RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Modified Danzhi Xiaoyao San (MDXS) is an effective clinical prescription for depression in China, which was deprived of Danzhi Xiaoyao San in the Ming Dynasty. MDSX has significant implications for the development of new antidepressants, but its pharmacological mechanism has been rarely studied. AIM OF THE STUDY: To reveal the active components and molecular mechanism of MDXS in treating depression through network pharmacology and experimental verification in vivo and in vitro. MATERIALS AND METHODS: UPLC-Q-TOF-MS/MS was used to identify the chemical components in the MDXS freeze-dried powder, drug-containing serum, and cerebrospinal fluid (CSF). Based on the analysis of prototype components in the CSF, the major constituents, potential therapeutic targets and possible pharmacological mechanisms of MDXS in treating depression were investigated using network pharmacological and molecular docking. Then corticosterone (CORT)-induced mice model of depression was established to investigate the antidepressant effects of MDXS. HT22 cells were cultured to verify the neuroprotective effects and core targets of the active components. RESULTS: There were 81 compounds in MDXS freeze-dried powder, 36 prototype components in serum, and 13 prototype components in CSF were identified, respectively. Network pharmacology analysis showed that these 13 prototype components in the CSF shared 190 common targets with depression, which were mainly enriched in MAPK and PI3K/AKT signaling pathways. PPI analysis suggested that AKT1 and MAPK1 (ERK1/2) were the core targets. Molecular docking revealed that azelaic acid (AA), senkyunolide A (SA), atractylenolide III (ATIII), and tokinolide B (TB) had the highest binding energy with AKT1 and MAPK1. Animal experiments verified that MDXS could reverse CORT-induced depression-like behaviors, improve synaptic plasticity, alleviate neuronal injury in hippocampal CA3 regions, and up-regulate the protein expression of p-ERK1/2 and p-AKT. In HT22 cells, azelaic acid, senkyunolide A, and atractylenolide III significantly protected the cell injury caused by CORT, and up-regulated the protein levels of p-ERK1/2 and p-AKT. CONCLUSIONS: These results suggested that MDXS may exert antidepressant effects partially through azelaic acid, senkyunolide A, and atractylenolide III targeting ERK1/2 and AKT.

Asunto(s)

Antidepresivos , Depresión , Medicamentos Herbarios Chinos , Simulación del Acoplamiento Molecular , Farmacología en Red , Animales , Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Ratones , Masculino , Línea Celular , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Corticosterona/sangre , Espectrometría de Masas en Tándem , Conducta Animal/efectos de los fármacos

RESUMEN

Schizophrenia (SCH) is a mental disorder that requires long-term antipsychotic treatment. SCH patients are thought to have an increased sensitivity to stress. The dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, observed in SCH, could include altered levels of glucocorticoids, glucocorticoid receptors (GRs), and associated proteins. The perinatal administration of phencyclidine (PCP) to rodents represents an animal model of SCH. This study investigated the effects of perinatal PCP exposure and subsequent haloperidol/clozapine treatment on corticosterone levels measured by ELISA and the expression of GR-related proteins (GR, pGR, HSP70, HSP90, FKBP51, and 11ß-Hydroxysteroid dehydrogenase-11ß-HSD) determined by Western blot, in different brain regions of adult rats. Six groups of male rats were treated on the 2nd, 6th, 9th, and 12th postnatal days (PN), with either PCP or saline. Subsequently, one saline and one PCP group received haloperidol/clozapine from PN day 35 to PN day 100. The results showed altered GR sensitivity in the rat brain after PCP exposure, which decreased after haloperidol/clozapine treatment. These findings highlight disturbances in the HPA axis in a PCP-induced model of SCH and the potential protective effects of antipsychotics. To the best of our knowledge, this is the first study to investigate the effects of antipsychotic drugs on the HPA axis in a PCP animal model of SCH.

Asunto(s)

Antipsicóticos , Modelos Animales de Enfermedad , Sistema Hipotálamo-Hipofisario , Fenciclidina , Sistema Hipófiso-Suprarrenal , Esquizofrenia , Animales , Fenciclidina/farmacología , Antipsicóticos/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Esquizofrenia/inducido químicamente , Masculino , Ratas , Receptores de Glucocorticoides/metabolismo , Corticosterona/sangre , Haloperidol/farmacología , Haloperidol/efectos adversos , Femenino , Clozapina/farmacología , Ratas Sprague-Dawley

RESUMEN

Pesticide exposure and its interaction with other natural stressors can play a role in amphibian population declines because disruptions in stress hormone regulatory mechanisms may inhibit immune responses during metamorphosis. Here, we determined the interactive effects of predation risk and sublethal concentration of two pesticides on immunological and physiological responses in tadpoles of the tropical frog Lithobates taylori. Using mesocosms, we used chronic exposure to three levels of chlorothalonil and ß-endosulfan in the presence or absence of Odonate larvae. Our results show that ß-endosulfan in high concentrations reduced the weight of the tadpoles and increased the neutrophil count and corticosterone (CORT) levels. Larval development was accelerated by high concentrations of chlorothalonil. Also, this pesticide in low and high concentrations increases the absolute values of lymphocytes. Tadpoles exposed to chlorothalonil increased the numbers of monocytes (in low concentrations), and lymphocytes (in high and low concentrations). The interactions of the low concentrations of both pesticides with and without the predator's presence also increased the number of lymphocytes. A combination of pesticides increases the number of lymphocytes in the blood due to synergistic cytotoxicity. This study proves that ß- endosulfan elevates circulating CORT and thus generates physiological stress in tadpoles. Given that both pesticides are widely used within the distribution of L. taylori in Costa Rica, it is likely that tadpoles' development and immune function are altered by pesticide use. In combination with stressors such as emerging diseases and altered precipitation regimes, widespread agrochemical uses likely caused this species enigmatic decline in recent decades.

Asunto(s)

Endosulfano , Larva , Nitrilos , Ranidae , Contaminantes Químicos del Agua , Animales , Nitrilos/toxicidad , Larva/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Ranidae/fisiología , Ranidae/inmunología , Endosulfano/toxicidad , Corticosterona/sangre , Conducta Predatoria/efectos de los fármacos

RESUMEN

AbstractThe overlap between spatial and physiological ecology is generally understudied, yet both fields are fundamentally related in assessing how individuals balance limited resources. Herein, we quantified the relationships between spatial ecology using two parameters of home range (annual home range area and number of burrows used in 1 yr) and four measures of physiology that integrate stress and immunity (baseline plasma corticosterone [CORT] concentration, plasma lactate concentration, heterophil-to-lymphocyte [H∶L] ratio, and bactericidal ability [BA]) in a wild free-ranging population of the gopher tortoise (Gopherus polyphemus) to test the hypothesis that space usage is correlated with physiological state. We also used structural equation models (SEMs) to test for causative relationships between the spatial and physiological parameters. We predicted that larger home ranges would be negatively correlated with traditional biomarkers of stress and positively correlated with immunity, consistent with our hypothesis that home ranges are determined based on individual condition. Males had larger home ranges, used more burrows, and had higher baseline CORT than females. We found significant negative correlations between lactate and home range (r=-0.456, df=21, P=0.029). CORT was negatively correlated with the number of burrows used in both sexes (F=7.322, df=2,20, P=0.003, adjusted R2=0.383). No correlations were observed between space use and BA or, notably, H∶L ratio. SEMs suggested that variation in the number of burrows used was a result of variation in baseline CORT. The lack of a relationship between H∶L ratio and home range suggests that home range differences are not associated with differences in chronic stress, despite the pattern between baseline CORT and number of burrows used. Instead, this study indicates that animals balance trade-offs in energetics, likely by way of baseline corticosteroid, in such a way as to maintain function across continuously variable home range strategies.

Asunto(s)

Tortugas , Animales , Tortugas/fisiología , Tortugas/sangre , Tortugas/inmunología , Masculino , Femenino , Fenómenos de Retorno al Lugar Habitual/fisiología , Corticosterona/sangre , Estrés Fisiológico/fisiología , Ácido Láctico/sangre

RESUMEN

Corticosterone, an end product of the hypothalamic-pituitary-adrenal (HPA) axis, is a crucial stress hormone. A dysregulated HPA axis and corticosterone release play pivotal roles in the onset and persistence of symptoms of stress-related psychiatric disorders, such as anxiety. The intake of nutrients, probiotics, and prebiotic supplements decreases blood corticosterone levels. The dipeptide L-carnosine is composed of beta-alanine and L-histidine and is commercially available as a nutritional supplement for recovery from fatigue. L-carnosine is involved in stress-induced corticosterone responses and anxiety behaviors in rodents. Here, we assessed the effect of L-carnosine in CD157 knockout (KO) mice, a murine model of autism spectrum disorder (ASD). The uptake of L-carnosine suppressed the increase in plasma corticosterone levels in response to acute stress and attenuated anxiety-like behaviors in CD157 KO mice. These results suggest that L-carnosine supplementation may relieve anxiety by suppressing excessive stress responses in individuals with ASD.

Asunto(s)

Ansiedad , Carnosina , Corticosterona , Suplementos Dietéticos , Ratones Noqueados , Estrés Psicológico , Animales , Corticosterona/sangre , Carnosina/farmacología , Masculino , Ratones , Modelos Animales de Enfermedad , Trastorno del Espectro Autista , Conducta Animal/efectos de los fármacos , Administración Oral , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Ratones Endogámicos C57BL , Proteínas Ligadas a GPI/metabolismo

RESUMEN

INTRODUCTION AND AIM: Vitamin D supplementation in aging subjects manifests a positive effect on various health-related parameters. We performed a functionally-histological analysis of the adrenal cortex regarding the factors of vitamin D activity and corticosterone output after vitamin D3 application in a rat model of the andropause. MATERIAL AND METHODS: Middle-aged Wistar rats were divided into sham operated (SO; n=8), orchidectomized (Orx; n=8) and vitamin D3-treated orchidectomized (Orx+vit. D; n=8) groups. Vitamin D3 (5 µg/kg b.m.) was administered subcutaneously for three weeks, while the SO and Orx groups received the vehicle alone. Set objectives were achieved using histochemistry/immunohistochemistry, stereology, ultrastructural and biochemical analyses. RESULTS: Orchidectomy (Orx) decreased the adrenal cortex-related volume densities of vascular (p<0,0001), vitamin D receptor (VDR; p<0,0166), cytochrome P450 oxidase 2R1 (CYP 2R1; p<0,0001) and cytochrome P450 oxidase 24 (CYP 24; p<0,0001) depots, but increased the volume density of cytochrome P450 27B1 (CYP 27B1; p<0,0001) depots. In Orx+vit. D rats, increase of the adrenal cortex-related volume densities of collagen (p<0,0001), VDR (p<0,0001) and CYP 2R1 (p<0,0001) depots as well as the lipid-droplet diameter (p<0,0001) in adrenocortical outer zona fasciculata cells was observed, while a decrease of volume densities of the vascular (p<0,0001), CYP 27B1 (p<0,0001) and CYP 24 (p<0,0001) depots was registered, all versus Orx group. Plasma level of ACTH was decreased (p=0,0155) and serum concentrations of 25-hydroxyvitamin D3 and corticosterone were increased (p<0,0001 and p=0,0187, respectively), all after the same treatment. CONCLUSIONS: Increased corticosterone output after vitamin D3 application to andropausal rats appears not to be related to increased availability of 25-hydroxyvitamin D3 and decreased degradation of 1,25-dihydroxyvitamin D3 in adrenal tissue, but rather involves the central regulatory mechanisms.

Asunto(s)

Corteza Suprarrenal , Andropausia , Colecalciferol , Orquiectomía , Ratas Wistar , Animales , Masculino , Corteza Suprarrenal/efectos de los fármacos , Corteza Suprarrenal/metabolismo , Corteza Suprarrenal/ultraestructura , Ratas , Andropausia/efectos de los fármacos , Corticosterona/sangre , Receptores de Calcitriol/metabolismo , Inmunohistoquímica

RESUMEN

Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system, usually diagnosed during the reproductive period. Both MS and its commonly used animal model, experimental autoimmune encephalomyelitis (EAE), exhibit sex-specific features regarding disease progression and disturbances in the neuroendocrine and endocrine systems. This study investigates the hypothalamic-pituitary-adrenal (HPA) axis response of male and female Dark Agouti rats during EAE. At the onset of EAE, Crh expression in the hypothalamus of both sexes is decreased, while males show reduced plasma adrenocorticotropic hormone levels. Adrenal gland activity is increased during EAE in both males and females, as evidenced by enlarged adrenal glands and increased StAR gene and protein expression. However, only male rats show increased serum and adrenal corticosterone levels, and an increased volume of the adrenal cortex. Adrenal 3ß-HSD protein and progesterone levels are elevated in males only. Serum progesterone levels of male rats are also increased, although testicular progesterone levels are decreased during the disease, implying that the adrenal gland is the source of elevated serum progesterone levels in males. Our results demonstrate a sex difference in the response of the HPA axis at the adrenal level, with male rats showing a more pronounced induction during EAE.

Asunto(s)

Encefalomielitis Autoinmune Experimental , Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , Animales , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Femenino , Masculino , Sistema Hipófiso-Suprarrenal/metabolismo , Ratas , Sistema Hipotálamo-Hipofisario/metabolismo , Corticosterona/sangre , Hormona Adrenocorticotrópica/sangre , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/patología , Caracteres Sexuales , Progesterona/sangre

RESUMEN

Paradoxical sleep deprivation (PSD) presents different effects on metabolism and neurological functions. In addition, over long duration, sleep restriction (SR) can promote permanent changes. The prostate is an endocrine-dependent organ with homeostatic regulation directly related to hormone levels. Our study proposed to demonstrate the experimental prostatic effects of PSD (96 h), PSD with recovery (PSR - 96/96 h), and sleep restriction (SR - 30 PSD cycles/recovery). PSD and SR promoted decrease in serum testosterone and significant increase in serum and intraprostatic corticosterone. In agreement, androgen receptors (AR) were less expressed and glucocorticoid receptors (GR) were enhanced in PSR and SR. Thus, the prostate, especially under SR, demonstrates a castration-like effect due to loss of responsiveness and sensitization by androgens. SR triggered an important inflammatory response through enhancement of serum and intraprostatic pro- (IL-1α, IL-6, TNF-α) and anti-inflammatory (IL-10) cytokines. Furthermore, the respective receptors of anti-inflammatory cytokines (IL-1RI and TNF-R) were highly expressed in the prostatic epithelium and stroma. PSR can partially restore prostate homeostasis, as it restores testosterone and the prostate proliferation index, in addition to promoting balance in the inflammatory response that is considered protective. PSD and SR are key factors in the endocrine axis that coordinate prostatic homeostasis, and significant changes in these factors have consequences on prostate functionality.

Asunto(s)

Gerbillinae , Próstata , Receptores Androgénicos , Privación de Sueño , Testosterona , Animales , Masculino , Privación de Sueño/metabolismo , Privación de Sueño/patología , Próstata/metabolismo , Próstata/patología , Testosterona/sangre , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Corticosterona/sangre , Citocinas/metabolismo , Inflamación/metabolismo , Inflamación/patología , Castración , Andrógenos/metabolismo

RESUMEN

Stress-related disorders are becoming increasingly common and are often associated with cognitive impairments. Within this context, the endocannabinoid (ECB) system, particularly the type 1 cannabinoid (CB1) receptor, seems to play a decisive role in restoring body homeostasis. There is consistent evidence in the literature that disrupted CB1-mediated neurotransmission can ultimately contribute to stress-related diseases. Therefore, the present study aimed to evaluate the participation of CB1 receptors in the integrity of stress-induced peripheral and behavioral responses. For this purpose, male adult Wistar rats underwent physical restraint (1 h/day, for 7 days), followed by a single administration of rimonabant (CB1 receptor antagonist, 3 mg/Kg, intraperitonial) at the end of stress protocol. Animals were then subjected to evaluation of neuroendocrine responses, behavioral tests and quantification of Iba-1 (microglial) immunoreactivity in the parvocellular subdivisions of the paraventricular nucleus of the hypothalamus (PVN). No effects of restraint stress or rimonabant administration were detected on body mass variation. However, stress significantly increased adrenal relative mass and corticosterone secretion, and reduced thymus relative size. The stress effects on adrenal size and corticosterone plasma levels were absent in rimonabant-treated rats, but the thymus size was further reduced in the restraint-rimonabant group. Restraint stress also induced anhedonia, a depression-like behavior, and reduced object recognition index, indicating memory recovery impairment. Treatment with the CB1 antagonist significantly reversed stress-induced anhedonia and memory deficit. In the PVN, restraint stress reduced the number of Iba-1 positive cells in the medial parvocellular region of vehicle- but not rimonabant-treated animals. Taken together, these results indicate that the acute inhibition of the CB1-mediated endogenous pathway restores stress-induced depression-like behaviors and memory loss, suggesting a role for endocannabinoids in the neuro-immune-endocrine interplay at both peripheral and hypothalamic levels.

Asunto(s)

Anhedonia , Antagonistas de Receptores de Cannabinoides , Corticosterona , Trastornos de la Memoria , Ratas Wistar , Receptor Cannabinoide CB1 , Restricción Física , Rimonabant , Estrés Psicológico , Animales , Rimonabant/farmacología , Masculino , Estrés Psicológico/metabolismo , Anhedonia/efectos de los fármacos , Anhedonia/fisiología , Ratas , Trastornos de la Memoria/tratamiento farmacológico , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB1/antagonistas & inhibidores , Corticosterona/sangre , Antagonistas de Receptores de Cannabinoides/farmacología , Núcleo Hipotalámico Paraventricular/metabolismo , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Modelos Animales de Enfermedad , Conducta Animal/efectos de los fármacos , Piperidinas/farmacología , Pirazoles/farmacología

RESUMEN

Poor maternal diet and psychosocial stress represent two environmental factors that can significantly impact maternal health during pregnancy. While various mouse models have been developed to study the relationship between maternal and offspring health and behaviour, few incorporate multiple sources of stress that mirror the complexity of human experiences. Maternal high-fat diet (HF) models in rodents are well-established, whereas use of psychosocial stress interventions in female mice are still emerging. The social instability stress (SIS) paradigm, serves as a chronic and unpredictable form of social stress. To evaluate the combined effects of a poor maternal diet and intermittent social stress on maternal health and behaviour, we developed a novel maternal stress model using adult female C57Bl/6 mice. We observed that all HF+ mice demonstrated rapid weight gain, elevated fasting blood glucose levels and impaired glucose tolerance independent of the presence (+) or absence (-) of SIS. Behavioural testing output revealed anxiety-like behaviours remained similar across all groups prior to pregnancy. However, integrated anxiety z-scores revealed a mixed anxious profile amongst HF+/SIS+ females prior to pregnancy. HF+/SIS+ females also did not show reduced plasma ACTH and corticosterone levels that were observed in our other HF+ and HF- stress groups after SIS exposure. Further, HF+/SIS+ females demonstrated significant postpartum maternal neglect, resulting in fewer numbers of live offspring. These findings suggest that prolonged maternal HF diet consumption, coupled with previous exposure to SIS, places a significant burden on the maternal stress response system, resulting in reduced parental investment and negative postpartum behaviour towards offspring.

Asunto(s)

Ansiedad , Dieta Alta en Grasa , Conducta Materna , Ratones Endogámicos C57BL , Estrés Psicológico , Femenino , Animales , Dieta Alta en Grasa/efectos adversos , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Embarazo , Ratones , Conducta Materna/fisiología , Conducta Materna/psicología , Ansiedad/metabolismo , Ansiedad/psicología , Corticosterona/sangre , Efectos Tardíos de la Exposición Prenatal/metabolismo , Conducta Animal/fisiología , Adaptación Psicológica/fisiología , Glucemia/metabolismo , Hormona Adrenocorticotrópica/sangre , Aumento de Peso/fisiología

RESUMEN

The symptoms of post-traumatic stress disorder (PTSD) include re-experiencing trauma, avoidance behaviors, negative alterations in cognition and mood. However, the underlying molecular mechanisms are unclear. Dysfunction of hypothalamic-pituitary-adrenal axis (HPA-axis) and dysregulation of glutamatergic and GABAergic systems were shown during PTSD. Therefore, regulating hormonal change or glutamate energy metabolism are considered as a therapeutic approach to alleviate this condition. Herbal medicine may be effective in treating PTSD due to its ability to target multiple underlying mechanisms with various compounds. Hominis placenta (HP) is a traditional medicine widely used in East Asia for various conditions. However, the effect on PTSD has not been clarified. We aimed to investigate the effects of HP treatment in single-prolonged stress with shock (SPSS)-induced PTSD mice and explore its possible mechanisms. HP treatment at ST36 acupoints, combined with herbal medicine and acupuncture point stimulation, was applied three times/week for 2 weeks. HP treatment effectively alleviated anxiety and cognitive decline in SPSS-induced PTSD mice, as detected by Open field and the Y-maze test. Additionally, HP decreased the corticosterone levels and proinflammatory cytokines in the serum, modulated brain energy metabolism, and inhibited glutamate excitotoxicity, while regulating neuronal activity through modulating brain-derived neurotrophic factor (BDNF) levels, as demonstrated by western blot and immunohistochemistry, and flow cytometry analyses. These findings reveal that HP treatment effectively alleviates PTSD-like behaviors by regulating energy metabolism and neuronal activity though modulation of the HPA-axis and BDNF levels in PTSD mice, indicating that HP treatment is a promising therapeutic approach for PTSD.

Asunto(s)

Conducta Animal , Metabolismo Energético , Neuronas , Trastornos por Estrés Postraumático , Animales , Trastornos por Estrés Postraumático/metabolismo , Trastornos por Estrés Postraumático/tratamiento farmacológico , Trastornos por Estrés Postraumático/psicología , Metabolismo Energético/efectos de los fármacos , Femenino , Ratones , Embarazo , Masculino , Conducta Animal/efectos de los fármacos , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Placenta/metabolismo , Modelos Animales de Enfermedad , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Ansiedad/metabolismo , Ansiedad/tratamiento farmacológico , Corticosterona/sangre , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Citocinas/metabolismo

RESUMEN

Foot-shock paradigms have provided valuable insights into the neurobiology of stress and fear conditioning. An extensive body of literature indicates that shock exposure can elicit both conditioned and unconditioned effects, although delineating between the two is a challenging task. This distinction holds crucial implications not only for the theoretical interpretation of fear conditioning, but also for properly evaluating putative preclinical models of post-traumatic stress disorder (PTSD) involving shock exposure. The characteristics of shocks (intensity and number) affect the strength of learning, but how these characteristics interact to influence conditioned and unconditioned consequences of shocks are poorly known. In this study, we aimed to investigate in adult male rats the impact of varying shock number and intensity on the endocrine and behavioral response to contextual fear conditioning and fear generalization to a novel environment markedly distinct from the shock context (i.e., fear generalization). Classical biological markers of stress (i.e., ACTH, corticosterone, and prolactin) were sensitive to manipulations of shock parameters, whereas these parameters had a limited effect on contextual fear conditioning (evaluated by freezing and distance traveled). In contrast, behavior in different novel contexts (fear generalization) was specifically sensitive to shock intensity. Notably, altered behavior in novel contexts markedly improved, but not completely normalized after fear extinction, hypoactivity apparently being the result of both conditioned and unconditioned effects of foot-shock exposure. The present results will contribute to a better understanding of shock exposure as a putative animal model of PTSD.

Asunto(s)

Hormona Adrenocorticotrópica , Condicionamiento Clásico , Corticosterona , Electrochoque , Miedo , Generalización Psicológica , Animales , Masculino , Miedo/fisiología , Miedo/psicología , Generalización Psicológica/fisiología , Condicionamiento Clásico/fisiología , Corticosterona/sangre , Ratas , Hormona Adrenocorticotrópica/sangre , Ratas Wistar

RESUMEN

Maternal separation can have long-lasting effects on an individual's susceptibility to stress later in life. Maternal separation during the postnatal period is a commonly used paradigm in rodents to investigate the effects of early life stress on neurobehavioural changes and stress responsiveness. However, maternal separation during stress hyporesponsive and responsive periods of postnatal development may differ in its effects on stress resilience. Therefore, we hypothesised that late maternal separation (LMS) from postnatal day 10 to 21 in mice may have different effect on resilience than early maternal separation during the first week of postnatal life. Our results suggested that male LMS mice are more resilient to chronic variable stress (CVS)-induced anxiety and depressive-like behaviour as confirmed by the open field, light-dark field, elevated plus maze, sucrose preference and tail suspension tests. In contrast, female LMS mice were equally resilient as non-LMS female mice. We found increased expression of NPY, NPY1R, NPY2R, NPFFR1, and NPFFR2 in the hypothalamus of male LMS mice whereas the opposite effect was observed in the hippocampus. LMS in male and female mice did not affect circulating corticosterone levels in response to psychological or physiological stressors. Thus, LMS renders male mice resilient to CVS-induced neurobehavioural disorders in adulthood.

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Sexual dimorphism exists in the effects of late maternal separation (LMS)LMS provides resilience to stress-induced anxiety and depression in male miceLMS upregulates NPY and NPVF system in the hypothalamus of male miceNo effect of LMS on stress-induced corticosterone levels.

Asunto(s)

Ansiedad , Corticosterona , Depresión , Privación Materna , Resiliencia Psicológica , Estrés Psicológico , Animales , Femenino , Masculino , Ratones , Estrés Psicológico/fisiopatología , Ansiedad/fisiopatología , Depresión/fisiopatología , Corticosterona/sangre , Conducta Animal/fisiología , Hipocampo/metabolismo , Factores Sexuales , Hipotálamo/metabolismo , Hipotálamo/fisiopatología , Neuropéptido Y/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Receptores de Neuropéptido Y

RESUMEN

BACKGROUND: Stress is one of the most common precipitating factors in migraine and is identified as a trigger in nearly 70% of patients. Responses to stress include release of glucocorticoids as an adaptive mechanism, but this may also contribute to migraine attacks. Here, we investigated the role of glucocorticoids on stress-induced migraine-like behaviors. METHODS: We have shown previously that repeated stress in mice evokes migraine-like behavioral responses and priming to a nitric oxide donor. Metyrapone, mifepristone, and corticosterone (CORT) were used to investigate whether CORT contributes to the stress-induced effects. Facial mechanical hypersensitivity was evaluated by von Frey testing and grimace scoring assessed the presence of non-evoked pain. We also measured serum CORT levels in control, stress, and daily CORT injected groups of both male and female mice. RESULTS: Metyrapone blocked stress-induced responses and priming in male and female mice. However, repeated CORT injections in the absence of stress only led to migraine-like behaviors in females. Both female and male mice showed similar patterns of serum CORT in response to stress or exogenous administration. Finally, administration of mifepristone, the glucocorticoid receptor antagonist, prior to each stress session blocked stress-induced behavioral responses in male and female mice. CONCLUSIONS: These findings demonstrate that while CORT synthesis and receptor activation is necessary for the behavioral responses triggered by repeated stress, it is only sufficient in females. Better understanding of how glucocorticoids contribute to migraine may lead to new therapeutic opportunities.

Asunto(s)

Corticosterona , Modelos Animales de Enfermedad , Glucocorticoides , Metirapona , Mifepristona , Trastornos Migrañosos , Estrés Psicológico , Animales , Trastornos Migrañosos/metabolismo , Ratones , Masculino , Femenino , Estrés Psicológico/metabolismo , Estrés Psicológico/complicaciones , Metirapona/farmacología , Corticosterona/sangre , Mifepristona/farmacología , Transducción de Señal/fisiología , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos C57BL , Conducta Animal/efectos de los fármacos

RESUMEN

The aim of the study is to understand the rationale behind the application of deep brain stimulation (DBS) in the treatment of depression. Male Wistar rats, rendered depressive with chronic unpredictable mild stress (CUMS) were implanted with electrode in the lateral hypothalamus-medial forebrain bundle (LH-MFB) and subjected to deep brain stimulation (DBS) for 4 h each day for 14 days. DBS rats, as well as controls, were screened for a range of parameters indicative of depressive state. Symptomatic features noticed in CUMS rats like the memory deficit, anhedonia, reduction in body weight and 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels in mPFC and elevated plasma corticosterone were reversed in rats subjected to DBS. DBS arrested CUMS induced degeneration of 5-HT cells in interfascicular region of dorsal raphe nucleus (DRif) and fibers in LH-MFB and induced dendritic proliferation in mPFC neurons. MFB is known to serve as a major conduit for the DRif-mPFC serotoninergic pathway. While the density of serotonin fibers in the LH-MFB circuit was reduced in CUMS, it was upregulated in DBS-treated rats. Furthermore, microinjection of 5-HT1A receptor antagonist, WAY100635 into mPFC countered the positive effects of DBS like the antidepressant and memory-enhancing action. In this background, we suggest that DBS at LH-MFB may exercise positive effect in depressive rats via upregulation of the serotoninergic system. While these data drawn from the experiments on rat provide meaningful clues, we suggest that further studies aimed at understanding the usefulness of DBS at LH-MFB in humans may be rewarding.

Asunto(s)

Estimulación Encefálica Profunda , Depresión , Haz Prosencefálico Medial , Ratas Wistar , Serotonina , Animales , Estimulación Encefálica Profunda/métodos , Masculino , Serotonina/metabolismo , Depresión/terapia , Depresión/metabolismo , Área Hipotalámica Lateral/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/terapia , Disfunción Cognitiva/terapia , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/etiología , Modelos Animales de Enfermedad , Ratas , Corticosterona/sangre , Ácido Hidroxiindolacético/metabolismo , Corteza Prefrontal/metabolismo

RESUMEN

Fear conditioning evokes a physiologic release of glucocorticoids that assists learning. As a cochaperone in the glucocorticoid receptor complex, FKBP51 modulates stress-induced glucocorticoid signaling and may influence conditioned fear responses. This study combines molecular and behavioral approaches to examine whether locally reducing FKBP51 expression in the ventral hippocampus is sufficient to affect fear-related behaviors. We hypothesized that reducing FKBP51 expression in the VH would increase glucocorticoid signaling to alter auditory fear conditioning. Adult male rats were injected with an adeno-associated virus (AAV) vector expressing short hairpin - RNAs (shRNA) targeting FKBP5 into the ventral hippocampus to reduce FKBP5 levels or a control AAV. Infusion of FKBP5-shRNA into the ventral hippocampus decreased auditory fear acquisition and recall. Although animals injected with FKBP5-shRNA showed less freezing during extinction recall, the difference was due to a reduced fear recall rather than improved extinction. Reducing ventral hippocampus FKBP51 did not affect exploratory behavior in either the open field test or the elevated zero maze test but did increase passive behavior in the forced swim test, suggesting that the reduction in auditory fear recall was not due to more active responses to acute stress. Furthermore, lower ventral hippocampus FKBP51 levels did not alter corticosterone release in response to restraint stress, suggesting that the reduced fear recall was not due to lower corticosterone release. Our findings suggest FKBP51 in the ventral hippocampus plays a selective role in modulating fear-learning processes and passive behavioral responses to acute stress rather than hypothalamic-pituitary-adrenal axis reactivity or exploratory responses.

Asunto(s)

Miedo , Hipocampo , Proteínas de Unión a Tacrolimus , Animales , Masculino , Miedo/fisiología , Proteínas de Unión a Tacrolimus/metabolismo , Proteínas de Unión a Tacrolimus/genética , Hipocampo/metabolismo , Ratas , Corticosterona/metabolismo , Corticosterona/sangre , Ratas Sprague-Dawley , ARN Interferente Pequeño/metabolismo , ARN Interferente Pequeño/genética , Receptores de Glucocorticoides/metabolismo , Extinción Psicológica/fisiología

RESUMEN

Adolescence is a critical developmental period when the brain is plastic, and stress exposure can have lasting physiological consequences. One mechanism through which adolescent stress may have lasting effects is by altering microRNAs (miRNAs), leading to wide-scale gene expression changes. Three prior independent studies used unbiased approaches (RNA sequencing or microarray) to identify miRNAs differentially expressed by chronic variable stress in male rodents. In all three studies, miRNA-200a was differentially expressed in areas of the brain associated with emotion regulation. The current study extends this research to determine if chronic non-variable adolescent stress downregulates miRNA-200a expression by looking at two strains (BALB/cJ and C57BL/6J) of male and female mice. We utilized a 14-day (2 h/day) restraint stress protocol and verified stress effects on adolescent body weight gain and circulating corticosterone concentrations relative to non-restraint controls. Mice were then left undisturbed until they were euthanized in adulthood, at which time brains were collected to measure miRNA-200a in the ventral hippocampus. Three weeks after adolescent stress ended, differences in body weight between groups were no longer significant; however, animals exposed to stress had less miRNA-200a expression in the ventral hippocampus than control animals. These data implicate miRNA-200a expression as a potential mechanism by which adolescent stress can have persistent impacts on multiple outcomes in both male and female mice.

Asunto(s)

Ratones Endogámicos C57BL , MicroARNs , Restricción Física , Estrés Psicológico , Animales , MicroARNs/genética , Femenino , Masculino , Ratones , Estrés Psicológico/genética , Ratones Endogámicos BALB C , Regulación hacia Abajo , Hipocampo/metabolismo , Corticosterona/sangre

RESUMEN

The etiology of interstitial cystitis/bladder pain syndrome (IC/BPS) is unknown but likely multifactorial. IC/BPS symptoms can be exacerbated by psychological stress, but underlying mechanisms remain to be defined. Transient receptor potential vanilloid 1 (TRPV1) channels, expressed on nerve fibers, have been implicated in bladder dysfunction and colonic hypersensitivity with stress in rodents. Histamine/H1R activation of TRPV1+ nerves increases bladder afferent fiber sensitivity to distension. TRPV1 channels are also expressed on mast cells, previously implicated in contributing to IC/BPS etiology and symptoms. We have examined the contribution of TRPV1 and mast cells to bladder dysfunction after repeated variate stress (RVS). RVS increased (P ≤ 0.05) serum and fecal corticosterone expression and induced anxiety-like behavior in wild-type (WT) mice. Intravesical instillation of the selective TRPV1 antagonist capsazepine (CPZ) rescued RVS-induced bladder dysfunction in WT mice. Trpv1 knockout (KO) mice did not increase voiding frequency with RVS and did not exhibit increased serum corticosterone expression despite exhibiting anxiety-like behavior. Mast cell-deficient mice (B6.Cg-Kitw-sh) failed to demonstrate RVS-induced increased voiding frequency or serum corticosterone expression, whereas control (no stress) mast cell-deficient mice had similar functional bladder capacity to WT mice. TRPV1 protein expression was significantly increased in the rostral lumbar (L1-L2) spinal cord and dorsal root ganglia (DRG) in WT mice exposed to RVS, but no changes were observed in lumbosacral (L6-S1) spinal segments or DRG. These studies demonstrated TRPV1 and mast cell involvement in RVS-induced increased voiding frequency and suggest that TRPV1 and mast cells may be useful targets to mitigate stress-induced urinary bladder dysfunction.NEW & NOTEWORTHY Using pharmacological tools and transgenic mice in a repeated variate stress (RVS) model in female mice, we demonstrate that transient receptor potential vanilloid 1 (TRPV1) and mast cells contribute to the increased voiding frequency observed following RVS. TRPV1 and mast cells should continue to be considered as targets to improve bladder function in stress-induced bladder dysfunction.

Asunto(s)

Corticosterona , Mastocitos , Ratones Endogámicos C57BL , Ratones Noqueados , Estrés Psicológico , Canales Catiónicos TRPV , Vejiga Urinaria , Animales , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genética , Mastocitos/metabolismo , Femenino , Vejiga Urinaria/metabolismo , Vejiga Urinaria/inervación , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo , Corticosterona/sangre , Modelos Animales de Enfermedad , Cistitis Intersticial/metabolismo , Cistitis Intersticial/fisiopatología , Cistitis Intersticial/patología , Cistitis Intersticial/genética , Ratones , Micción , Capsaicina/farmacología , Capsaicina/análogos & derivados , Conducta Animal , Ansiedad/metabolismo

RESUMEN

The thymus, where T lymphocytes develop and mature, is sensitive to insults such as tissue ischemia or injury. The insults can cause thymic atrophy and compromise T-cell development, potentially impairing adaptive immunity. The objective of this study was to investigate whether myocardial infarction (MI) induces thymic injury to impair T lymphopoiesis and to uncover the underlying mechanisms. When compared with sham controls, MI mice at day 7 post-MI exhibited smaller thymus, lower cellularity, as well as less thymocytes at different developmental stages, indicative of T-lymphopoiesis impairment following MI. Accordingly, the spleen of MI mice has less T cells and recent thymic emigrants (RTEs), implying that the thymus of MI mice releases fewer mature thymocytes than sham controls. Interestingly, the secretory function of splenic T cells was not affected by MI. Further experiments showed that the reduction of thymocytes in MI mice was due to increased thymocyte apoptosis. Removal of adrenal glands by adrenalectomy (ADX) prevented MI-induced thymic injury and dysfunction, whereas corticosterone supplementation in ADX + MI mice reinduced thymic injury and dysfunction, indicating that glucocorticoids mediate thymic damage triggered by MI. Eosinophils play essential roles in thymic regeneration postirradiation, and eosinophil-deficient mice exhibit impaired thymic recovery after sublethal irradiation. Interestingly, the thymus was fully regenerated in both wild-type and eosinophil-deficient mice at day 14 post-MI, suggesting that eosinophils are not critical for thymus regeneration post-MI. In conclusion, our study demonstrates that MI-induced glucocorticoids trigger thymocyte apoptosis and impair T lymphopoiesis, resulting in less mature thymocyte release to the spleen.NEW & NOTEWORTHY The thymus is essential for maintaining whole body T-cell output. Thymic injury can adversely affect T lymphopoiesis and T-cell immune response. This study demonstrates that MI induces thymocyte apoptosis and compromises T lymphopoiesis, resulting in fewer releases of mature thymocytes to the spleen. This process is mediated by glucocorticoids secreted by adrenal glands. Therefore, targeting glucocorticoids represents a novel approach to attenuate post-MI thymic injury.

Asunto(s)

Adrenalectomía , Apoptosis , Linfopoyesis , Ratones Endogámicos C57BL , Infarto del Miocardio , Timo , Animales , Timo/patología , Timo/inmunología , Timo/efectos de los fármacos , Infarto del Miocardio/patología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/inmunología , Infarto del Miocardio/fisiopatología , Masculino , Timocitos/metabolismo , Timocitos/patología , Timocitos/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Glucocorticoides/farmacología , Eosinófilos/metabolismo , Eosinófilos/inmunología , Bazo/inmunología , Bazo/metabolismo , Bazo/patología , Modelos Animales de Enfermedad , Ratones , Corticosterona/sangre

RESUMEN

Chronic stress refers to the activation of the hypothalamic-pituitary-adrenal (HPA) axis and elevated blood contents of ACTH and corticosterone (CORT), exhibiting significant adverse effects on health outcomes. Currently, natural polyphenol compounds are increasingly being explored as potential therapeutic agents and have been considered as a treatment option for a variety of stress-induced diseases. Curcumin (CUR) is the main substance in Curcuma longa (Zingiberacea) rhizome that has strong health-beneficial properties. The study aimed to assess the potential protective effects of CUR on hepatic oxidative stress damage and abnormal lipid deposition in a chronic CORT-induced stress (CCIS) model in broilers. One hundred and twenty experimental broilers were randomly divided into 1) control group (CON), 2) CUR group (200 mg/kg feed), 3) CORT group (4 mg/kg BW CORT) and 4) CORT+CUR group (200 mg/kg feed plus 4 mg/kg BW CORT). The liver histology, glycolipid metabolism and oxidative stress were determined. In addition, qPCR was performed to identify shifts in genes expression. Compared with CON group, broilers under CCIS showed a decreased body weight, body weight gain and average daily gain, while dietary CUR significantly reversed these adverse effects. Furthermore, the plasma contents of TCH, TG, HDL-C, LDL-C, TP, GLB and AST were all significantly increased in CCIS broilers, while dietary CUR obviously alleviated the increase of TCH, HDL-C, LDL-C and AST, and relieved the hepatic lipid deposition disorder and liver injury. Moreover, CCIS significantly increased the contents of MDA in both liver and plasma, and decreased the content of plasma SOD, while CUR obviously reversed these changes, showing reduced oxidative stress damage. Finally, the mRNA expressions of FAS, ACC, SCD and the protein level of PPAR-γ were significantly increased, meanwhile the mRNA expression of lipolytic genes ACOX1, ATGL and CPT as well as two major intracellular antioxidant enzymes SOD1 and GPX1 were obviously decreased, while CUR effectively reversed these effects. These results showed that dietary CUR effectively alleviated CCIS-induced body weight loss, hepatic oxidative damage and lipid deposition disorder, suggesting the possible therapeutic effectiveness of CUR against hepatic damage and function abnormality caused by CCIS.

Asunto(s)

Pollos , Corticosterona , Curcumina , Suplementos Dietéticos , Hígado , Estrés Oxidativo , Animales , Curcumina/farmacología , Corticosterona/sangre , Estrés Oxidativo/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Estrés Fisiológico/efectos de los fármacos , Masculino