Higher Corticosterone Levels Research Articles

Tissue-specific regulation of 11β hydroxysteroid dehydrogenase type-1 mRNA expressions in Cushing’s syndrome mouse model

The 11β hydroxysteroid dehydrogenase type-1 (11βHSD-1) is a predominant 11β-reductase regenerating bioactive glucocorticoids (cortisol, corticosterone) from inactive 11-keto forms (cortisone, dehydrocorticosterone), expressed mainly in the brain, liver and adipose tissue. Although the expression levels of 11β HSD-1 mRNA are known to be influenced by glucocorticoids, its tissue-specific regulation is not completely elucidated. In this study, we examined the effect of persistent glucocorticoid excess on the expression of 11β HSD-1 mRNA in the hippocampus, liver, and abdominal adipose tissue in vivo using quantitative real-time PCR. We found that, in C57BL/6J mice treated with corticosterone (CORT) pellet for 2 weeks, 11β HSD-1 mRNA decreased in the hippocampus (HIPP) and liver, whereas it increased in the abdominal fat (FAT), compared with placebo treatment [HIPP: placebo 1.00 ± 0.14, CORT 0.63 ± 0.04; liver: placebo 1.00 ± 0.08, CORT 0.73 ± 0.06; FAT: placebo 1.00 ± 0.16, CORT 2.26 ± 0.39]. Moreover, in CRH transgenic mice, an animal model of Cushing’s syndrome with high plasma CORT level, 11β HSD-1 mRNA was also decreased in the hippocampus and liver, and increased in the abdominal adipose tissue compared to that in wild-type mice. These changes were reversed after adrenalectomy in CRH-Tg mice. Altogether, these results reveal the differential regulation of 11β HSD-1 mRNA by glucocorticoid among the tissues examined.

Maternal deprivation effect on morphine-induced CPP is related to changes in opioid receptors in selected rat brain regions (hippocampus, prefrontal cortex, and nucleus accumbens)

Early-life environmental conditions affect offspring's development. Maternal deprivation (MD) can induce persistent changes that give rise to neuropsychiatric diseases including substance abuse disorders. However, long-lasting mechanisms that determine vulnerability to drug addiction remain unknown. We hypothesized that MD could induce changes in Opioid system, HPA (hypothalamic-pituitary-adrenal) axis, and BDNF (brain-derived neurotrophic factor), so may be involved in the drug abuse in later life. Male offspring of Wistar rats (n = 8 per group) were subjected to 3 h of daily MD during postnatal days 1–14. In adulthood, morphine-induced CPP (conditioned place preference) was investigated using two doses of morphine (3 and 5 mg/kg). Serum corticosterone level was measured by ELISA method. The expression level of genes in selected brain regions (hippocampus, prefrontal cortex, and nucleus accumbens) was determined by qPCR (quantitative PCR). A greater morphine-induced CPP was observed in MD rats with 3 and 5 mg/kg morphine compared to controls. MD group had a higher corticosterone level. A significant decrease was observed in the expression of BDNF gene (in all of the selected brain regions) and GR (glucocorticoid receptor) gene (in the hippocampus and nucleus accumbens) in MD rats. Also, a significant increase in the expression of μ Opioid receptor (in all of the selected brain regions) and κ Opioid receptor (in the prefrontal cortex and nucleus accumbens) was observed in MD rats. Our results suggest that MD induces alterations in the HPA axis function, BDNF level, and Opioid receptors system that enhance vulnerability to morphine at adulthood.

Cinnamaldehyde prevents intergenerational effect of paternal depression in mice via regulating GR/miR-190b/BDNF pathway.

Paternal stress exposure-induced high corticosterone (CORT) levels may contribute to depression in offspring. Clinical studies disclose the association of depressive symptoms in fathers with their adolescent offspring. However, there is limited information regarding the intervention for intergenerational inheritance of depression. In this study we evaluated the intervention of cinnamaldehyde, a major constituent of Chinese herb cinnamon bark, for intergenerational inheritance of depression in CORT- and CMS-induced mouse models of depression. Depressive-like behaviors were induced in male mice by injection of CORT (20 mg·kg-1·d-1, sc) for 6 weeks or by chronic mild stress (CMS) for 6 weeks. We showed that co-administration of cinnamaldehyde (10, 20, or 40 mg·kg-1·d-1, ig) for 6 weeks in F0 males prevented the depressive-like phenotypes of F1 male offspring. In addition, co-administration of cinnamaldehyde (20 mg·kg-1·d-1, ig) for 4 weeks significantly ameliorated depressive-like behaviors of chronic variable stress (CVS)-stimulated F1 offspring born to CMS mice. Notably, cinnamaldehyde had no reproductive toxicity, while positive drug fluoxetine showed remarkable reproductive toxicity. We revealed that CMS and CORT significantly reduced testis glucocorticoid receptor (GR) expression, and increased testis and sperm miR-190b expression in F0 depressive-like models. Moreover, pre-miR-190b expression was upregulated in testis of F0 males. The amount of GR on miR-190b promoter regions was decreased in testis of CORT-stimulated F0 males. Cinnamaldehyde administration reversed CORT-induced GR reduction in testis, miR-190b upregulation in testis and sperm, pre-miR-190b upregulation in testis, and the amount of GR on miR-190b promoter regions of F0 males. In miR-190b-transfected Neuro 2a (N2a) cells, we demonstrated that miR-190b might directly bind to the 3'-UTR of brain-derived neurotrophic factor (BDNF). In the hippocampus of F1 males of CORT- or CMS-induced depressive-like models, increased miR-190b expression was accompanied by reduced BDNF and GR, which were ameliorated by cinnamaldehyde. In conclusion, cinnamaldehyde is a potential intervening agent for intergenerational inheritance of depression, probably by regulating GR/miR-190b/BDNF pathway.

Mercury toxicity risk and corticosterone levels across the breeding range of the Yellow-breasted Chat

Mercury (Hg) is an environmental contaminant that can negatively impact human and wildlife health. For songbirds, Hg risk may be elevated near riparian habitats due to the transfer of methylmercury (MeHg) from aquatic to terrestrial food webs. We measured Hg levels in tail feathers sampled across the breeding range of the Yellow-breasted Chat (Icteria virens), a riparian songbird species of conservation concern. We assessed the risk of Hg toxicity based on published benchmarks. Simultaneously, we measured corticosterone, a hormone implicated in the stress response system, released via the hypothalamus-pituitary-adrenal axis. To better understand range-wide trends in Hg and corticosterone, we examined whether age, sex, subspecies, or range position were important predictors. Lastly, we examined whether Hg and corticosterone were correlated. Hg levels in chats were relatively low: 0.30 ± 0.02 µg/g dry weight. 148 out of 150 (98.6%) had Hg levels considered background, and 2 (1.6%) had levels considered low toxicity risk. Hg levels were similar between sexes and subspecies. Younger chats (<1 year) had higher Hg levels than older chats (>1 year). Hg levels were lowest in the northern and central portion of the eastern subspecies’ range. Corticosterone concentrations in feathers averaged 3.68 ± 0.23 pg/mm. Corticosterone levels were similar between ages and sexes. Western chats had higher levels of corticosterone than eastern chats. Hg and corticosterone were not correlated, suggesting these low Hg burdens did not affect the activity of the hypothalamus-pituitary-adrenal axis. Altogether, the chat has low Hg toxicity risk across its breeding range, despite living in riparian habitats.

Birds of a feather cope with challenges together

Global climate change and the transformation of habitats due to the unstoppable human invasion of pristine territories are bad for life on Earth. However, recent research has shown that many organisms can tweak their physiology in order to cope well with change. A current challenge for wildlife ecologists and managers is to connect physiological measurements with subsequent changes in the health status of populations and species. This is exactly what interested the team led by Ashlee Mikkelsen, Oregon State University and USDA Forest Service (Oregon, USA). Focusing on a vulnerable species that is currently considered at risk, the northern spotted owl (Strix occidentalis caurina), they explored the connections between physiological stress responses with environmental factors that might predict the population declines of this species.Corticosterone is a main hormonal regulator of energy allocation in birds and generally increases in response to life challenges. Over 15 consecutive years (2001–2017), Mikkelsen and her team quantified the concentration of the hormone in 4720 feathers from 1056 juvenile spotted owls across 7 different study areas, in order to measure the stress responses of the youngsters as they developed. To minimise harm to the owls, most of the feathers were collected when the owls were banded and weighed as part of the annual historical monitoring of the population. Additionally, the team knew how big each owl territory was at the time of feather collection, how much cover – for breeding and foraging – each patch of forest provided and how good the parents were at caring for their chicks. They also gathered information on the local weather when the feather collections took place, to find out the conditions that the youngsters were facing.When the team crunched all the data together to assess the connection between feather corticosterone levels and individual and landscape conditions, the analysis revealed three interesting patterns. First, feather corticosterone decreased as the body mass of the owl increased; the largest chicks were the least stressed. As heavier juvenile spotted owls are fitter and have greater chances of survival, this result confirms feather corticosterone as a reliable indicator of the overall health of free-living birds. Second, the levels of corticosterone in the spotted owl feathers were higher when it was warm and rainy, rather than when it was cold and dry, suggesting that the youngsters may have experienced higher energy demands possibly to avoid, or endure, higher temperatures or getting drenched. And third, the smallest owls had the highest corticosterone levels when there was heavy rain, so the owls’ size had an impact on how stressful the youngsters found wet conditions. In addition, the owls experienced the most stress during the fledging period, when they were gradually leaving their nests to begin facing the daily demands and dangers of an independent life.Mikkelsen's study is one of the first to provide long-term data in a wild bird, showing that feather corticosterone can be a reliable indicator of individual stress responses to life challenges that they experienced in the past. But most importantly, these results show that feather corticosterone can help wildlife ecologists to predict how stress responses related to climate changes and global warming might affect bird populations, marking a significant step forward in the field.

Effects of Glucomannan Feed Additives on Large White Turkey Female Performance, Gastrointestinal Microbial Population, and Blood Corticosterone Levels in a Simulated Transport Challenge

Turkeys may experience stress due to conditions of transport, heat, and in some cases, feed and water restrictions. This may include experiencing conditions present when female turkeys are transported from the brooder house to the grow-out house, typically at 4 to 5 wk of age. This study’s objective was to determine the effect of glucomannan feed additives on performance and corticosterone response in Large White commercial females after an application of simulated conditions which birds might experience during transportation at 4 to 5 wk of age. The transport simulation consisted of reducing the space per bird from 0.198 m2 /bird to 0.028m2 /bird, with no food and water, and exposed to heat lamps, for no more than 18 h. Fourteen hundred and forty Large White female turkeys were randomly assigned to 48 concrete, pine shavings covered floor pens. The experimental design was a completely randomized block design with a one-factor arrangement of 2 sources of glucomannans (medium-chain and long-chain) with two inclusion levels of each (0.02 and 0.20% of the diet). These treatments were compared to two control treatments (no glucomannans), however, one with no simulated transport conditions and one exposed to simulated transport conditions. Bird’s performance, bursa, spleen, and blood corticosterone levels were analyzed in SAS 9.4 in a mixed model. No effects on growth performance of birds fed 0.02% glucomannans were observed. Birds fed glucomannans at 0.20% in the diet had a higher corticosterone level after the transport simulation was applied when compared to other treatments. However, birds fed medium-chain glucomannans at 0.20% had an improved performance after the transport simulation compared to birds fed the other glucomannan treatments. All birds recuperated their performance by d 45. No differences were found in the spleen and bursa weights at 45 d of age. Both glucomannans reduced the stress impact on intestinal bacteria by controlling the overgrowth of Lactobacillus and Fusobacteria while maintaining Bacteroidetes. In conclusion, glucomannans can be used in diets with no change in performance or health at 45 d of age while preserving intestinal microbiota from the negative effects of stress. At 45d, all birds recuperated from the simulated transport conditions applied at 29 d. Thus, the effects of glucomannans on turkey performance and health should be further investigated.

Alteration of the α5 GABA receptor and 5HTT lead to cognitive deficits associated with major depressive-like behaviors in a 14-day combined stress rat model

Introduction: Current models used to study the pathophysiology of major depressive disorder (MDD) are laborious and time consuming. This study examined the effect of a 14-day combined stress model (CS; corticosterone injection and restraint stress) in male Sprague-Dawley rats and also compare the effect of CS versus 28-day corticosterone treatment on depressive-like behaviour and cognitive deficits. Materiel and methods: Depressive-like behaviours and cognitive deficits were assessed in the forced swim test (FST), sucrose preference (SPT), Morris water maze (MWM) and novel object recognition (NORT) tests. Real-time PCR and ELISA were respectively used to detect expression of the serotonin transporter (5-HTT), serotonin 1 A receptor (5-HT1A), α5 GABAA receptor, and the concentrations of corticosterone (plasma), GABA and acetylcholinesterase (AChE) in the hippocampus and Prefrontal cortex (PFC). Results CS group showed increased immobility time in the FST, time to reach the MWM platform, higher corticosterone level, and increased expressions of hippocampal and PFC 5-HT1A and α5 GABAA receptors, and AChE compared to their control groups. In contrast, reductions in SPT ratio, discrimination index in NORT, time in target quadrant, and hippocampal 5-HTT expression was noted relative to their control group. Compared to the 28-day corticosterone only group, PFC 5-HT1A, Hippocampal 5-HTT were reduced, while PFC 5-HTT, Hippocampal α5 GABAA receptors, and AChE concentrations were higher in the CS group. Conclusion: Our CS model induced depressive-like behaviour with early cognitive deficits in rats affecting both hippocampus and PFC. The CS model may be useful in investigating new and comprehensive treatment strategies for MDD.

Circadian gene × environment perturbations influence alcohol drinking in Cryptochrome-deficient mice.

Alcohol use disorder (AUD) is a widespread addiction disorder with severe consequences for health. AUD patients often suffer from sleep disturbances and irregular daily patterns. Conversely, disruptions of circadian rhythms are considered a risk factor for AUD and alcohol relapses. In this study, we investigated the extent to which circadian genetic and environmental disruptions and their interaction alter alcohol drinking behaviour in mice. As a model of genetic circadian disruption, we used Cryptochrome1/2-deficient (Cry1/2-/- ) mice with strongly suppressed circadian rhythms and found that they exhibit significantly reduced preference for alcohol but increased incentive motivation to obtain it. Similarly, we found that low circadian SCN amplitude correlates with reduced alcohol preference in WT mice. Moreover, we show that the low alcohol preference of Cry1/2-/- mice concurs with high corticosterone and low levels of the orexin precursor prepro-orexin and that WT and Cry1/2-/- mice respond differently to alcohol withdrawal. As a model of environmentally induced disruption of circadian rhythms, we exposed mice to a "shift work" light/dark regimen, which also leads to a reduction in their alcohol preference. Interestingly, this effect is even more pronounced when genetic and environmental circadian perturbations interact in Cry1/2-/- mice under "shift work" conditions. In conclusion, our study demonstrates that in mice, disturbances in circadian rhythms have pronounced effects on alcohol consumption as well as on physiological factors and other behaviours associated with AUD and that the interaction between circadian genetic and environmental disturbances further alters alcohol consumption behaviour.

Gender Differences in Nicotine Induced Dyslipidemia and Hyperglycemia in Mice

The purpose of this study is to examine the prevalence of metabolic syndrome in nicotine treated male and female mice and to evaluate gender related differences. For these purposes adult male and female BALB/C mice were subjected to chronic nicotine treatment (3.08mg/100ml in drinking water) for 4 weeks. Serum glucose, albumin, corticosterone and lipid profile levels were determined. Body weight changes were also monitored. We have found that nicotine treatment raises total cholesterol and glucose levels more in male as compared to female mice. Low density lipoprotein cholesterol (LDL-C) levels were increased by 35% (P&lt;0.01) only in male mice. However rise in triglycerides were greater in females (28%) than males (21%) when compared with their respective controls. Serum albumin levels were increased in both sexes showing 13% greater increase in males as compared to females. However nicotine treatment had no effect on high density lipoprotein cholesterol, corticosterone levels and body weights in both genders. It is concluded that nicotine use is positively associated with LDL-C in males; the results are discussed in relation to prevalence of metabolic syndrome andrisk of cardiovascular events in nicotine users.

Prenatal and Postnatal Methyl-Modulator Intervention Corrects the Stress-Induced Glucocorticoid Response in Low-Birthweight Rats.

Low body weight at birth has been shown to be a risk factor for future metabolic disorders, as well as stress response abnormalities and depression. We showed that low-birthweight rats had prolonged high blood corticosterone levels after stress exposure, and that an increase in Gas5 lncRNA, a decoy receptor for glucocorticoid receptors (GRs), reduces glucocorticoid responsiveness. Thus, we concluded that dampened pituitary glucocorticoid responsiveness disturbed the glucocorticoid feedback loop in low-birthweight rats. However, it remains unclear whether such glucocorticoid responsiveness is suppressed solely in the pituitary or systemically. The expression of Gas5 lncRNA increased only in the pituitary, and the intact induction of expression of the GR co-chaperone factor Fkbp5 against dexamethasone was seen in the liver, muscle, and adipose tissue. Intervention with a methyl-modulator diet (folate, VB12, choline, betaine, and zinc) immediately before or one week after delivery reversed the expression level of Gas5 lncRNA in the pituitary of the offspring. Consequently, it partially normalized the blood corticosterone levels after restraint stress exposure. In conclusion, the mode of glucocorticoid response in low-birthweight rats is impaired solely in the pituitary, and intervention with methyl-modulators ameliorates the impairment, but with a narrow therapeutic time window.

High-intensity infrasound effects on glucose metabolism in rats

Recent focus has been given on the effects of high-intensity infrasound (HII) exposure, and whether it induces changes in pancreatic morphology and glucose metabolism is still unknown. As such, we have studied the impact of HII exposure on glucose tolerance, insulin sensitivity, pancreatic islet morphology, muscle GLUT4 and plasma insulin and corticosterone levels. Normal and glucose intolerant wild-type Wistar rats were randomly divided in two groups: one group not exposed to HII and the other continuously exposed to HII. Animals were sacrificed at three timepoints of exposure (1, 6 or 12 weeks). An intraperitoneal glucose tolerance test was performed, blood samples were collected and the pancreas and the quadriceps femoris muscle were excised. Circulating insulin and corticosterone levels were determined and pancreatic and muscular tissue were routinely processed for histochemistry and immunohistochemistry with an anti-GLUT4 antibody. Animals exposed to HII had higher corticosterone levels than animals not exposed. No differences were found on insulin concerning HII exposure or glucose intolerance. Glucose intolerant animals had pancreatic islet fibrosis and no differences were found in GLUT4 ratio concerning HII exposure. In conclusion, we found that continuous exposure to HII increases stress hormone levels without inducing glucose intolerance in rats.

Therapeutic Potential of Curcumin in Reversing the Depression and Associated Pseudodementia via Modulating Stress Hormone, Hippocampal Neurotransmitters, and BDNF Levels in Rats.

Depressive state adversely affects the memory functions, especially in the geriatric population. The initial stage of memory deficits associated with depression is particularly called as pseudodementia. It is the starting point of memory disturbance before dementia. The purpose of this research was to study depression and its consequent pseudodementia. For this purpose 24 male albino Wistar rats were divided into four groups. Depression was induced by 14 days of chronic restraint stress (CRS) daily for 4h. After developing a depression model, pattern separation test was conducted to monitor pseudodementia in rats. Morris water maze test (MWM) was also performed to observe spatial memory. It was observed that model animals displayed impaired pattern separation and spatial memory. Treatment was started after the development of pseudodementia in rats. Curcumin at a dose of 200mg/kg was given to model rats for one week along with the stress procedure. Following the treatment with curcumin, rats were again subjected to the aforementioned behavioral tests before decapitation. Corticosterone levels, brain derived neurotrophic factor (BDNF) and neurochemical analysis were conducted. Model rats showed depressogenic behavior and impaired memory performance. In addition to this, high corticosterone levels and decreased hippocampal BDNF, 5-HT, dopamine (DA), and acetylcholine (ACh) levels were also observed in depressed animals. These behavioral biochemical and neurochemical changes were effectively restored following treatment with curcumin. Hence, it is suggested from this study that pseudodementia can be reversed unlike true dementia by controlling the factors such as depression which induce memory impairment.

Intrauterine growth restriction leads to a high-corticosterone producing offspring: An implication for pulmonary infection susceptibility

AimsAlthough intrauterine growth restriction (IUGR) impairs immune system homeostasis and lung development, its relationship with the susceptibility to pulmonary infections remains unclear. Thus, this study aimed to investigate the impact of IUGR on acute lung inflammatory response induced by bacterial stimulus. Materials and methodsPregnant female Wistar rats were subjected to 50% caloric-protein food restriction during gestation. To mimic bacterial lung infection, adult male offspring (12 weeks old) were challenged with a single lipopolysaccharide (LPS) intranasal instillation, and 6 h later, we assessed the acute inflammatory response. Normal birth weight (NBW) animals represent the control group. Key findingsLPS instillation increased the protein levels in the airways of both the NBW and low birth weight (LBW) groups, indicating vascular leakage. LBW animals exhibited a lower number of neutrophils, reduced production of interleukin-6 and macrophage-inflammatory protein-2 and decreased upregulation of intercellular adhesion molecule-1 gene expression in lung tissues. Further analysis revealed that the LBW group produced lower levels of prostaglandin-E2 and failed to secrete leukotriene-B4 upon LPS stimulation, which correlated with impaired cyclooxygenase-2 and 5-lipoxygenase expression. These results were probably associated with their inability to upregulate the expression of Toll-like receptor-4 and downstream signaling proteins, such as nuclear factor kappa-B, in the lungs. The LBW group also exhibited abnormal airway thickening and high corticosterone levels under basal conditions. SignificanceThis study suggests that IUGR-induced foetal programming in LBW offspring threatens HPA axis physiology and corticosterone biodisponibility, and impairs the innate response to bacterial antigens, increasing future susceptibility to pulmonary infection.

Intrauterine endogenous high glucocorticoids program ovarian dysfunction in female offspring secondary to prenatal caffeine exposure

Ovarian dysfunction has an intrauterine origin, and prenatal caffeine exposure (PCE) could lead to abnormal follicle counts in offspring after birth. However, the effect of PCE on offspring ovarian function and its mechanism of intrauterine programming have not been reported thus far. In this study, pregnant Wistar rats were intragastrically administered caffeine (30 and 120 mg/kg·d) at gestational days 9–20 (GD9–20). Certain tests were performed on the blood, ovaries and hypothalamus of female offspring at different time points. PCE female offspring had ovarian dysfunction in adulthood compared with the control. Further results showed that in utero ovarian morphological development and estradiol synthesis were inhibited but rapidly increased during puberty in the PCE group. The histone 3 lysine 27 acetylation (H3K27ac) level of the insulin-like growth factor 1 (IGF1) promoter region and its expression were decreased in the ovary, which was due to exposure to high levels of fetal blood corticosterone, and the H3K27ac level of IGF1 and its expression shifted to increase after birth with a decrease in serum corticosterone levels. Chronic stress led to increased serum corticosterone levels in adult offspring, whereas ovarian morphological development, the H3K27ac level of IGF1 and its expression, and estradiol synthesis were significantly inhibited. Moreover, the activity of the hypothalamic-pituitary-ovarian (HPO) axis was increased in the early postnatal period of PCE offspring, and chronic stress reversed these changes. In the KGN cell line, it was found that cortisol could promote the translocation of the glucocorticoid receptor (GR) into the nucleus and upregulate histone deacetylase 10 (HDAC10) to inhibit the H3K27ac level of IGF1 and its expression and estradiol synthesis. In summary, PCE is associated with ovarian dysfunction in female adult offspring, and the potential mechanism is related to intrauterine high glucocorticoid exposure by activating the GR and recruiting HDAC10 to affect ovarian glucocorticoid-IGF1 axis programming and to inhibit estradiol synthesis.

Antidepressant-like effects of acupuncture via modulation of corticosterone, sex hormones, and hippocampal BDNF expression in male rats

BackgroundPost-weaning social isolated rodents exhibit pathophysiological changes associated with depression including adrenal axis hyperactivity, gonadal hormone level disturbances, molecular alterations in hippocampus, and immobility behavior in the forced swimming test (FST). Although acupuncture by absorbable thread implantation (acu-catgut, AC) elicits antidepressant-like effects in social isolated rats, AC effects on neuroendocrine and hippocampal molecular alterations have been less characterized. ObjectiveTo investigate the participation of gonadal hormones, corticosterone, and brain-derived neurotrophic factor (BDNF) hippocampal expression, on the AC antidepressant-like effects in social isolated male rats. MethodsSprague-Dawley male rats were raised in social isolation (SI) or standard conditions, for 11 weeks. AC (on Baihui (Du20), Yintang (E X-HN3), Shenshu (BL 23), Pishu (BL 20), Ganshu (BL 18), Xinshu (BL 15) and Guanyuan (Ren 4)), or Sham-AC (puncturing of acupoints without embedding the thread), was applied during the last three weeks of isolation period. Rats were evaluated in the FST; hormones plasmatic levels and hippocampal BDNF content were quantified by ELISA and Western blotting, respectively. ResultsSocial isolated rats showed more immobility in the FST and had lower testosterone and estradiol levels, higher corticosterone levels, and reduced hippocampal BDNF content than controls. BDNF level in hippocampus inversely correlated to depression-like behavior. AC but not sham-AC normalized immobility behavior, steroid hormone levels, and BDNF content, as in rats raised in a social environment. ConclusionsAC antidepressant effect could be related to an improvement of hippocampal BDNF protein expression, as well as corticosterone and sex hormones disturbances associated with prolonged exposure to stress caused by social isolation. Present findings have implications for depression treatment in individuals early exposed to stress.

Glucocorticoid-Mediated Changes in Male Green Treefrog Vocalizations Alter Attractiveness to Females.

Adrenal glucocorticoids (GCs) are increasingly recognized as important modulators of male courtship signals, suggesting that circulating levels of these steroids can play a central role in sexual selection. However, few studies have examined whether GC-mediated effects on male sexual signals actually impact mate choice by females. Here, we examine how corticosterone (CORT)-mediated changes in the vocalizations of male green treefrogs, Dryophytes cinereus, influence attractiveness to females. In this species, agonistic acoustic signaling between rival males competing for mates increases circulating CORT levels in contest losers. Acute elevations in CORT, in turn, decrease the duration of male advertisement calls and increase the latency between successive calls, resulting in a net reduction in vocal effort (the amount of signaling per unit time) that occurs independently of changes in circulating androgens. Based on known preferences for acoustic features in D. cinereus, and other anuran species, the direction of CORT-mediated effects on temporal call characteristics is expected to compromise attractiveness to females, but whether they are of sufficient magnitude to impact female mate choice decisions is unclear. To examine whether CORT-mediated effects on male advertisement calls reduce attractiveness to females, we broadcast vocalizations in dual speaker playback experiments approximating the mean and 1 SD above and below the mean call duration and vocal effort values (the two primary vocal features impacted by elevated CORT) of males with low and high CORT levels. Results revealed strong preferences by females for the calls characteristic of males with low CORT in tests using the approximate mean and 1 SD above the mean call duration and vocal effort values, but females did not show a preference for calls of males with low CORT in trials using call values approximating 1 SD below the mean. Overall, females preferred males with signal traits predictive of low CORT, however this effect was nonlinear with attenuated preferences when signal alternatives differed only marginally indicating a possible thresholding effect. Specifically, females appeared to discriminate between males with low versus high CORT based primarily on differences in call rates associated with CORT-mediated changes in call duration and vocal effort. Our results highlight that changes in circulating CORT during male-male vocal interactions can decrease attractiveness to females, suggesting that circulating levels of CORT can play a critical role in both intra- and intersexual selection.

The Effects of Chronic Stress on Brown Adipose Tissue Remodeling and Metabolism

Adipose tissue has been found to exist in two predominant forms, white and brown. White adipose tissue (WAT) is the body's conventional storage organ, while brown adipose tissue (BAT) is responsible for non-shivering thermogenesis, which allows mammals to produce heat and regulate body temperature. Studies examining BAT and its role in whole-body metabolism have found that active BAT can lead to improved metabolic outcomes. While the beiging/ browning of WAT is a growing area of interest, the possibility of the BAT depot to “whiten” and store more triglycerides and adopt a lipid storage phenotype of WAT may have important health implications. Currently, there are limited studies that examine the direct effects of chronic stress in BAT and its ability to induce a white-like phenotype in this adipose tissue depot. This current research aimed to determine the impact of high levels of the murine stress hormone, corticosterone, on the whitening process of BAT. Six-week-old male C57BL/6J mice were exposed to high levels (100µg/ml) of corticosterone in their drinking water for four weeks. The effect of the corticosterone on BAT was investigated for its impact on insulin resistance, and the expression of uncoupling protein 1 (UCP1), which is integral to the non-shivering thermogenesis pathway. Corticosterone treatment significantly (p≤0.05) increased body weight, both WAT and BAT mass, and adipocyte size in each adipose depot. Corticosterone treatment significantly (p≤0.05) increased plasma insulin concentrations. The homeostatic model of assessment for insulin resistance (HOMA-IR) demonstrated that the corticosterone treated mice were also significantly (p≤0.05) more insulin resistant than controls. Surprisingly, the BAT of the corticosterone treated mice had significantly (p≤0.05) higher protein expression levels of UCP1 than controls. The alterations found in our in vivo model illustrated that chronic treatment with corticosterone for 4 weeks resulted in tissue remodeling, altered glucose metabolism, and adipose tissue whitening. By understanding these altered adipocyte morphologies and metabolic phenotypes in mice under chronic stress, we will be better equipped to uncover pathological effects of metabolic diseases weighing the world down today.

Therapeutic Potential of Metformin to Ameliorate Behavioral Symptoms of Autism

Autism spectrum disorders (ASD) affect 1/39 boys and 1/144 girls and manifest in lifelong social interaction deficits and restrictive-repetitive traits of varying severity. Currently no treatments capable of both enhancing social interaction and curbing restrictive repetitive behaviors have been identified. In light of strikingly higher incidence of autism in males versus females, it is surprising that treatments for dysfunctions of steroid hormone metabolism have not been more extensively studied. Clinical evidence supports this approach, as in several studies prepubertal boys and adolescent girls with autism had more androgens and other steroids than age matched children without autism. The antidiabetic drug metformin was found to inhibit adrenergic steroid synthesis, particularly of androgens, through antagonism of melanocortin receptors. Metformin is already co-administered with antipsychotics to manage weight in some autism patients. The goal of this study was to establish in mice if an androgen inhibitor, metformin, can enhance social or reduce repetitive behavior with chronic use. BTBR T+Itpr3tf/J (BTBR) mice were used because this strain is a popular behavioral autism model with high testosterone, corticosterone and progesterone levels, and low serotonin (5-HT) transporter (SERT) density as compared to C57BL/6J (B6) mice, which were used as a strain control. Initially acute metformin treatment dose-dependently enhanced male BTBR mouse social interaction preference for a stranger mouse versus a novel object (p <0.05 different from control at 150 mg/kg dose, N= 9-11 mice), and had no adverse effects on B6 social behaviors. Metformin (150 mg/kg/d) was administered to 10 each adult male and female mice via drinking water for 28 days, yielding a steady state concentration in brain of 36 ± 12 ng/ml. A series of autism relevant behavior tests were performed to compare BTBR and B6 treatment responses. Three chamber social interaction preference tests revealed no effect of chronic metformin treatment on social preference in either strain by the measure of time spent in chambers. Yet BTBR male and female social dominance, measured by the tube test, increased slightly with chronic metformin treatment, but was still less than B6 mouse dominance, which was unaffected by chronic metformin treatment. Marble burying by mice over 30 min did not differ by strain, sex or metformin treatment. Cognitive flexibility in the water T-maze test, measured by number of errors made on day 1 of reversal learning, was unaffected by metformin treatment (F(1,100) = 0.02, p = 0.9). Males and females were pooled for this measure. [3H] histamine and [3H] metformin uptake were greater in hippocampal synaptosomes isolated from metformin treated male B6 mice than in untreated ones (N = 4). This finding may indicate chronic metformin treatment increases hippocampal expression of common transporters of these substrates such as organic cation transporters (OCTs), which also transport 5-HT and other monoamines. Overall, our findings indicate that metformin treatment can enhance social preference and dominance, and chronically it may enhance expression of OCTs.

Simulated vehicle exhaust exposure induces sex-dependent behavioral deficits in rats

Chronic exposure to vehicle exhaust emissions are known to cause several adverse health effects. In this study, we examined the impact of several parameters of behavioral, cardiovascular and biochemical functions upon exposure of pro-oxidants CO2, NO2 and CO (simulated vehicle exhaust exposure: SVEE) in male and female rats. Adult rats were subjected to SVEE or ambient air in whole body chambers (5 h/day, 2 weeks). Male, but not female, rats developed memory deficits, and exhibited anxiety- and depression-like behavior, accompanied with significantly high levels of serum corticosterone, oxidative stress, and inflammatory markers (CRP and TNFα), associated with lower levels of total antioxidant capacity, glutathione, glyoxalase and superoxide dismutase (SOD) activities. Brain region-specific downregulation of Cu/Zn SOD, Mn SOD, GSR, PKCα, ERK1/2, CaMKIV, CREB, BDNF and NMDAR subunit protein expression were also observed in male, but not female, rats. Blood pressure, heart rate and eGFR were not negatively impacted by SVEE. Our results suggest that SVEE, through its pro-oxidant content, induces oxido-inflammation in susceptible brain regions in a sex-dependent manner.

Developmental retardation in neonates of aldehyde reductase (AKR1A)-deficient mice is associated with low ascorbic acid and high corticosterone levels

Aldehyde reductase encoded by the Akr1a gene catalyzes the NADPH-dependent reduction of a variety of aldehyde compounds, and it plays a role in the biosynthesis of ascorbic acid (AsA) by converting D-glucuronate to L-gulonate. Although supplementing drinking water with AsA (1.5 mg/mL) ameliorates the fertility of Akr1a−/− (KO) female mice, litter sizes in the KO mice are typically smaller than those for Akr1a+/+ (WT) mice, and about one-third of the neonates have a reduced stature. Half of the neonates in the smallest, developmentally retarded group died before weaning, and the remaining half (less than 6 g in weight) also barely grew to adulthood. While no difference was found in the number of fetuses between the KO and WT mice at 14.5-embryonic days, the sizes of the KO fetuses had already diverged. Among the organs of these retarded KO neonates at 30 d, the spleen and thymus were characteristically small. While an examination of spleen cells showed the normal proportion of immune cells, apoptotic cell death was increased in the thymus, which would lead to thymic atrophy in the retarded KO neonates. Plasma AsA levels were lower in the small neonates despite the fact that their mothers had received sufficient AsA supplementation, and the corticosterone levels were inversely higher compared to wild-type mice. Thus, insufficient AsA contents together with a defect in corticosterone metabolism might be the cause of the retarded growth of the AKR1A-deficient mice embryos and neonates.