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1.
BMC Res Notes ; 14(1): 363, 2021 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-34538274

RESUMO

OBJECTIVE: Neuroscience research using laboratory animals has increased over the years for a number of reasons. Some of these studies require the use of anesthetics for surgical procedures. However, the use of anesthetics promotes several physiological changes that may interfere with experimental results. Although the anesthetics and methods of delivery used to vary, one of the most common is ketamine associated with another compound such as xylazine. We aimed to evaluate the effect of ketamine and xylazine (KX) on corticosterone levels and on the degree of phosphorylation of p44/42 (ERK1/2), Src kinases and calcium/calmodulin-dependent kinase II (CAMKII). We also compared the effects of KX on sleep deprivation, which is known to affect the hormonal profile including corticosterone. RESULTS: We found that the use of KX can increase corticosterone levels and alter the degree of phosphorylation of signaling proteins.


Assuntos
Anestesia , Ketamina , Animais , Corticosterona , Ketamina/farmacologia , Fosforilação , Xilazina/farmacologia
2.
Sci Total Environ ; 792: 148440, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34465058

RESUMO

Previously, we systemically confirmed that prenatal caffeine exposure (PCE) could cause intrauterine growth retardation (IUGR) and adrenal steroid synthesis dysfunction in offspring rats. However, the multi-generation inheritance of adrenal dysfunction and its epigenetic mechanism has not been reported. In this study, the PCE rat model was established, part of the pregnant rats were executed on gestational day 20, while the others were delivered normally and the fetal rats were reared into adulthood. The PCE female rats of filial generation 1 (F1) were mated with wild males to produce F2 offspring, and the same way to produce F3 offspring. All the adult female rats of three generations were sacrificed for the related detection. Results showed that PCE could decrease fetal weight, increase IUGR rate, and elevate serum corticosterone level. Meanwhile, the expression of fetal adrenal GR, DNMT3a/3b, miRNA let-7c increased while those of CTCF, H19, and StAR decreased, and the total methylation rate of the H19 promoter region was enhanced. We used SW-13 cells to clarify the molecular mechanism and found that cortisol-induced in vitro changes of these indexes were consistent with those in vivo. We confirmed that high level of cortisol through activating GR, on the one hand, promoted let-7 expression and inhibited StAR expression; on the other hand, caused high methylation and low expression of H19 by down-regulating CTCF and up-regulating DNMT3a/3b, then enhanced let-7 inhibitory effect on StAR by "molecular sponge" effect. Finally, in vivo experiments showed that the adrenal steroid synthesis function and H19/let-7 axis presented the glucocorticoid-dependent changes in the adult female F1, F2, and F3. In conclusion, PCE can cause female adrenal dysfunction with matrilineal multi-generation inheritance, which is related to the programming alteration of the H19/let-7 axis. This study provides a novel perspective to explain the multi-generation inheritance of fetal-originated disease in IUGR offspring.


Assuntos
Cafeína , Efeitos Tardios da Exposição Pré-Natal , Animais , Corticosterona , Feminino , Retardo do Crescimento Fetal/induzido quimicamente , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Ratos Wistar
3.
Chin J Physiol ; 64(4): 186-193, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34472449

RESUMO

Adult hippocampal neurogenesis (AHN) is suppressed by chronic stress. The negative effect of stress is mainly attributed to increased levels of stress hormones (e.g. glucocorticoids, GCs). Exercise enhances AHN, yet it also stimulates GC secretion. To delineate the paradoxical role of GCs, we took the advantage of a unique mouse strain (L/L) which exhibits an inert response to stress-induced secretion of GCs to study the role of GCs in exercise-induced AHN. Our results showed that basal corticosterone (CORT), the main GCs in rodents, levels were similar between the L/L mice and wild-type (WT) mice. However, levels of CORT in the L/L mice were barely altered and significantly lower than those of the WT mice during treadmill running (TR). AHN was enhanced by 4 weeks of TR in the WT mice, but not L/L mice. WT mice that received daily injection of CORT to evoke serum CORT levels similar to those during exercise for 4 weeks did not affect AHN, whereas injection with large amount of CORT inhibited AHN. Taken together, our results indicated that exercise-related elevation of CORT participates in exercise-enhanced AHN. CORT alone is not sufficient to elicit AHN and may inhibit AHN if the levels are high.


Assuntos
Corticosterona , Corrida , Animais , Glucocorticoides , Hipocampo , Camundongos , Neurogênese
4.
Toxicol Lett ; 351: 155-162, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34517056

RESUMO

Perfluorooctanoic acid (PFOA), a member of the Per- and polyfluoroalkyl substances, is a highly persistent "forever" chemicals with increasing concern for its potential health effects. However, the mechanisms of PFOA immunotoxic effects are poorly understood. We assessed the antibody response to a physiological antigen stimulation and associated cytokine response upon PFOA exposure. The significant decrease in the IgM antibody response to the T cell dependent antigen keyhole limpet hemocyanin (KLH) at a dose lower than the previously documented LOAEL was accompanied by a significant reduction of the Th2 serum cytokines IL-5 and IL-13, a non-significant dose-response reduction of IL-4, a significant reduction of the Th1 cytokine IL-12, and a non-significant dose-response increase in IL-2 and IFNγ. PFOA significantly decreased the pro-inflammatory cytokines IL-17α and IL-1α, decreased (non-significantly but dose-response) IL-6, and a significantly increased TNFα. Overall, the modulation of serum Th1/Th2 cytokines could explain the reduction in antibody response, pointing to a potential role for T helper cells in the immunotoxicity of PFOA. Further, the higher than anticipated weight loss and increased liver weight, compared to previous studies using similar doses, highlight the potential importance of the route and duration of exposure, contributing to the total accumulated dose, in assessing the toxicity of PFOA.


Assuntos
Caprilatos/toxicidade , Citocinas/metabolismo , Fluorcarbonetos/toxicidade , Imunoglobulina M/metabolismo , Animais , Corticosterona/metabolismo , Citocinas/genética , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hemocianinas/imunologia , Camundongos
5.
Dokl Biochem Biophys ; 499(1): 247-250, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34426921

RESUMO

The aim of the work was to study changes in the time range of heart rate variability (HRV) against the background of changes in the concentration of corticosterone in blood plasma in rats after surgical trauma to the nasal septum. Septoplasty was simulated in 30 mature male Wistar rats weighing 210-290 g. ECG was recorded with subsequent analysis of the time domain of HRV, as well as blood sampling to estimate changes in the concentration of corticosterone in the blood plasma was performed. As a result, SDNN significantly increased in comparison with the control on days 2 and 3 (p < 0.001) but decreased on days 4-5 (p < 0.001) and 6 (p < 0.01). rMSSD changed in waves with two irregular peaks on days 1 and 6. SDNN/rMSSD, in comparison with the 1st day of the postoperative period, increased on the 2nd day, continued to increase (p < 0.05), and then began to decrease on day 4 (p < 0.01). The total HRV power of was low throughout the postoperative period (p < 0.001), except for day 3, when it was equal to the control data. The increase in the total power index fell on day 3 after the operation (p <0.01), after which its decline was observed again. The concentration of corticosterone in the blood plasma in rats was significantly higher than before (p < 0.001). On postoperative day 2 to 4, its plateau was determined. Simulation of septoplasty leads to changes in the time range of HRV, an increase in the concentration of corticosterone in the blood plasma in rats with its maximum at the time of surgery and 24 h later, and the formation of a "plateau" on postoperative days 2 to 4, which coincides with the changes in HRV.


Assuntos
Corticosterona/sangue , Frequência Cardíaca , Septo Nasal/lesões , Septo Nasal/cirurgia , Animais , Masculino , Ratos , Ratos Wistar , Fatores de Tempo
6.
Molecules ; 26(16)2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34443522

RESUMO

Five new thiohydantoin derivatives (1-5) were isolated from the rhizomes of Lepidium meyenii Walp. NMR (1H and 13C NMR, 1H-1H COSY, HSQC, and HMBC), HRESIMS, and ECD were employed for the structure elucidation of new compounds. Significantly, the structure of compound 1 was the first example of thiohydantoins with thioxohexahydroimidazo [1,5-a] pyridine moiety. Additionally, compounds 2 and 3 possess rare disulfide bonds. Except for compound 4, all isolates were assessed for neuroprotective activities in corticosterone (CORT)-stimulated PC12 cell damage. Among them, compound (-)-3 exhibited moderate neuroprotective activity (cell viability: 68.63%, 20 µM) compared to the positive control desipramine (DIM) (cell viability: 88.49%, 10 µM).


Assuntos
Lepidium/química , Fármacos Neuroprotetores/química , Extratos Vegetais/química , Tioidantoínas/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Corticosterona/farmacologia , Desipramina/farmacologia , Humanos , Fármacos Neuroprotetores/farmacologia , Células PC12 , Extratos Vegetais/farmacologia , Piridinas/química , Ratos , Tioidantoínas/isolamento & purificação
7.
ACS Chem Neurosci ; 12(16): 2981-3001, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34339164

RESUMO

We explored sex-biased effects of the primary stress glucocorticoid hormone corticosterone on the miRNA expression profile in the rat hippocampus. Adult adrenalectomized (ADX) female and male rats received a single corticosterone (10 mg/kg) or vehicle injection, and after 6 h, hippocampi were collected for miRNA, mRNA, and Western blot analyses. miRNA profiling microarrays showed a basal sex-biased miRNA profile in ADX rat hippocampi. Additionally, acute corticosterone administration triggered a sex-biased differential expression of miRNAs derived from genes located in several chromosomes and clusters on the X and 6 chromosomes. Putative promoter analysis unveiled that most corticosterone-responsive miRNA genes contained motifs for either direct or indirect glucocorticoid actions in both sexes. The evaluation of transcription factors indicated that almost 50% of miRNA genes sensitive to corticosterone in both sexes was under glucocorticoid receptor regulation. Transcription factor-miRNA regulatory network analyses identified several transcription factors that regulate, activate, or repress miRNA expression. Validated target mRNA analysis of corticosterone-responsive miRNAs showed a more complex miRNA-mRNA interaction network in males compared to females. Enrichment analysis revealed that several hippocampal-relevant pathways were affected in both sexes, such as neurogenesis and neurotrophin signaling. The evaluation of selected miRNA targets from these pathways displayed a strong sex difference in the hippocampus of ADX-vehicle rats. Corticosterone treatment did not change the levels of the miRNA targets and their corresponding tested proteins. Our data indicate that corticosterone exerts a sex-biased effect on hippocampal miRNA expression, which may engage in sculpting the basal sex differences observed at higher levels of hippocampal functioning.


Assuntos
Corticosterona , MicroRNAs , Adrenalectomia , Animais , Corticosterona/farmacologia , Feminino , Hipocampo/metabolismo , Masculino , MicroRNAs/genética , Ratos , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo
8.
Toxicol Lett ; 351: 78-88, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34454011

RESUMO

We previously found that prenatal ethanol exposure (PEE) induced adrenal dysplasia in offspring, which was related to intrauterine maternal glucocorticoid overexposure. This study investigated the intergenerational genetic effect and sex differences of PEE-induced changes in the synthetic function of adrenal corticosterone in offspring, and to clarify the intrauterine origin programming mechanism. Wistar pregnant rats were gavaged with ethanol (4 g/kg bw/d) from gestation day (GD) 9-20, and F1 generation was born naturally. The F1 generation female rats in the PEE group were mated with normal male rats to produce F2 generation. Serum and adrenal glands of fetal rats and F1/F2 adult rats were collected at GD20 and postnatal week 28. PEE increased the serum corticosterone level, while diminishing the expression of adrenal steroid synthases of fetal rats. Moreover, PEE enhanced the mRNA expression of GR and HDAC1, but inhibited the mRNA expression of SF1 and reduced the H3K9ac level of P450scc in the fetal adrenal gland. In PEE adult offspring of F1 and F2 generation the serum corticosterone level, the H3K9ac level of P450scc and its expression were decreased in males but were increased in females. In NCI-H295R cells, cortisol reduced the production of endogenous cortisol, down-regulated SF1, and up-regulated HDAC1 expression by activating GR, and decreased H3K9ac level and expression of P450scc. In conclusion, PEE could induce adrenal dysplasia in offspring with sex differences and intergenerational genetic effects, and the adrenal insufficiency in male offspring was related to the induction of low functional genetic programming of P450scc by intrauterine high corticosterone through the GR/SF1/HDAC1 pathway.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Corticosterona/biossíntese , Etanol/toxicidade , Glândulas Suprarrenais/crescimento & desenvolvimento , Animais , Linhagem Celular , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Hidrocortisona , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , Ratos , Ratos Wistar , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Fatores Sexuais , Organismos Livres de Patógenos Específicos
9.
Psychopharmacology (Berl) ; 238(9): 2555-2568, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34342672

RESUMO

RATIONALE: Guanosine has been shown to potentiate ketamine's antidepressant-like actions, although its ability to augment the anxiolytic effect of ketamine remains to be determined. OBJECTIVE: This study investigated the anxiolytic-like effects of a single administration with low doses of ketamine and/or guanosine in mice subjected to chronic administration of corticosterone and the role of NLRP3-driven signaling. METHODS: Corticosterone (20 mg/kg, p.o.) was administered for 21 days, followed by a single administration of ketamine (0.1 mg/kg, i.p.), guanosine (0.01 mg/kg, p.o.), or ketamine (0.1 mg/kg, i.p.) plus guanosine (0.01 mg/kg, p.o.). Anxiety-like behavior and NLRP3-related targets were analyzed 24 h following treatments. RESULTS: Corticosterone reduced the time spent in the open arms and the central zone in the elevated plus-maze test and open-field test, respectively. Corticosterone raised the number of unsupported rearings and the number and time of grooming, and decreased the latency to start grooming in the open-field test. Disturbances in regional distribution (increased rostral grooming) and grooming transitions (increased aborted and total incorrect transitions) were detected in corticosterone-treated mice. These behavioral alterations were accompanied by increased immunocontent of Iba-1, ASC, NLRP3, caspase-1, TXNIP, and IL-1ß in the hippocampus, but not in the prefrontal cortex. The treatments with ketamine, guanosine, and ketamine plus guanosine were effective to counteract corticosterone-induced anxiety-like phenotype, but not disturbances in the hippocampal NLRP3 pathway. CONCLUSIONS: Our study provides novel evidence that low doses of ketamine and/or guanosine reverse corticosterone-induced anxiety-like behavior and shows that the NLRP3 inflammasome pathway is likely unrelated to this response.


Assuntos
Ketamina , Animais , Ansiedade/induzido quimicamente , Ansiedade/tratamento farmacológico , Comportamento Animal , Corticosterona , Depressão , Guanosina , Hipocampo , Inflamassomos , Ketamina/farmacologia , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR
10.
Artigo em Inglês | MEDLINE | ID: mdl-34224981

RESUMO

Corticosterone (CORT)-mediated adaptive plasticity improves animal fitness in stressful environments. Although it brings ecological benefits, the cost potentially constrains its expression and evolution. Revealing the factors affecting plasticity costs is of great ecological and evolutionary significance. Evidence indicates that both CORT and background colour can induce metabolic changes in animals, which in turn determine phenotypic plasticity. However, whether and/or how CORT and background colour jointly act on plastic responses has not been studied. Here, this question has been investigated in amphibian tadpoles (Microhyla fissipes) exposed to CORT at different background colours (white or black) using integrated morphological, histological, and transcriptomic analyses. The results showed that CORT exposure increased relative tail length, immune function, and metabolic maintenance (i.e., transcription of substrate catabolism and oxidative phosphorylation) at the expense of reduction in growth rate and skin melanin level. The black background also increased relative tail length and metabolic maintenance (i.e., transcription of oxidative phosphorylation) at the cost of reduction in growth rate, but increased skin melanin level. The expression of critical pigmentation genes indicated that black background activated a distinct and opposite pigmentation regulating route to CORT. Although there was no interactive effect of background colour and CORT on phenotypic and metabolic variations, their additive effects further impact the trade-off between somatic growth, metabolic maintenance, and pigmentation in terms of resource allocation. In conclusion, the individual and additive effects of background colour and CORT exposure on tadpole plasticity were revealed. These results likely provide new insights into the environmental adaptation of animals.


Assuntos
Adaptação Fisiológica , Anuros/fisiologia , Cor , Corticosterona/farmacologia , Larva/fisiologia , Pigmentação , Estresse Fisiológico , Animais , Anti-Inflamatórios/farmacologia , Regulação da Expressão Gênica , Larva/efeitos dos fármacos , Transcriptoma
11.
Poult Sci ; 100(9): 101361, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34320452

RESUMO

The measurement of feather corticosterone concentrations (fCORT) is a comparatively new method for the evaluation of stress in wild and captive birds and may be a useful indicator in animal welfare research. The aim of this study was to assess the suitability of fCORT as an indicator of stress, and for this purpose a prolonged stress period was experimentally simulated by oral intake of corticosterone via drinking water and corticosterone concentrations were analyzed in feathers grown during this period. Layer pullets of both a control group (n = 20) and a CORT group (n = 20) were offered drinking water ad libitum throughout the entire experimental phase. The drinking water of the CORT group was supplemented with corticosterone at a concentration of 20 mg/l from the 64th to the 114th day of life. The vaned parts of the primaries 5 (P5s) were clipped on d 114 and fCORT was analyzed by ELISA after extraction. Body weights increased from day 64 until d 114 in both groups, however, at the end of the experiment, mean body mass in the CORT group was significantly lower than in the control group (P < 0.001). Pullets of the CORT group also showed shorter and lighter P5s as well as a retarded molt of the primaries. The supplementation of drinking water with corticosterone increased the average fCORT in the P5s of the CORT pullets compared with the control group (median: 110.3 pg/mm [interquartile range (IQR): 47.2] vs. 10.0 pg/mm [IQR: 2.5], P < 0.001). The results show that experimentally increased systemic corticosterone concentrations over a period of seven weeks in layer pullets are reflected in corticosterone concentrations of feathers grown during that time. This indicates that the measurement of fCORT may be a useful and minimally invasive tool for the evaluation of long-term stress in chicken and provides the basis for further investigations on its use in animal welfare research.


Assuntos
Água Potável , Plumas , Animais , Galinhas , Corticosterona , Suplementos Nutricionais , Feminino
12.
Behav Neurosci ; 135(3): 380-388, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34264691

RESUMO

Environmental enrichment (EE) has been a widely used tool to improve animal welfare, as well as to study brain plasticity. Traditional EE settings in the field of neuroscience employ highly complex cages with numerous objects and increased space, whereas more simple additions included for the control treatment are rarely considered in the experimental design. This leads to a lack of consistency of what neuroscientists designate as "standard housing," which might compromise the reproducibility of the results. Therefore, we employed standard-sized cages to study how different EE configurations can affect several biological markers of animal welfare. We first compared barren cages with cages containing nest material and a cardboard roll or cages having a complex set of elements. For this purpose, we studied anxiety-like behavior, corticosterone metabolites in feces, and cell survival in the hippocampus. Complex enrichment (CE) increased the concentration of corticosterone metabolites while also decreasing anxiety-like behavior. Interestingly, both simple and CEs were able to promote cell survival in the hippocampus, and this measure was positively correlated to corticosterone metabolites. Furthermore, in a second experiment, one of the elements of the CE was able to reduce anxiety-like behavior and blood glucose reactivity after exposure to a stressful situation. Altogether, this study calls attention about how sensitive experimental outcomes are to these simple EE elements. Even though EE is recommended by most guidelines for the care and use of laboratory animals, a detailed analysis of the EE protocol that is going to be implemented is highly encouraged. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Meio Ambiente , Comportamento Exploratório , Animais , Comportamento Animal , Corticosterona , Feminino , Abrigo para Animais , Camundongos , Reprodutibilidade dos Testes
13.
Poult Sci ; 100(8): 101294, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34237550

RESUMO

Cold temperature is a common environmental stressor that induces pathophysiological stress in birds with profound economic losses. Current methods used for preventing cold stress, such as reducing ventilation and using gas heaters, are facing challenges due to poor indoor air quality and deleterious effects on bird and caretaker health. The aim of this study was to examine if the novel designed warmed perch system, as a thermal device, can reduce cold stress-associated adverse effects on laying hens. Seventy-two 32-week-old DeKalb hens were randomly assigned to 36 cages arranged to 3 banks. The banks were assigned to 1 of 3 treatments: cages with warmed perches (WP; perches with circulating water at 30°C), air perches (AP, regular perches only), or no perches (NP) for a 21-d trial. The room temperature was set at 10°C during the entire experimental period. Rectal temperature and body weight were measured from the same bird of each cage at d 1, 8, 15, and 21 during the cold exposure. Egg production was recorded daily. Feed intake, egg and eggshell quality were determined during the 1st and 3rd wk of cold stress. Plasma levels of corticosterone, thyroid hormones (3, 3', 5-triiodothyronine and thyroxine), interleukin (IL)-6 and IL-10, were determined after 1 d and 21 d of cold exposure. Compared to both AP and NP hens, WP hens were able to maintain their body temperature without increasing feed intake and losing BW. The eggs from WP hens had thicker eggshell during the 3rd wk of cold exposure. Warmed perch hens also had a lower thyroxine conversion rate (3, 3', 5-triiodothyronine/thyroxine) at d 1, while higher plasma concentrations of IL-6 at d 21. Plasma levels of corticosterone, 3, 3', 5-triiodothyronine, and IL-10 were not different among treatments. Our results indicate that the warmed perch system can be used as a novel thermal device for preventing cold stress-induced negative effects on hen health and welfare through regulating immunity and metabolic hormonal homeostasis.


Assuntos
Abrigo para Animais , Percas , Criação de Animais Domésticos , Bem-Estar do Animal , Animais , Galinhas , Temperatura Baixa , Resposta ao Choque Frio , Corticosterona , Feminino , Oviposição , Óvulo
14.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206322

RESUMO

Increasing epidemiological evidence highlights the association between systemic insulin resistance and Alzheimer's disease (AD). As insulin resistance can be caused by high-stress hormone levels and since hypercortisolism appears to be an important risk factor of AD, we aimed to investigate the systemic insulin functionality and circulating stress hormone levels in a mutant humanized amyloid precursor protein (APP) overexpressing (hAPP23+/-) AD mouse model. Memory and spatial learning of male hAPP23+/- and C57BL/6 (wild type, WT) mice were assessed by a Morris Water Maze (MWM) test at the age of 4 and 12 months. The systemic metabolism was examined by intraperitoneal glucose and insulin tolerance tests (GTT, ITT). Insulin and corticosterone levels were determined in serum. In the hippocampus, parietal and occipital cortex of hAPP23+/- brains, amyloid-beta (Aß) deposits were present at 12 months of age. MWM demonstrated a cognitive decline in hAPP23+/- mice at 12 but not at 4 months, evidenced by increasing total path lengths and deteriorating probe trials compared to WT mice. hAPP23+/- animals presented increased serum corticosterone levels compared to WT mice at both 4 and 12 months. hAPP23+/- mice exhibited peripheral insulin resistance compared to WT mice at 4 months, which stabilized at 12 months of age. Serum insulin levels were similar between genotypes at 4 months of age but were significantly higher in hAPP23+/- mice at 12 months of age. Peripheral glucose homeostasis remained unchanged. These results indicate that peripheral insulin resistance combined with elevated circulating stress hormone levels could be potential biomarkers of the pre-symptomatic phase of AD.


Assuntos
Doença de Alzheimer/sangue , Biomarcadores/sangue , Disfunção Cognitiva , Corticosterona/sangue , Resistência à Insulina , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Síndrome de Cushing/complicações , Modelos Animais de Doenças , Insulina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
15.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203952

RESUMO

Endocannabinoids play a role in adaptation to stress and regulate the release of glucocorticoids in stressed and unstressed conditions. We recently found that basal corticosterone pulsatility may significantly impact the vulnerability for developing post-traumatic-stress-disorder (PTSD), suggesting that the endocannabinoid system may contribute to its development. To examine this, we exposed rats to predator scent stress (PSS). Behavioral reactions were recorded seven days post-PSS. Cerebrospinal fluid (CSF) was collected from anesthetized rats shortly after PSS exposure to determine the levels of 2-arachidonoyl glycerol (2-AG) and anandamide (AEA). To correlate between endocannabinoids and corticosterone levels, rats were placed in metabolic cages for urine collection. To assess the levels of endocannabinoids in specific brain regions, rats' brains were harvested one day after behavioral analysis for staining and fluorescence quantification. Moreover, 2-AG was elevated in the CSF of PTSD-phenotype rats as compared with other groups and was inversely correlated with corticosterone urinary secretion. Eight days post-PSS exposure, hippocampal and hypothalamic 2-AG levels and hippocampal AEA levels were significantly more reduced in the PTSD-phenotype group compared to other groups. We posit that maladaptation to stress, which is propagated by an abnormal activation of endocannabinoids, mediates the subsequent stress-induced behavioral disruption, which, later, reduces neuronal the expression of endocannabinoids, contributing to PTSD symptomology.


Assuntos
Endocanabinoides/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/patologia , Transtornos de Estresse Pós-Traumáticos/patologia , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Animais , Comportamento Animal , Corticosterona/urina , Endocanabinoides/líquido cefalorraquidiano , Masculino , Fenótipo , Ratos Sprague-Dawley , Transtornos de Estresse Pós-Traumáticos/urina , Estresse Psicológico/urina
16.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205191

RESUMO

Previously, we found that basal corticosterone pulsatility significantly impacts the vulnerability for developing post-traumatic stress disorder (PTSD). Rats that exhibited PTSD-phenotype were characterized by blunted basal corticosterone pulsatility amplitude and a blunted corticosterone response to a stressor. This study sought to identify the mechanisms underlining both the loss of pulsatility and differences in downstream responses. Serial blood samples were collected manually via jugular vein cannula at 10-min intervals to evaluate suppression of corticosterone following methylprednisolone administration. The rats were exposed to predator scent stress (PSS) after 24 h, and behavioral responses were assessed 7 days post-exposure for retrospective classification into behavioral response groups. Brains were harvested for measurements of the glucocorticoid receptor, mineralocorticoid receptor, FK506-binding protein-51 and arginine vasopressin in specific brain regions to assess changes in hypothalamus-pituitary-adrenal axis (HPA) regulating factors. Methylprednisolone produced greater suppression of corticosterone in the PTSD-phenotype group. During the suppression, the PTSD-phenotype rats showed a significantly more pronounced pulsatile activity. In addition, the PTSD-phenotype group showed distinct changes in the ventral and dorsal CA1, dentate gyrus as well as in the paraventricular nucleus and supra-optic nucleus. These results demonstrate a pre-trauma vulnerability state that is characterized by an over-reactivity of the HPA and changes in its regulating factors.


Assuntos
Encéfalo/metabolismo , Corticosterona/sangue , Angústia Psicológica , Transtornos de Estresse Pós-Traumáticos/genética , Animais , Arginina Vasopressina/sangue , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Humanos , Metilprednisolona/farmacologia , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Receptores de Glucocorticoides/sangue , Receptores de Mineralocorticoides/sangue , Transtornos de Estresse Pós-Traumáticos/sangue , Transtornos de Estresse Pós-Traumáticos/patologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Proteínas de Ligação a Tacrolimo/sangue
17.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206635

RESUMO

White matter tract (WMT) degeneration has been reported to occur following a stroke, and it is associated with post-stroke functional disturbances. White matter pathology has been suggested to be an independent predictor of post-stroke recovery. However, the factors that influence WMT remodeling are poorly understood. Cortisol is a steroid hormone released in response to prolonged stress, and elevated levels of cortisol have been reported to interfere with brain recovery. The objective of this study was to investigate the influence of corticosterone (CORT; the rodent equivalent of cortisol) on WMT structure post-stroke. Photothrombotic stroke (or sham surgery) was induced in 8-week-old male C57BL/6 mice. At 72 h, mice were exposed to standard drinking water ± CORT (100 µg/mL). After two weeks of CORT administration, mice were euthanised and brain tissue collected for histological and biochemical analysis of WMT (particularly the corpus callosum and corticospinal tract). CORT administration was associated with increased tissue loss within the ipsilateral hemisphere, and modest and inconsistent WMT reorganization. Further, a structural and molecular analysis of the WMT components suggested that CORT exerted effects over axons and glial cells. Our findings highlight that CORT at stress-like levels can moderately influence the reorganization and microstructure of WMT post-stroke.


Assuntos
Corticosterona/administração & dosagem , Gliose/metabolismo , Gliose/patologia , Vias Neurais/efeitos dos fármacos , Acidente Vascular Cerebral/metabolismo , Substância Branca/efeitos dos fármacos , Substância Branca/fisiologia , Animais , Axônios/metabolismo , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Modelos Animais de Doenças , Progressão da Doença , Suscetibilidade a Doenças , Gliose/tratamento farmacológico , Gliose/etiologia , Imuno-Histoquímica , Masculino , Camundongos , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia
18.
Nature ; 595(7867): 409-414, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34194038

RESUMO

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.


Assuntos
Encéfalo/citologia , Encéfalo/fisiologia , Microbioma Gastrointestinal/fisiologia , Neurônios/metabolismo , Comportamento Social , Estresse Psicológico , Animais , Corticosterona/sangue , Hormônio Liberador da Corticotropina/metabolismo , Enterococcus faecalis/metabolismo , Vida Livre de Germes , Glucocorticoides/metabolismo , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais
19.
Behav Neurosci ; 135(5): 622-628, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34323518

RESUMO

The developmental onset of aversive learning processes depends on complex interactions between endocrine, neural, and social influences. Emergence of avoidance conditioning in rat pups is triggered by elevated plasma corticosterone activating the amygdala. Further, the mother's ability to buffer the corticosterone response delays the onset of avoidance in ˜2-week-old pups. Eyeblink conditioning (EBC) also develops during the pre-weaning period. In previous work, little or no conditioning was observed on Day 17 for pups housed in the home cage with mother and littermates between training sessions, whereas pups isolated between training sessions did show some conditioning. This suggests that social buffering may also delay the onset of this form of aversive learning. In the present study with Day-17 pups, one session of periorbital shock, the typical EBC unconditioned stimulus for young rat pups, resulted in lower plasma corticosterone levels and neural activity in the central nucleus of the amygdale (CeA) of pups returned to the mother and homecage following the session as compared to pups isolated following the shock session. These findings demonstrate social buffering of the physiological response to aversive stimulus exposure under conditions of EBC and support the hypothesis that social buffering of early adverse experience may adjust the timing of emergence of EBC in rat pups. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Condicionamento Palpebral , Corticosterona , Tonsila do Cerebelo , Animais , Piscadela , Condicionamento Clássico , Feminino , Humanos , Mães , Ratos
20.
J Vet Intern Med ; 35(5): 2152-2158, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34331479

RESUMO

BACKGROUND: The frequency with which multiple corticosteroid abnormalities occur in cats with aldosterone secreting adrenocortical tumors is unknown. OBJECTIVES: To evaluate adrenal-derived corticosteroids in cats in which blood samples were submitted for measure of aldosterone. ANIMALS: Two hundred ninety-seven cats. METHODS: Retrospective study. Analysis of a convenience sample of previously submitted serum or plasma. Progesterone, corticosterone, and cortisol were measured in feline serum or plasma samples submitted to an endocrinology laboratory for aldosterone measurements. Demographics and clinical history were retrieved from submittal forms when provided. Statistical testing was performed to investigate associations among the adrenal corticosteroids. RESULTS: Progesterone and corticosterone concentrations were strongly correlated (ρ = 0.74; P < .001). Progesterone (median, 5 nmol/L; interquartile range, 3-10 nmol/L) and corticosterone (113 nmol/L, 38-250 nmol/L) in cats with markedly increased aldosterone concentrations (≥3000 pmol/L) were higher than progesterone (1 nmol/L, 1-2 nmol/L) and corticosterone (12 nmol/L, 3-25 nmol/L) in cats with normal aldosterone concentrations (P < .001 for both comparisons). Progesterone concentrations ≥10 nmol/L (normal, ≤2 nmol//L) occurred in 24 of 76 (32%) cats with aldosterone concentrations ≥3000 pmol/L. Cortisol was lower in cats with aldosterone concentrations ≥3000 pmol/L as compared to those with aldosterone concentrations <500 pmol/L (59 nmol/L, 27-103 nmol/L vs 103 nmol/L, 49-182 nmol/L; P = .002). CONCLUSIONS AND CLINICAL IMPORTANCE: Multiple corticosteroid abnormalities occur in a subset of cats with hyperaldosteronism. The magnitude of increases in progesterone and corticosterone in some cats with hyperaldosteronism is likely to be clinically relevant.


Assuntos
Doenças do Gato , Hiperaldosteronismo , Hormônio Adrenocorticotrópico , Aldosterona , Animais , Gatos , Corticosterona , Hidrocortisona , Hiperaldosteronismo/veterinária , Estudos Retrospectivos
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