurogenesis. Adult-born hippocampal neurons are required for several effects of antidepressants and increasing the rate of adult hippocampal neurogenesis (AHN) before exposure to chronic corticosterone is sufficient to protect against its harmful effects on behavior. However, it is an open question if increasing AHN after the onset of chronic stress exposure would be able to rescue behavioral deficits and which mechanisms might be involved in recovery. We investigated this question by using a 10-week unpredictable chronic mild stress (UCMS) model on a transgenic mouse line (iBax mice), in which the pro-apoptotic gene Bax can be inducibly ablated in neural stem cells following Tamoxifen injection, therefore enhancing the survival of newborn neurons in the adult brain. We did not observe any effect of our treatment in non-stress conditions, but we did find that increasing AHN after 2 weeks of UCMS is sufficient to counteract the effects of UCMS on certain behaviors (splash test and changes in coat state) and endocrine levels and thus to display some antidepressant-like effects. We observed that increasing AHN lowered the elevated basal corticosterone levels in mice exposed to UCMS. This was accompanied by a tamoxifen-induced reversal of the lack of stress-induced decrease in neuronal activation in the anteromedial division of the bed nucleus of the stria terminalis (BSTMA) after intrahippocampal dexamethasone infusion, pointing to a possible mechanism through which adult-born neurons might have exerted their effects. Our results contribute to the neurogenesis hypothesis of depression by suggesting that increasing AHN may be beneficial not just before, but also after exposure to stress by counteracting several of its effects, in part through regulating the HPA axis.

Repeated Cold Stress Enhances the Acute Restraint Stress-Induced Hyperthermia in Mice.

The rodents exposed to repeated cold stress according to a specific schedule, known as specific alternation of rhythm in temperature (SART), exhibit autonomic imbalance, and is now used as an experimental model of fibromyalgia. To explore the susceptibility of SART-stressed animals to novel acute stress, we tested whether exposure of mice to SART stress for 1 week alters the extent of acute restraint stress-induced hyperthermia. Mice were subjected to 7-d SART stress sessions; i.e., the mice were alternately exposed to 24 and 4°C at 1-h intervals during the daytime (09:00-16:00) and kept at 4°C overnight (16:00-09:00). SART-stressed and unstressed mice were exposed to acute restraint stress for 20-60 min, during which rectal temperature was monitored. Serum corticosterone levels were measured before and after 60-min exposure to restraint stress. SART stress itself did not alter the body temperature or serum corticosterone levels in mice. Acute restraint stress increased the body temperature and serum corticosterone levels, both responses being greater in SART-stressed mice than unstressed mice. The enhanced hyperthermic responses to acute restraint stress in SART-stressed mice were significantly attenuated by SR59230A, a β3 adrenoceptor antagonist, but unaffected by diazepam, an anxiolytic, mifepristone, a glucocorticoid receptor antagonist, or indomethacin, a cyclooxygenase inhibitor. These results suggest that SART stress enhances the susceptibility of mice to acute restraint stress, characterized by increased hyperthermia and corticosterone secretion, and that the increased hyperthermic responses to acute stress might involve accelerated activation of sympathetic β3 adrenoceptors, known to regulate non-shivering thermogenesis in the brown adipose tissue.

Applicability of Commercially Available ELISA Kits for the Quantification of Faecal Immunoreactive Corticosterone Metabolites in Mice.

Commercially available ELISA kits are popular among investigators that quantify faecal corticosterone or cortisol metabolites (FCM) for stress assessment in animals. However, in faeces, these assays mainly detect immunoreactive glucocorticoid metabolites. Since different assays contain antibodies of different origin, the detection level and cross-reactivity towards different metabolites and other steroids differ considerably between assays. Thus, the validity of one assay for FCM quantification in stress assessment is not necessarily the same for another assay. The present study was designed to investigate corticosterone (CORT) in serum and FCM levels in faeces of laboratory mice, as quantified in four different ELISA kits (DRG EIA-4164, Demeditec DEV9922, Enzo ADI-900-097 and Cayman EIA kit 500655). Assay kits were chosen based on the origin of the antibody, detection level and variation in cross-reactivity. As expected, all four assay kits could detect higher serum CORT levels in mice treated with adrenocorticotropic hormone (ACTH), compared to untreated mice. Unexpectedly though, the measured concentration of serum CORT differed significantly between assays, in both groups of mice. In faecal samples, there was no consistent positive correlation between the levels detected in the four assays and the measured concentration of FCM also differed between assays. Whereas commercially available CORT ELISAs are frequently successfully used for FCM quantification, validation of the assays is necessary as all assays do not work well under all circumstances. In this study, the ELISAs could determine relative differences in serum CORT levels and FCM levels between samples; however, the fidelity of the measurements to the true concentrations was low.

Type-7 metabotropic glutamate receptors negatively regulate α1-adrenergic receptor signalling

We studied the interaction between mGlu7 and α1-adrenergic receptors in heterologous expression systems, brain slices, and living animals. L-2-Amino-4-phosphonobutanoate (L-AP4), and l-serine-O-phosphate (L-SOP), which activate group III mGlu receptors, restrained the stimulation of polyphosphoinositide (PI) hydrolysis induced by the α1-adrenergic receptor agonist, phenylephrine, in HEK 293 cells co-expressing α1-adrenergic and mGlu7 receptors. The inibitory action of L-AP4 was abrogated by (i) the mGlu7 receptor antagonist, XAP044; (ii) the C-terminal portion of type-2 G protein coupled receptor kinase; and (iii) the MAP kinase inhibitors, UO126 and PD98059. This suggests that the functional interaction between mGlu7 and α1-adrenergic receptors was mediated by the βγ-subunits of the Gi protein and required the activation of the MAP kinase pathway. Remarkably, activation of neither mGlu2 nor mGlu4 receptors reduced α1-adrenergic receptor-mediated PI hydrolysis. In mouse cortical slices, both L-AP4 and L-SOP were able to attenuate norepinephrine- and phenylephrine-stimulated PI hydrolysis at concentrations consistent with the activation of mGlu7 receptors. L-AP4 failed to affect norepinephrine-stimulated PI hydrolysis in cortical slices from mGlu7−/− mice, but retained its inhibitory activity in slices from mGlu4−/− mice. At behavioural level, i.c.v. injection of phenylephrine produced antidepressant-like effects in the forced swim test. The action of phenylephrine was attenuated by L-SOP, which was inactive per se. Finally, both phenylephrine and L-SOP increased corticosterone levels in mice, but the increase was halved when the two drugs were administered in combination. Our data demonstrate that α1-adrenergic and mGlu7 receptors functionally interact and suggest that this interaction might be targeted in the treatment of stress-related disorders.

Effects of early adolescent methamphetamine exposure on anxiety-like behavior and corticosterone levels in mice

Methamphetamine (MA) is an addictive psychomotor stimulant that affects the central nervous system and alters behavior. The effects of MA are modulated by age, and while much research has examined the effects of MA use in adults, relatively little research has examined the effects in adolescents. As the brain is developing during adolescence, it is important that we understand the effects of MA exposure in adolescence. This research examined the effects of acute MA exposure on locomotor and anxiety-like behavior in the open field test and plasma corticosterone levels in adolescent male C57BL/6J mice. Baseline locomotor and anxiety-like behaviors were assessed in the open field test. Immediately following baseline measurements, mice were exposed to saline or 4mg/kg MA and locomotor and anxiety-like behavior were measured. Serum was collected immediately after testing and plasma corticosterone levels measured. There were no group differences in baseline behavioral measurements. MA-exposed adolescent mice showed increased locomotor activity and anxiety-like behavior in the open field compared with saline controls. There was no effect of MA on plasma corticosterone levels. These data suggest that acute MA exposure during adolescence increases locomotor activity and anxiety-like behavior, but does not alter plasma corticosterone levels.

The effects of group and single housing and automated animal monitoring on urinary corticosterone levels in male C57BL/6 mice.

Mice are used extensively in physiological research. Automated home-cage systems have been developed to study single-housed animals. Increased stress by different housing conditions might affect greatly the results when investigating metabolic responses. Urinary corticosteroid concentration is considered as a stress marker. The aim of the study was to compare the effects of different housing conditions and an automated home-cage system with indirect calorimetry located in an environmental chamber on corticosterone levels in mice. Male mice were housed in different conditions and in automated home-cage system to evaluate the effects of housing and measuring conditions on urine corticosterone levels. Corticosterone levels in single-housed mice in the laboratory animal center were consistently lower compared with the group-housed mice. Single-housed mice in a separate, small animal unit showed a rise in their corticosterone levels a day after they were separated to their individual cages, which decreased during the following 2days. The corticosterone levels of group-housed mice in the same unit were increased during the first 7days and then decreased. On day 7, the corticosterone concentrations of group-housed mice were significantly higher compared with that of single-housed mice, including the metabolic measurement protocol. In conclusion, single housing caused less stress when compared with group-housed mice. In addition, the urine corticosterone levels were decreased in single-housed mice before the metabolic measurement started. Thus, stress does not affect the results when utilizing the automated system for measuring metabolic parameters like food and water intake and calorimetry.

Somatostatin Is Essential for the Sexual Dimorphism of GH Secretion, Corticosteroid-Binding Globulin Production, and Corticosterone Levels in Mice

Distinct male and female patterns of pituitary GH secretion produce sexually differentiated hepatic gene expression profiles, thereby influencing steroid and xenobiotic metabolism. We used a fully automated system to obtain serial nocturnal blood samples every 15 minutes from cannulated wild-type (WT) and somatostatin knockout (Sst-KO) mice to determine the role of SST, the principal inhibitor of GH release, in the generation of sexually dimorphic GH pulsatility. WT males had lower mean and median GH values, less random GH secretory bursts, and longer trough periods between GH pulses than WT females. Each of these parameters was feminized in male Sst-KO mice, whereas female Sst-KO mice had higher GH levels than all other groups, but GH pulsatility was unaffected. We next performed hepatic mRNA profiling with high-density microarrays. Male Sst-KO mice exhibited a globally feminized pattern of GH-dependent mRNA levels, but female Sst-KO mice were largely unaffected. Among the differentially expressed female-predominant genes was Serpina6, which encodes corticosteroid-binding globulin (CBG). Increased CBG was associated with elevated diurnal peak plasma corticosterone in unstressed WT females and both sexes of Sst-KO mice compared with WT males. Sst-KO mice also had exaggerated ACTH and corticosterone responses to acute restraint stress. However, consistent with their lack of phenotypic signs of excess glucocorticoids, cerebrospinal fluid concentrations of free corticosterone in Sst-KO mice were not elevated. In summary, SST is necessary for the prolonged interpulse troughs that define masculinized pituitary GH secretion. SST also contributes to sexual dimorphism of the hypothalamic-pituitary-adrenal axis via GH-dependent regulation of hepatic CBG production.

Glucocorticoids regulate the metabolic hormone FGF21 in a feed-forward loop.

Hormones such as fibroblast growth factor 21 (FGF21) and glucocorticoids (GCs) play crucial roles in coordinating the adaptive starvation response. Here we examine the interplay between these hormones. It was previously shown that FGF21 induces corticosterone levels in mice by acting on the brain. We now show that this induces the expression of genes required for GC synthesis in the adrenal gland. FGF21 also increases corticosterone secretion from the adrenal in response to ACTH. We further show that the relationship between FGF21 and GCs is bidirectional. GCs induce Fgf21 expression in the liver by acting on the GC receptor (GR). The GR binds in a ligand-dependent manner to a noncanonical GR response element located approximately 4.4 kb upstream of the Fgf21 transcription start site. The GR cooperates with the nuclear fatty acid receptor, peroxisome proliferator-activated receptor-α, to stimulate Fgf21 transcription. GR and peroxisome proliferator-activated receptor-α ligands have additive effects on Fgf21 expression both in vivo and in primary cultures of mouse hepatocytes. We conclude that FGF21 and GCs regulate each other's production in a feed-forward loop and suggest that this provides a mechanism for bypassing negative feedback on the hypothalamic-pituitary-adrenal axis to allow sustained gluconeogenesis during starvation.

GLP-1 receptor agonists have a sustained stimulatory effect on corticosterone release after chronic treatment.

Glucagon-like peptide 1 (GLP-1) receptor agonists are a new group of antidiabetic medications quickly gaining popularity. We aimed to examine behavioural and neuroendocrine changes following chronic treatment with GLP-1 receptor agonists in animal models. The effects of chronic treatment with GLP-1 receptor agonists were determined on behavioural parameters [anxiety level in the light-dark compartment test, the motor activity in automated activity cages, immobility in the forced swimming test (FST)] and on corticosterone release in mice. The possible antidepressant effect of chronic liraglutide treatment was also studied in Flinders Sensitive Line (FSL) rats, a genetic model of depression. Two weeks of treatment with exenatide (10 µg/kg twice daily) or liraglutide (1200 µg/kg once daily) did not affect the anxiety level in a light-dark compartment test nor induce an antidepressant-like effect in the FST in mice. Moreover, chronic treatment with liraglutide had no effect on depression-related behaviour in FSL rats. Interestingly, hypolocomotion induced by the drugs in mice disappeared after chronic dosing. Both of the GLP-1 receptor agonists induced robust increases in corticosterone levels in mice under basal conditions as well as in the case of combination with swimming stress. Remarkably, exenatide was as potent a stimulator of corticosterone release after 2 weeks as after acute administration. The increases in corticosterone release seen after acute exenatide or liraglutide treatment do not abate after 2 weeks of treatment demonstrating that tolerance does not develop towards this particular effect of GLP-1 agonists.

Role of the NMDA receptor in cognitive deficits, anxiety and depressive-like behavior in juvenile and adult mice after neonatal dexamethasone exposure

Postnatal dexamethasone (DEX) therapy has been used to treat or prevent chronic lung disease after premature births. However, there are many reports of long-term negative neurodevelopmental sequelae following this treatment. In contrast, hydrocortisone (HYD), which has fewer neurodevelopment adverse effects, is used as an alternative for DEX. In this study, we report that neonatal DEX exposure (days 1–3) caused alterations of amino acids affecting N-methyl-d-aspartate (NMDA) receptor neurotransmission in mouse brains. Neonatal DEX, but not HYD, exposure (days 1–3) significantly decreased the GluN2B subunit of NMDA receptor in the hippocampus at juvenile and adult stages. Mice treated with DEX showed cognitive deficits, as well as anxiety and depressive-like behavior at juvenile and adult stages. In contrast, mice treated with HYD (days 1–3) showed no behavioral abnormalities at these stages. In the DEX suppression test, plasma levels of corticosterone in mice exposed neonatally to DEX and HYD were significantly higher at juvenile, but not adult stages. Pretreatment with Ro 63-1908, an antagonist at GluN2B subunit, 30min before each injection of DEX, prevented cognitive deficits, as well as anxiety and depressive-like behavior in juvenile and adult mice. Interestingly, subsequent repeated (days 29–33) administration of Ro 63-1908 or L701324, an antagonist of the glycine modulatory site on the NMDA receptor, significantly suppressed behavioral abnormalities in juvenile and adult mice after neonatal DEX exposure. These results indicate that neonatal DEX, but not HYD, exposure produced behavioral abnormalities in juvenile and adult mice by altering glutamatergic neurotransmission via the NMDA receptor. The NMDA receptor antagonists may prevent or treat these DEX-induced neonatal behavioral abnormalities in later life.