Showing papers on "Corticosterone published in 2018"
TL;DR: It is argued that a balanced response during the two phases of the brain's response to stress are essential for resilience and may become compromised after repeated stress exposure, particularly in genetically vulnerable individuals and aggravate disease manifestation.
Abstract: The brain is continuously exposed to varying levels of adrenal corticosteroid hormones such as corticosterone in rodents and cortisol in humans. Natural fluctuations occur due to ultradian and circadian variations or are caused by exposure to stressful situations. Brain cells express two types of corticosteroid receptors, i.e. mineralocorticoid and glucocorticoid receptors, which differ in distribution and affinity. These receptors can mediate both rapid non-genomic and slow gene-mediated neuronal actions. As a consequence of these factors, natural (e.g. stress-induced) shifts in corticosteroid level are associated with a complex mosaic of time- and region-dependent changes in neuronal activity. A series of experiments in humans and rodents have revealed that these time- and region-dependent cellular characteristics are also reflected in distinct cognitive patterns after stress. Thus, directly after a peak of corticosteroids, attention and vigilance are increased, and areas involved in emotional responses and simple behavioral strategies show enhanced activity. In the aftermath of stress, areas involved in higher cognitive functions become activated allowing individuals to link stressful events to the specific context and to store information for future use. Both phases of the brain's response to stress are important to face a continuously changing environment, promoting adaptation at the short as well as long term. We argue that a balanced response during the two phases is essential for resilience. This balance may become compromised after repeated stress exposure, particularly in genetically vulnerable individuals and aggravate disease manifestation. This not only applies to psychiatric disorders but also to neurological diseases such as epilepsy.
113 citations
TL;DR: The brain's response to stress depends on an individual's genetic background in interaction with life events, and studies in rodents point to the possibility to prevent or reverse long‐term consequences of early life adversity on cognitive processing by normalizing the balance between the two receptor types for corticosteroid hormones at a critical moment just before the onset of puberty.
Abstract: After stress, the brain is exposed to waves of stress mediators, including corticosterone (in rodents) and cortisol (in humans). Corticosteroid hormones affect neuronal physiology in two time-domains: rapid, non-genomic actions primarily via mineralocorticoid receptors; and delayed genomic effects via glucocorticoid receptors. In parallel, cognitive processing is affected by stress hormones. Directly after stress, emotional behaviour involving the amygdala is strongly facilitated with cognitively a strong emphasis on the "now" and "self," at the cost of higher cognitive processing. This enables the organism to quickly and adequately respond to the situation at hand. Several hours later, emotional circuits are dampened while functions related to the prefrontal cortex and hippocampus are promoted. This allows the individual to rationalize the stressful event and place it in the right context, which is beneficial in the long run. The brain's response to stress depends on an individual's genetic background in interaction with life events. Studies in rodents point to the possibility to prevent or reverse long-term consequences of early life adversity on cognitive processing, by normalizing the balance between the two receptor types for corticosteroid hormones at a critical moment just before the onset of puberty.
99 citations
TL;DR: Novel evidence is shown that corticosterone produced during stress enhances the release of proinflammatory monocytes from the bone marrow into circulation, augments their recruitment to the brain and the induction of a neuroinflammatory profile.
Abstract: Repeated social defeat (RSD) stress promotes the release of bone marrow-derived monocytes into circulation that are recruited to the brain, where they augment neuroinflammation and cause prolonged anxiety-like behavior. Physiological stress activates the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal gland (HPA) axis, and both of these systems play a role in the physiological, immunological, and behavioral responses to stress. The purpose of this study was to delineate the role of HPA activation and corticosterone production in the immunological responses to stress in male C57/BL6 mice. Here, surgical (adrenalectomy) and pharmacological (metyrapone) interventions were used to abrogate corticosterone signaling during stress. We report that both adrenalectomy and metyrapone attenuated the stress-induced release of monocytes into circulation. Neither intervention altered the production of monocytes during stress, but both interventions enhanced retention of these cells in the bone marrow. Consistent with this observation, adrenalectomy and metyrapone also prevented the stress-induced reduction of a key retention factor, CXCL12, in the bone marrow. Corticosterone depletion with metyrapone also abrogated the stress-induced glucocorticoid resistance of myeloid cells. In the brain, these corticosterone-associated interventions attenuated stress-induced microglial remodeling, neurovascular expression of the adhesion molecule ICAM-1, prevented monocyte accumulation and neuroinflammatory signaling. Overall, these results indicate that HPA activation and corticosterone production during repeated social defeat stress are critical for monocyte release into circulation, glucocorticoid resistance of myeloid cells, and enhanced neurovascular cell adhesion molecule expression. SIGNIFICANCE STATEMENT Recent studies of stress have identified the presence of monocytes that show an exaggerated inflammatory response to immune challenge and are resistant to the suppressive effects of glucocorticoids. Increased presence of these proinflammatory monocytes has been implicated in neuropsychiatric symptoms and the development of chronic cardiovascular, autoimmune and metabolic disorders. In the current study, we show novel evidence that corticosterone produced during stress enhances the release of proinflammatory monocytes from the bone marrow into circulation, augments their recruitment to the brain and the induction of a neuroinflammatory profile. Overproduction of corticosterone during stress is also the direct cause of glucocorticoid resistance, a key phenotype in individuals exposed to chronic stress. Inhibiting excess corticosterone production attenuates these inflammatory responses to stress.
93 citations
TL;DR: The data highlight the importance of the NTS as a key regulatory node for coordination of acute and chronic stress, being important in HPA activation to both systemic and psychogenic stressors as well as HPA axis sensitization under conditions of chronic stress.
Abstract: Hindbrain neurons in the nucleus of the solitary tract (NTS) are critical for regulation of hypothalamo-pituitary-adrenocortical (HPA) responses to stress. It is well known that noradrenergic (as well as adrenergic) neurons in the NTS send direct projections to hypophysiotropic corticotropin-releasing hormone (CRH) neurons and control activation of HPA axis responses to acute systemic (but not psychogenic) stressors. Norepinephrine (NE) signaling via alpha1 receptors is primarily excitatory, working either directly on CRH neurons or through presynaptic activation of glutamate release. However, there is also evidence for NE inhibition of CRH neurons (possibly via beta receptors), an effect that may occur at higher levels of stimulation, suggesting that NE effects on the HPA axis may be context-dependent. Lesions of ascending NE inputs to the paraventricular nucleus attenuate stress-induced ACTH but not corticosterone release after chronic stress, indicating reduction in central HPA drive and increased adrenal sensitivity. Non-catecholaminergic NTS glucagon-like peptide 1/glutamate neurons play a broader role in stress regulation, being important in HPA activation to both systemic and psychogenic stressors as well as HPA axis sensitization under conditions of chronic stress. Overall, the data highlight the importance of the NTS as a key regulatory node for coordination of acute and chronic stress.
72 citations
TL;DR: It is shown that the microbiota modulates emotional behavior in social conflicts and the response of the HPA axis, colon and mesenteric lymph nodes (MLN) to chronic psychosocial stress and indicates possible pathways by which the environment can interact with glucocorticoid signaling.
Abstract: The commensal microbiota affects brain functioning, emotional behavior and ACTH and corticosterone responses to acute stress. However, little is known about the role of the microbiota in shaping the chronic stress response in the peripheral components of the hypothalamus-pituitary-adrenocortical (HPA) axis and in the colon. Here, we studied the effects of the chronic stress-microbiota interaction on HPA axis activity and on the expression of colonic corticotropin-releasing hormone (CRH) system, cytokines and 11β-hydroxysteroid dehydrogenase type 1 (11HSD1), an enzyme that determines locally produced glucocorticoids. Using specific pathogen-free (SPF) and germ-free (GF) BALB/c mice, we showed that the microbiota modulates emotional behavior in social conflicts and the response of the HPA axis, colon and mesenteric lymph nodes (MLN) to chronic psychosocial stress. In the pituitary gland, microbiota attenuated the expression of Fkbp5, a gene regulating glucocorticoid receptor sensitivity, while in the adrenal gland, it attenuated the expression of genes encoding steroidogenesis (MC2R, StaR, Cyp11a1) and catecholamine synthesis (TH, PNMT). The pituitary expression of CRH receptor type 1 (CRHR1) and of proopiomelanocortin was not influenced by microbiota. In the colon, the microbiota attenuated the expression of 11HSD1, CRH, urocortin UCN2 and its receptor, CRHR2, but potentiated the expression of cytokines TNFα, IFNγ, IL-4, IL-5, IL-6, IL-10, IL-13 and IL-17, with the exception of IL-1β. Compared to GF mice, chronic stress upregulated in SPF animals the expression of pituitary Fkbp5 and colonic CRH and UCN2 and downregulated the expression of colonic cytokines. Differences in the stress responses of both GF and SPF animals were also observed when immunophenotype of MLN cells and their secretion of cytokines were analyzed. The data suggest that the presence of microbiota/intestinal commensals plays an important role in shaping the response of peripheral tissues to stress and indicates possible pathways by which the environment can interact with glucocorticoid signaling.
62 citations
TL;DR: It is shown that stressful events during pregnancy can lead to long-lasting structural and neurochemical effects in the offspring, which affect behavior in adulthood.
Abstract: Stress or high levels of glucocorticoids (GCs) during developmental periods is known to induce persistent effects in the neuroendocrine circuits that control stress response, which may underlie individuals' increased risk for developing neuropsychiatric conditions later in life, such as anxiety or depression. We developed a rat model (Wistar han) of mild exposure to unpredictable prenatal stress (PS), which consists in a 4-h stressor administered three times per week on a random basis; stressors include strobe lights, noise and restrain. Pregnant dams subjected to this protocol present disrupted circadian corticosterone secretion and increased corticosterone secretion upon acute stress exposure. Regarding progeny, both young adult (2 months old) male and female rats present increased levels of circulating corticosterone and hyperactivity of the hypothalamus-pituitary-adrenal axis to acute stress exposure. Both sexes present anxious- and depressive-like behaviors, shown by the decreased time spent in the open arms of the elevated plus maze (EPM) and in the light side of the light-dark box (LDB), and by increased immobility time in the forced swim test, respectively. Interestingly, these results were accompanied by structural modifications of the bed nucleus of stria terminalis (BNST) and hippocampus, as well as decreased norepinephrine and dopamine levels in the BNST, and serotonin levels in the hippocampus. In summary, we characterize a new model of mild PS, and show that stressful events during pregnancy can lead to long-lasting structural and neurochemical effects in the offspring, which affect behavior in adulthood.
61 citations
TL;DR: The antidepressant‐like ability of drug treatments against chronic CORT induced stress model, as revealed in this study, may be due to their potential to mitigate inflammatory damage and oxidative stress via modulation of hippocampal NF‐&kgr;B p65, COX‐2, HDAC2 and phosphorylated JNK levels.
58 citations
TL;DR: Overall, these results indicate that brief, acute elevations in glucocorticoids in adulthood can have long-term consequences, and individuals that mount a greater or longer acute stress response may be more likely to experience lingering effects of stress.
Abstract: Acutely stressful experiences can have profound and persistent effects on phenotype. Across taxa, individuals differ remarkably in their susceptibility to stress. However, the mechanistic causes of enduring stress effects, and of individual differences in stress susceptibility, are poorly understood. Here, we tested whether brief, acute increases in glucocorticoid hormones have persistent effects on phenotype, and whether effects differ according to the magnitude or duration of elevation. We used a novel method to non-invasively manipulate hormone levels on short time scales: the application of corticosterone gel to a model egg secured in the nest. Free-living female tree swallows ( Tachycineta bicolor ) exposed to several brief corticosterone increases during incubation showed dose-dependent differences in behaviour throughout the reproductive period. Birds receiving treatments that simulated higher or longer acute stress responses later provisioned larger broods at lower rates; the resulting offspring were smaller in size. Treatment did not influence female body condition, oxidative stress, reproductive success or inter-annual survival, but exposed females maintained higher baseline corticosterone after treatments ceased. Overall, these results indicate that brief, acute elevations in glucocorticoids in adulthood can have long-term consequences. Furthermore, individuals that mount a greater or longer acute stress response may be more likely to experience lingering effects of stress.
54 citations
TL;DR: Findings indicated that magnolol possessed antidepressant effects in mice exposed to CORT, which might be partially related to modulate HPA axis, up‐regulate BDNF expression and increase neurotransmitters levels in the hippocampus.
47 citations
TL;DR: The present results show that social isolation in male rats alters basal HPA axis activity and impairs glucocorticoid‐mediated negative feedback after acute stress, and alters the hypothalamic endocannabinoid system.
44 citations
TL;DR: Results suggest that T is synthesized within the mesocorticolimbic system, and provide a foundation for future studies examining how neurosteroids influence behaviors mediated by the mesoporous system.
Abstract: Steroid hormones can modulate motivated behaviors through the mesocorticolimbic system. Gonadectomy (GDX) is a common method to determine how steroids influence the mesocorticolimbic system, and caloric restriction (CR) is often used to invigorate motivated behaviors. A common assumption is that the effects of these manipulations on brain steroid levels reflects circulating steroid levels. We now know that the brain regulates local steroid levels in a region-specific manner; however, previous studies have low spatial resolution. Using ultrasensitive liquid chromatography tandem mass spectrometry, we examined steroids in microdissected regions of the mesocorticolimbic system (ventral tegmental area, nucleus accumbens, medial prefrontal cortex). We examined whether GDX or CR influences systemic and local steroids, particularly testosterone (T) and steroidogenic enzyme transcripts. Adult male rats underwent a GDX surgery and/or CR for either 2 or 6 weeks. Levels of T, the primary steroid of interest, were higher in all brain regions than in the blood, whereas corticosterone (CORT) was lower in the brain than in the blood. Importantly, GDX completely eliminated T in the blood and lowered T in the brain. Yet, T remained present in the brain, even 6 weeks after GDX. CR decreased both T and CORT in the blood and brain. Steroidogenic enzyme (Cyp17a1, 3β-hydroxysteroid dehydrogenase, aromatase) transcripts and androgen receptor transcripts were expressed in the mesocorticolimbic system and differentially affected by GDX and CR. Together, these results suggest that T is synthesized within the mesocorticolimbic system. These results provide a foundation for future studies examining how neurosteroids influence behaviors mediated by the mesocorticolimbic system.
TL;DR: These findings indicate that while TSPO is not critical for achieving baseline testicular and adrenal steroidogenesis, either indirect effects of T SPO on steroidogenic processes, or compensatory mechanisms and functional redundancy, lead to subtle steroidogenic abnormalities which become exacerbated with aging.
Abstract: The translocator protein (TSPO) has been proposed to act as a key component in a complex important for mitochondrial cholesterol importation, which is the rate-limiting step in steroid hormone synthesis. However, TSPO function in steroidogenesis has recently been challenged by the development of TSPO knockout (TSPO-KO) mice, as they exhibit normal baseline gonadal testosterone and adrenal corticosteroid production. Here, we demonstrate that despite normal androgen levels in young male TSPO-KO mice, TSPO deficiency alters steroidogenic flux and results in reduced total steroidogenic output. Specific reductions in the levels of progesterone and corticosterone as well as age-dependent androgen deficiency were observed in both young and aged male TSPO-KO mice. Collectively, these findings indicate that while TSPO is not critical for achieving baseline testicular and adrenal steroidogenesis, either indirect effects of TSPO on steroidogenic processes, or compensatory mechanisms and functional redundancy, lead to subtle steroidogenic abnormalities which become exacerbated with aging.
TL;DR: Using transcriptomic profiling in adrenals from three mouse models, it was demonstrated that disturbances in adrenal redox homeostasis are mediated not only by under expression of NNT but also by its overexpression, implying a central role for it in the control of steroidogenesis.
Abstract: Nicotinamide nucleotide transhydrogenase, NNT, is a ubiquitous protein of the inner mitochondrial membrane with a key role in mitochondrial redox balance. NNT produces high concentrations of NADPH for detoxification of reactive oxygen species by glutathione and thioredoxin pathways. In humans, NNT dysfunction leads to an adrenal-specific disorder, glucocorticoid deficiency. Certain substrains of C57BL/6 mice contain a spontaneously occurring inactivating Nnt mutation and display glucocorticoid deficiency along with glucose intolerance and reduced insulin secretion. To understand the underlying mechanism(s) behind the glucocorticoid deficiency, we performed comprehensive RNA-seq on adrenals from wild-type (C57BL/6N), mutant (C57BL/6J) and BAC transgenic mice overexpressing Nnt (C57BL/6JBAC). The following results were obtained. Our data suggest that Nnt deletion (or overexpression) reduces adrenal steroidogenic output by decreasing the expression of crucial, mitochondrial antioxidant (Prdx3 and Txnrd2) and steroidogenic (Cyp11a1) enzymes. Pathway analysis also revealed upregulation of heat shock protein machinery and haemoglobins possibly in response to the oxidative stress initiated by NNT ablation. In conclusion, using transcriptomic profiling in adrenals from three mouse models, we showed that disturbances in adrenal redox homeostasis are mediated not only by under expression of NNT but also by its overexpression. Further, we demonstrated that both under expression or overexpression of NNT reduced corticosterone output implying a central role for it in the control of steroidogenesis. This is likely due to a reduction in the expression of a key steroidogenic enzyme, Cyp11a1, which mirrored the reduction in corticosterone output.
TL;DR: It was observed that corticosterone treatment resulted in depressive‐like behavior with established oxidative stress in mice, while cholecalciferol ameliorated both, behavioral (immobility time and grooming latency) and biochemical (protein carbonyl and nitrite levels) changes induced by CORT model, suggesting that chole CALCiferol has antidepressant‐like effect with the involvement of the oxidative stress modulation.
TL;DR: Silymarin significantly reversed the CUMS-induced changes in the hippocampus and cerebral cortex in mice, correlated to the alleviation of monoaminergic, neurogenesis, and attenuation of inflammatory cytokines system and oxidative stress by modulation of corticosterone response, restoration of antioxidant defense system in cerebral cortex and hippocampus.
Abstract: Silymarin, a plant-derived polyphenolic flavonoid of Silybum marianum, elicited significant antidepressant-like activity in an acute restraint stress model of depression. It improved monoamines, mainly 5-hydroxytryptamine (5-HT) levels in the cortex, dopamine (DA) and norepinephrine (NE) in the cerebellum in mice. The present study was undertaken to explore the antidepressant potential of silymarin in chronic unpredictable mild stress (CUMS) induced depressive-like behavior in mice, and to find out its probable mechanism(s) of action, mainly neurogenesis, neuroinflammation, and/or oxidative stress. The mice were subjected to CUMS for 28 days (4 weeks) and administered with silymarin (100 mg/kg and 200 mg/kg), or fluoxetine or vehicle from days 8 to 28 (3 weeks simultaneously). Animals were evaluated for behavioral changes, such as anhedonia by sucrose preference test, behavioral despair by forced swim test, and exploratory behaviors by an open field test. In addition, neurobiochemical alterations, mainly monoamines, 5-HT, NE, DA, neurotrophic factor BDNF, and cytokines, IL-6, TNF-α, oxidant-antioxidant parameters by determining the malondialdehyde formation (an index of lipid peroxidation process), superoxide dismutase (SOD) and catalase (CAT) activity in hippocampus and cerebral cortex along with serum corticosterone were investigated. Our findings reveal that mice subjected to CUMS exhibited lower sucrose preference, increase immobility time without affecting general locomotion of the animals, and reduce BDNF, 5-HT, NE, and DA level, increased serum corticosterone, IL-6 and TNF-α along with an oxidant-antioxidant imbalance in the hippocampus and cerebral cortex. Silymarin significantly reversed the CUMS-induced changes in the hippocampus and cerebral cortex in mice. Thus, the possible mechanism involved in the antidepressant-like activity of silymarin is correlated to the alleviation of monoaminergic, neurogenesis (enhancing 5-HT, NE, and BDNF levels), and attenuation of inflammatory cytokines system and oxidative stress by modulation of corticosterone response, restoration of antioxidant defense system in cerebral cortex and hippocampus.
TL;DR: The results suggest that the increase in hippocampal proliferation induced by agmatine may contribute, at least in part, to the antidepressant‐like response of this compound in this mouse model of stress induced by chronic exposure to corticosterone.
Abstract: Agmatine is an endogenous neuromodulator that has been shown to have beneficial effects in the central nervous system, including antidepressant-like effects in animals. In this study, we investigated the ability of agmatine (0.1mg/kg, p.o.) and the conventional antidepressant fluoxetine (10mg/kg, p.o.) to reverse the behavioral effects and morphological alterations in the hippocampus of mice exposed to chronic corticosterone (20mg/kg, p.o.) treatment for a period of 21days as a model of stress and depressive-like behaviors. Chronic corticosterone treatment increased the immobility time in the tail suspension test (TST), but did not cause anhedonic-like and anxiety-related behaviors, as assessed with the splash test and the open field test (OFT), respectively. Of note, the depressive-like behaviors induced by corticosterone were accompanied by a decrease in hippocampal cell proliferation, although no changes in hippocampal neuronal differentiation were observed. Our findings provide evidence that, similarly to fluoxetine, agmatine was able to reverse the corticosterone-induced depressive-like behaviors in the TST as well as the deficits in hippocampal cell proliferation. Additionally, fluoxetine but not agmatine, increased hippocampal differentiation. Agmatine, similar to fluoxetine, was capable of increasing both dendritic arborization and length in the entire dentate hippocampus, an effect more evident in the ventral portion of the hippocampus, as assessed with the modified Sholl analysis. Altogether, our results suggest that the increase in hippocampal proliferation induced by agmatine may contribute, at least in part, to the antidepressant-like response of this compound in this mouse model of stress induced by chronic exposure to corticosterone.
TL;DR: Results indicate that OT has inhibitory effects on CORT-induced neuronal death in primary hippocampal neurons via acting on OTR, and suggest a therapeutic potential of OT in the treatment of stress-related disorders.
TL;DR: The data indicate the existence of sex and regional differences in the generation of neuroactive steroids in the brain following acute stress, especially for the 5α‐reduced steroids, and further suggest a sex‐specific expression of steroidogenic enzymes in thebrain.
Abstract: Sex differences in hypothalamic-pituitary-adrenal (HPA) axis activity are well established in rodents. In addition to glucocorticoids, stress also stimulates the secretion of progesterone and deoxycorticosterone (DOC) from the adrenal gland. Neuroactive steroid metabolites of these precursors can modulate HPA axis function; however, it is not known whether levels of these steroids differ between male and females following stress. In the present study, we aimed to establish whether neuroactive steroid concentrations in the brain display sex- and/or region-specific differences under basal conditions and following exposure to acute stress. Brains were collected from male and female rats killed under nonstress conditions or following exposure to forced swimming. Liquid chromatography-mass spectrometry was used to quantify eight steroids: corticosterone, DOC, dihydrodeoxycorticosterone (DHDOC), pregnenolone, progesterone, dihydroprogesterone (DHP), allopregnanolone and testosterone in plasma, and in five brain regions (frontal cortex, hypothalamus, hippocampus, amygdala and brainstem). Corticosterone, DOC and progesterone concentrations were significantly greater in the plasma and brain of both sexes following stress; however, the responses in plasma were greater in females compared to males. This sex difference was also observed in the majority of brain regions for DOC and progesterone but not for corticosterone. Despite observing no stress-induced changes in circulating concentrations of pregnenolone, DHDOC or DHP, concentrations were significantly greater in the brain and this effect was more pronounced in females than males. Basal plasma and brain concentrations of allopregnanolone were significantly higher in females; moreover, stress had a greater impact on central allopregnanolone concentrations in females. Stress had no effect on circulating or brain concentrations of testosterone in males. These data indicate the existence of sex and regional differences in the generation of neuroactive steroids in the brain following acute stress, especially for the 5α-reduced steroids, and further suggest a sex-specific expression of steroidogenic enzymes in the brain. Thus, differential neurosteroidogenesis may contribute to sex differences in HPA axis responses to stress.
TL;DR: This paper evaluated the utility of the novel glucocorticoid receptor (GR) antagonist CORT125281 for its potential to overcome adiposity, glucose intolerance, and dyslipidemia and compared this head-to-head with the classic GR antagonist RU486.
Abstract: Glucocorticoids influence a wide range of metabolic processes in the human body, and excessive glucocorticoid exposure is known to contribute to the development of metabolic disease. We evaluated the utility of the novel glucocorticoid receptor (GR) antagonist CORT125281 for its potential to overcome adiposity, glucose intolerance, and dyslipidemia and compared this head-to-head with the classic GR antagonist RU486 (mifepristone). We show that, although RU486 displays cross-reactivity to the progesterone and androgen receptor, CORT125281 selectively inhibits GR transcriptional activity. In a mouse model for diet-induced obesity, rhythmicity of circulating corticosterone levels was disturbed. CORT125281 restored this disturbed rhythmicity, in contrast to RU486, which further inhibited endogenous corticosterone levels and suppressed adrenal weight. Both CORT125281 and RU486 reduced body weight gain and fat mass. In addition, CORT125281, but not RU486, lowered plasma levels of triglycerides, cholesterol, and free fatty acids and strongly stimulated triglyceride-derived fatty acid uptake by brown adipose tissue depots. In combination with reduced lipid content in brown adipocytes, this indicates that CORT125281 enhances metabolic activity of brown adipose tissue depots. CORT125281 was also found to increase liver lipid accumulation. Taken together, CORT125281 displayed a wide range of beneficial metabolic activities that are in part distinct from RU486, but clinical utility may be limited due to liver lipid accumulation. This warrants further evaluation of GR antagonists or selective modulators that are not accompanied by liver lipid accumulation while preserving their beneficial metabolic activities.
TL;DR: Test the hypothesis that glucocorticoid receptor (GR) antagonist mifepristone (RU486) may attenuate IL‐1&bgr;‐induced depression‐like behavior by regulating the neuroinflammation and neurotrophin functions of microglia and astrocytes and concludes that RU486 may improve depression-like changes by suppressing microgla and inflammation and promoting astroCytes to restore neurotrophic function.
TL;DR: Microglia changes with prenatal stress were also sensitive to the antioxidant, N-acetylcysteine, suggesting redox dysregulation as a mechanism of prenatal stress.
Abstract: Maternal stress during pregnancy is associated with an increased risk of psychopathology in offspring. Resident immune cells of the brain, microglia, may be mediators of prenatal stress and altered neurodevelopment. Here, we demonstrate that neither the exogenous pro-inflammatory cytokine, interleukin-1β (IL-1β), nor the glucocorticoid hormone, corticosterone, recapitulated the full effects of prenatal stress on the morphology of microglial cells in the cortical plate of embryonic mice; IL-1β effects showed greater similarity to prenatal stress effects on microglia. Unexpectedly, oil vehicle alone, which has antioxidant properties, moderated the effects of prenatal stress on microglia. Microglia changes with prenatal stress were also sensitive to the antioxidant, N-acetylcysteine, suggesting redox dysregulation as a mechanism of prenatal stress.
TL;DR: It is suggested that exogenous ACE2 suppresses CRH synthesis, which alters the central processing of psychogenic stress, thereby blunting HPA axis activation and attenuating anxiety‐like behavior.
TL;DR: 2.45 GHz MW radiation exposure induced local stress suppresses signaling mechanism(s) of hippocampal memory formation in adult male mice, leading to slow learning and significantly increased number of working and reference memory errors in radial maze task.
TL;DR: An endogenous cannabinoid tone maintains the HPA axis in a stable basal state, which is lost with a noxious stimulus, indicating that the ECS dampens the response to stress allowing the recovery of homeostasis.
TL;DR: Although raising male mice in an EE may elicit aggressive interactions between sibling cage-mates (as indicated by a high number of wounds), this environment also enhances social behaviors and limits the corticosterone and cytokine impacts of mild social stressors encountered in early adulthood.
Abstract: Environmental enrichment is typically associated with enhanced well-being, improved cognitive function and stress resilience. However, in some instances grouping adult male mice in enriched conditions promoted a stressful environment, which resulted in elevated endocrine, monoamine and inflammatory outcomes in response to subsequent stressor exposure. The current investigation examined whether raising male mice in an enriched environment (EE) would modulate social and anxiety-like behaviors in early adulthood and influence brain expression of pro-inflammatory cytokines and brain-derived neurotrophic factor (BDNF). Immediately after weaning (postnatal day [PD] 21), CD-1 male mice were housed with their siblings (3/cage) for 6 weeks in an EE or a standard (SE) environment. Body weights and aggressive interactions were monitored weekly. Social avoidance behaviors in the social interaction test and anxiety-like behaviors in the elevated-plus maze were examined in early adulthood. Ninety minutes following the behavioral tests, mice were sacrificed and a blood sample and the prefrontal cortex (PFC) were collected for the determination of plasma corticosterone levels as well as cytokine and BDNF mRNA expression. Mice raised in an EE exhibited more wounds and gained less weight than mice housed in a SE. Enriched mice also spent a greater amount of time in proximity of a social target in the social interaction test and made fewer transitions into the closed arms of the elevated-plus maze. Interestingly, the elevated plasma corticosterone and upregulated prefrontal interleukin (IL)-1β expression observed after the social interaction test among the SE mice were not apparent among those housed in an EE. Enrichment also increased prefrontal BDNF expression, especially among mice that experienced the social interaction test. These results suggest that although raising male mice in an EE may elicit aggressive interactions between sibling cage-mates (as indicated by a high number of wounds), this environment also enhances social behaviors and limits the corticosterone and cytokine impacts of mild social stressors encountered in early adulthood.
TL;DR: A novel technique is used to experimentally induce acute corticosterone spikes on either three or six consecutive days in incubating tree swallows to demonstrate the importance of assessing multiple aspects of the hormonal stress response and have implications for understanding both individual and population resilience to repeated transient stressors.
Abstract: The glucocorticoid stress response mediates a suite of physiological and behavioural changes that allow vertebrates to cope with transient stressors. Chronically elevated glucocorticoid levels are known to result in a variety of organismal costs, but relatively little is known about the downstream effects of mounting a series of brief, acute spikes in circulating glucocorticoids. Conceptual models of stress suggest that repeated acute stressors might produce 'wear-and-tear' on the stress-response system when encountered in sequence. We used a novel technique to experimentally induce acute corticosterone spikes on either three or six consecutive days in incubating tree swallows. Consistent with the 'wear-and-tear' hypothesis, we found that (i) a sequence of corticosterone spikes produced cumulative effects on corticosterone regulation, (ii) treatment frequency predicted the severity of consequences, and (iii) individual variation in the ability to terminate the stress response through negative feedback predicted the duration of physiological disruption in the group that experienced the most frequent challenges. Our results illustrate the importance of assessing multiple aspects of the hormonal stress response and have implications for understanding both individual and population resilience to repeated transient stressors.
TL;DR: Results indicate an alteration in the typical physiological and behavioral responses to stress during the hyporesponsive period of the HPA axis as a function of perinatal HFD exposure, which involves changes in the regulation of key genes mediating the H PA axis.
TL;DR: There were significant pre-natal effects of increased maternal corticosterone on nestling growth and survival and on the eventual recruitment of offspring as breeding adults in the local population, broadly consistent with the environmental/maternal-matching hypothesis.
Abstract: Corticosterone plays a central role in maintaining homeostasis, promoting energy acquisition, and regulating the stress response in birds. Exposure to elevated levels of corticosterone during development can profoundly alter offspring behaviour and physiology, but the effects of elevated maternal corticosterone on offspring development remain poorly understood.We tested two competing hypotheses concerning the effect of maternally derived corticosterone on growth and development of free-living house wrens: (i) elevated maternal corticosterone causes damaging effects on nestling phenotype and fitness (collateral damage hypothesis) and (ii) increased maternal corticosterone enhances offspring fitness by preparing nestlings for the environment experienced by their mother (environmental/maternal-matching hypothesis).We used a non-invasive means to increase maternal corticosterone by providing females with corticosterone-injected mealworms prior to and during egg production in the absence of any overt pre-natal maternal stress. To disentangle pre- and post-natal effects of this elevation in maternal corticosterone, we cross-fostered young in two experiments: (i) nestlings of control and experimental females were reared by unmanipulated, natural females in a uniform maternal environment; (ii) a split-brood design that enabled us to assess the interaction between the mother's corticosterone treatment and that of the nestlings.There were significant pre-natal effects of increased maternal corticosterone on nestling growth and survival. Offspring of females experiencing experimentally increased corticosterone were heavier and larger than offspring of control females. There also was a significant interaction between maternal corticosterone treatment and the corticosterone treatment to which young were exposed within the egg in their effect on nestling survival while in the nest; experimental young exhibited greater survival than control young, but only when reared by control mothers. There was also a significant effect of maternal corticosterone treatment on nestling stress reactivity and, in both experiments, on the eventual recruitment of offspring as breeding adults in the local population.These patterns are broadly consistent with the environmental/maternal-matching hypothesis, and highlight the importance of disentangling pre- and post-natal effects of manipulations of maternal hormone levels on offspring phenotype.
TL;DR: This study investigates whether levels of baseline corticosterone correlate with environmental conditions and associated extinction risk across wild populations of the common lizard Zootoca vivipara and suggests that rapid population decline might be preceded by a downregulation of the cortic testosterone secretion.
Abstract: Climate change should lead to massive loss of biodiversity in most taxa, but the detailed physiological mechanisms underlying population extinction remain largely elusive so far. In vertebrates, baseline levels of hormones such as glucocorticoids (GCs) may be indicators of population state as their secretion to chronic stress can impair survival and reproduction. However, the relationship between GC secretion, climate change and population extinction risk remains unclear. In this study, we investigated whether levels of baseline corticosterone (the main GCs in reptiles) correlate with environmental conditions and associated extinction risk across wild populations of the common lizard Zootoca vivipara. First, we performed a cross‐sectional comparison of baseline corticosterone levels along an altitudinal gradient among 14 populations. Then, we used a longitudinal study in eight populations to examine the changes in corticosterone levels following the exposure to a heatwave period. Unexpectedly, baseline corticosterone decreased with increasing thermal conditions at rest in females and was not correlated with extinction risk. In addition, baseline corticosterone levels decreased after exposure to an extreme heatwave period. This seasonal corticosterone decrease was more pronounced in populations without access to standing water. We suggest that low basal secretion of corticosterone may entail downregulating activity levels and limit exposure to adverse climatic conditions, especially to reduce water loss. These new insights suggest that rapid population decline might be preceded by a downregulation of the corticosterone secretion.
TL;DR: Results show that selective activation of C1 CA neurons is sufficient to increase feeding, blood glucose levels, and corticosterone secretion and suggest that each of these responses is mediated by CA neurons concentrated at different levels of the C1 cell group.
Abstract: Catecholamine (CA) neurons in the ventrolateral medulla (VLM) contribute importantly to glucoregulation during glucose deficit. However, it is not known which CA neurons elicit different glucoregulatory responses or whether selective activation of CA neurons is sufficient to elicit these responses. Therefore, to selectively activate CA subpopulations, we injected male or female Th-Cre+ transgenic rats with the Cre-dependent DREADD construct, AAV2-DIO-hSyn-hM3D(Gq)-mCherry, at one of four rostrocaudal levels of the VLM: rostral C1 (C1r), middle C1 (C1m), the area of A1 and C1 overlap (A1/C1), and A1. Transfection was highly selective for CA neurons at each site. Systemic injection of the Designer Receptor Exclusively Activated by Designer Drugs (DREADD) receptor agonist, clozapine-N-oxide (CNO), stimulated feeding in rats transfected at C1r, C1m, or A1/C1 but not A1. CNO increased corticosterone secretion in rats transfected at C1m or A1/C1 but not A1. In contrast, CNO did not increase blood glucose or induce c-Fos expression in the spinal cord or adrenal medulla after transfection of any single VLM site but required dual transfection of both C1m and C1r, possibly indicating that CA neurons mediating blood glucose responses are more sparsely distributed in C1r and C1m than those mediating feeding and corticosterone secretion. These results show that selective activation of C1 CA neurons is sufficient to increase feeding, blood glucose levels, and corticosterone secretion and suggest that each of these responses is mediated by CA neurons concentrated at different levels of the C1 cell group.