Injection Of Corticosterone Research Articles

EFFECTS AND UNDERLYING MECHANISM OF 5-LIPOXYGENASE INHIBITOR (ZILEUTON) ON MICE DEPRESSIVE-LIKE BEHAVIOR

Objective: Treatment experiment was conducted to investigate the effectiveness and mechanism of the action of zileuton in corticosteroid-induced depressive mice model through neuroinflammation.
 Methods: The mice were randomly separated into four groups: (Veh+Veh), (Corticosteroid+Veh), (Corticosteroid+ZIL50), and (Corticosteroid+ZIL100). Intraperitoneal injection of corticosterone (CORT) (20 mg/kg for 6 weeks) was used in the mice to induce depression and neuroinflammation diverse from the Veh+Veh group, which was injected only physiological saline. The drug-treated groups (Corticosteroid+ZIL50 and Corticosteroid+ZIL100) were orally administered with the mentioned doses of zileuton. After confirming the effectiveness of zileuton through the behavioral tests, the mechanism of the action of the drug was explored through a set of biochemical assays.
 Results: Zileuton (50/100 mg/kg) administration improved the performance of the mice in the behavioral experiments (p<0.05 or 0.01). Immunohistochemistry detection of Iba1+ revealed over activation of microglial cells in the corticosteroid-treated mice which was suppressed by the zileuton (50 or 100 mg/kg [p<0.05 or 0.01]). Through Western blotting tests, it had been found that CORT (i.p.) administration led to the increment of the protein 5-Lipoxygenase in the mouse hippocampus associated with neuroinflammation, which was decreased significantly by zileuton (p<0.05 or 0.01). Level of tumor necrosis factor-alpha, interleukin-1 beta, nuclear factor kappa B p65 protein (for neuroinflammation), Bax, and cleaved caspase-3 and TUNEL assay increased, and Bcl-2 expression decreased in the CORT-induced depressive mice. These were significantly reversed by zileuton (50 or 100 mg/kg [p<0.05 or 0.01]).
 Conclusion: It can be concluded that selective 5-lipoxygenase inhibitor zileuton can efficiently inhibit the depressive-like behavior/activity in CORT-induced depressive mouse model. Moreover, the underlying mechanism may be the inhibition of hippocampal neuroinflammation and apoptosis.

Targeting the Stress System During Gestation: Is Early Handling a Protective Strategy for the Offspring?

The perinatal window is a critical developmental time when abnormal gestational stimuli may alter the development of the stress system that, in turn, influences behavioral and physiological responses in the newborns. Individual differences in stress reactivity are also determined by variations in maternal care, resulting from environmental manipulations. Despite glucocorticoids are the primary programming factor for the offspring’s stress response, therapeutic corticosteroids are commonly used during late gestation to prevent preterm negative outcomes, exposing the offspring to potentially aberrant stress reactivity later in life. Thus, in this study, we investigated the consequences of one daily s.c. injection of corticosterone (25 mg/kg), from gestational day (GD) 14–16, and its interaction with offspring early handling, consisting in a brief 15-min maternal separation until weaning, on: (i) maternal behavior; and (ii) behavioral reactivity, emotional state and depressive-like behavior in the adolescent offspring. Corticosterone plasma levels, under non-shock- and shock-induced conditions, were also assessed. Our results show that gestational exposure to corticosterone was associated with diminished maternal care, impaired behavioral reactivity, increased emotional state and depressive-like behavior in the offspring, associated with an aberrant corticosterone response. The early handling procedure, which resulted in increased maternal care, was able to counteract the detrimental effects induced by gestational corticosterone exposure both in the behavioral- and neurochemical parameters examined. These findings highlight the potentially detrimental consequences of targeting the stress system during pregnancy as a vulnerability factor for the occurrence of emotional and affective distress in the adolescent offspring. Maternal extra-care proves to be a protective strategy that confers resiliency and restores homeostasis.

Prenatal Corticosterone Exposure Alters Glucocorticoid Metabolic Enzyme Eene mRNA Associated with Increased Aggressive Behaviors and Tonic Immobility in Chicken

Exposure to excess Glucocorticoids (GCs) during embryonic development influences offspring physiology and behaviors and induces change in Hypothalamic-Pituitary-Adrenal (HPA) axis genes expression and serotonergic system in mammals. Whether prenatal corticosterone (CORT) exposure induces similar effects in avian species remains unclear. In the present study, we injected low (0.2 μg) and high (1 μg) doses of CORT in ovo before incubation and detected changes in aggressive behavior, Tonic Immobility (TI), HPA axis and 5-hydroxytryptamine (serotonin) (5-HT) system gene expression on post hatch chickens of different ages. High dose of CORT significantly (P<0.05) suppressed growth rate, increased the frequency of aggressive behaviors, which was associated with elevated plasma CORT concentration. Likewise, in ovo injection of CORT significantly (P<0.05) increased Tonic Immobility (TI) duration both in chickens from low and high doses of CORT treatments compared to control. In addition, administration of CORT significantly (P<0.05) up-regulated mRNA expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) whereas it down-regulated 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) and mineralocorticoid receptor (MR) mRNA expression in the hypothalamus. No significant differences were seen in Glucocorticoid Receptor (GR) and 20-hydroxysteroid dehydrogenase (20-HSD) mRNA levels upon CORT treatment. Moreover, CORT exposure significantly (P<0.05) increased hypothalamic 5-hydroxytryptamine (serotonin) receptor 1A (5-HTR1A) mRNA expression, but not 5-HT receptor 1B (5-HTR1B). In ovo administration of CORT may programs the aggressive behaviors in the chicken through alterations of HPA axis and 5-HT system.

Role of Hippocampal 5-HT6 Receptors in Glucocorticoid-Induced Enhancement of Memory Consolidation in Rats.

Introduction:of the study: Post-training administration of glucocorticoids enhance memory consolidation of inhibitory avoidance learning. Given the involvement of 5-HT6 receptors in memory processing and the interaction of glucocorticoids with the brain serotonergic system in modulating memory processing, we investigated whether the effect of glucocorticoids on the consolidation of emotionally arousing training depends on hippocampal 5-HT6 receptors.Methods:Rats were trained in an inhibitory avoidance task and immediately received the systemic injections of corticosterone (CORT) as well as the intra-hippocampal injections of 5-HT receptors agonist or antagonist. The memory retention test was done 48 hours after training and immediately after the behavioral test, the animals were sacrificed and the hippocampi (left and right) rapidly dissected out for molecular studies.Results:Post-training injections of different doses of CORT (1.25, 2.5, 5, and 10 mg/kg) enhanced memory retention in a dose-dependent manner. The CORT-induced enhancement of memory consolidation was blocked by bilateral intra-hippocampal injections of 5-HT6 receptor antagonist SB271046 (5 or 10 ng/per side), but not agonist EMD386088 (5 or 10 ng/per side). Furthermore, systemic CORT reduced 5-HT6 receptor mRNA and protein expression in the hippocampus. Both doses of 5-HT6 receptor agonist and antagonist significantly enhanced and reduced the expression of the 5-HT6 receptor, respectively, and both ligands at the higher dose (10 ng) enhanced memory consolidation. Moreover, CORT injection attenuated and enhanced, respectively, the effects of agonist and antagonist on 5-HT6 receptor expression.Conclusion:These behavioral and molecular findings indicated an interaction between glucocorticoids and hippocampal 5-HT6 receptors in the consolidation of emotionally arousing experiences.

Antidepressant-like mechanism of honokiol in a rodent model of corticosterone-induced depression.

Depression is closely linked to hypothalamus-pituitary-adrenal axis hyperactivity. Honokiol, a biphenolic lignan compound obtained from the traditional Chinese medicine Magnolia officinalis, can reduce the activity of the hypothalamus-pituitary-adrenal axis and improve depression-like behavior caused by hypothalamus-pituitary-adrenal axis hyperactivity. The current study investigated the specific mechanism of action of this effect. A depression model was established by repeated injections of corticosterone to study the antidepressant-like effect of honokiol and its potential mechanism. Honokiol prevented the elevated activity of the hypothalamus-pituitary-adrenal axis and the depression-like behavior induced by corticosterone. Treatment with honokiol resulted in greater glucocorticoid receptor mRNA expression, greater glucocorticoid receptor-positive expression, and a greater ratio of glucocorticoid receptor to the mineralocorticoid receptor in the hippocampus. Moreover, honokiol treatment led to lower levels of interleukin-1β in serum and the positive expression of the interleukin-1β receptor in the hippocampus. These results demonstrate that the antidepressant-like mechanism of honokiol, which has effects on inflammatory factors, may act through restoring the typical activity of the hypothalamus-pituitary-adrenal axis by regulating the glucocorticoid receptor-mediated negative feedback mechanism and the balance between glucocorticoid and mineralocorticoid receptors.

In ovo injection corticosterone method for physiological and behavioral studies in chickens

The phenotype of organisms is not only influenced by genetic factors, but also by environmental factors that play a critical role in shaping their morphology, physiology, behavior and reproductive capacity. In avian species, maternal influences have aroused much attention after the discovery that avian eggs contain a variety of maternal derived steroid hormones. Precocial birds offer a useful animal model so as to solve the mother-offspring interference problem. By removing the maternal effect, scientists can evaluate the effect of glucocorticoid exposure during the embryonic development and its effects on later of phenotypic traits. However, the study of bird's aggressive behaviors using in ovo injection of hormone has not been reported. We used in ovo injection of corticosterone to study aggressive and fearfulness behaviors in chicken in their life later.•Fertilized chicken egg consider as pregnant mother•In ovo injection of corticosterone by pass mother-offspring interference problem•The method allow scientist to evaluate the influences of stress hormone on embryonic development and its later life consequences

慢性コルチコステロン投与によるマウスうつ様行動に対するケタミン代謝物の異なる作用

慢性コルチコステロン投与によるマウスうつ様行動に対するケタミン代謝物の異なる作用

慢性コルチコステロン投与によるマウスうつ様行動に対するケタミン代謝物の異なる作用

慢性コルチコステロン投与によるマウスうつ様行動に対するケタミン代謝物の異なる作用

Social buffering enhances extinction of conditioned fear responses by reducing corticosterone levels in male rats

The presence of an affiliative conspecific reduces stress responses to a wide variety of stimuli, which is termed “social buffering.” We previously reported that social buffering in male rats ameliorated behavioral responses, as well as hypothalamic-pituitary-adrenal axis activation, elicited by an auditory conditioned stimulus (CS). In addition, subjects that experienced social buffering did not show stress responses when re-exposed to the CS the next day in the absence of an accompanying rat. However, the mechanisms underlying this enhancement of between-session extinction are poorly understood. In Experiment 1, we compared corticosterone levels at 0, 10, and 15 min after extinction training. Subjects that experienced social buffering had lower corticosterone levels than subjects that trained alone at the end of extinction training. However, corticosterone levels at 10 and 15 min after training were not affected by the experience of social buffering. These results suggest that a lower level of corticosterone during extinction training had an important role in the enhancement of extinction. To directly assess this, in Experiment 2, we manipulated the corticosterone level during extinction training. We found that a subcutaneous injection of corticosterone before extinction training blocked the enhancement of extinction by social buffering. These results demonstrate that the enhancement is caused by a low level of corticosterone during the training. Taken together, we suggest that social buffering enhances extinction of conditioned fear responses by reducing corticosterone levels in male rats.

Corticosterone Injection Impairs Follicular Development, Ovulation and Steroidogenesis Capacity in Mice Ovary.

Simple SummaryResearchers have hitherto established hundreds of animal stress models. However, these models have some limitations due to the complexity in operation and large differences between individual animals. In particular, there are few stress models that are specifically applied in mammalian ovaries. In this study, using intraperitoneal injection of cortisol/corticosterone (CORT), we successfully established a stress model that acts on the ovarian function. Our data showed that CORT inhibits ovarian and follicular development and blocks ovulation. The establishment of this model might provide a living platform for studying ovarian stress in future research.The aim of this study is to establish an ovarian stress model, and to investigate the effects of stress on follicular development. Our data showed that continuous intraperitoneal injection of CORT successfully created a stressful environment in the ovary. To assess the effects of CORT on ovarian functions, 80 three-week-old ICR (Institute of Cancer Research) female mice were randomly divided into control group and treatment group. All mice were injected intraperitoneally with pregnant horse serum gonadotropin (PMSG). At the same time, the treatment group were injected with CORT (1 mg/mouse) at intervals of 8 h; while the control group was injected with same volume of methyl sulfoxide (DMSO). Blood, ovaries, or ovarian granulosa cell samples were collected at 24 h, 48 h, and 55 h after PMSG injection. The results showed that, compared with the control group, CORT-injected mice revealed a significant decrease in ovulation rates, ovarian weight, ovarian index, the number of secondary follicles and mature follicles, levels of estrogen and progesterone, and mRNA expression of steroid synthase-related genes. Collectively, our findings clearly demonstrated that CORT injection could represent an effective practice to simulate stresses that inhibit ovarian functions by reducing follicular development and ovulation.

Administration of Asian Herb Bennet (Geum japonicum) Extract Reverses Depressive-Like Behaviors in Mouse Model of Depression Induced by Corticosterone.

Geum japonicum, commonly known as Asian herb bennet, has been used as a diuretic, astringent, anti-dizziness, and anti-headache agent in traditional medicine. Since the antidepressant-like effects of G. japonicum extract have not been well studied, we examined the antidepressant-like effects of G. japonicum extract using depressive-like behavior induced in mice through daily injection of corticosterone (CORT). ICR mice (male, 8 weeks old) were treated with CORT (40 mg/kg, i.p.) and orally administered using oral gavage needles with G. japonicum extract (30, 100, and 300 mg/kg) for 4 weeks. Behavioral experiments were performed 1 h after administration. The control mice exhibited a significant increase in the immobility times in the tail suspension and forced swim tests as well as the step-through latency time in the passive avoidance test. Further, the control group showed a significant decrease in their sucrose consumption. However, treatment with G. japonicum extract at doses of 100 and 300 mg/kg significantly improved these depression-like behaviors without altering the locomotor activity. Moreover, treatment with G. japonicum extract significantly prevented the decrease in the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. In addition, G. japonicum extract had neuroprotective effects against CORT-induced neurotoxicity in SH-SY5Y cells. Our study indicates that G. japonicum extract exhibits antidepressant-like activity in CORT-induced depressive mice, which might be as a result of increased BDNF expression.

Prior restraint stress inhibits habituation to novel objects in the European starlings (Sturnus vulgaris).

Animals often avoid novel objects, a behavior known as neophobia. We examined behavioral responses of captive European starlings to novel objects placed at their food dishes. Exposure occurred concurrently to food reintroduction following overnight fasting. Behavior was analyzed for 10 min via video recording. We expected an increase in avoidance behavior compared with trials in which food was reintroduced without a novel object. Seven of 10 novel objects increased latency to approach the dish. In contrast to our expectations, neither prior restraint nor exogenous corticosterone changed the neophobic response to novel objects. While exposure to a novel object increased approach latency, there was no additional effect of restraining animals in a cloth bag for 15 min before food reintroduction. Furthermore, the subcutaneous injection of corticosterone did not affect approach latency by itself, nor did it affect the response to a novel object. Finally, we expected repeated exposure to the same object to extinguishing the neophobic response, and that restraint stress would prevent habituation. Our results show that European starlings habituate rapidly to exposure to a novel object, as approach latency returned to baseline within three repeated exposures to the same object. When the repeated presentation of the object was combined with prior restraint, however, the latency to approach never returned to baseline. These results reveal that neophobia in starlings is object-specific and that, while neither acute stress nor corticosterone directly affects the behavioral response to a novel object, acute stress appears to have a permissive effect on neophobia by inhibiting habituation.

A Discovery of Relevant Hepatoprotective Effects and Underlying Mechanisms of Dietary Clostridium butyricum Against Corticosterone-Induced Liver Injury in Pekin Ducks.

Clostridium butyricum (C. butyricum) can attenuate oxidative stress, inflammation, and hepatic fatty deposition in poultry, however, the underlying mechanisms for this in Pekin ducks remain unclear. This study evaluated these hepatoprotective effects and the underlying mechanisms in a corticosterone (CORT)-induced liver injury model in Pekin ducks fed a C. butyricum intervention diet. A total of 500 Pekin ducks were randomly divided into five groups: one group (CON group) was only provided with a basal diet, three groups were provided a basal diet with 200 mg/kg (LCB group), 400 mg/kg (MCB group), or 600 mg/kg (HCB group) C. butyricum, respectively, and one group was provided a basal diet with 150 mg/kg aureomycin (ANT group) for 42 d. At 37 days-old, all ducks received daily intraperitoneal injections of CORT for five days to establish a liver injury model. C. butyricum intervention alleviated liver injury by decreasing the liver organ indices, hepatic steatosis and hepatocyte necrosis, and improving liver function, antioxidant capacity, and inflammatory factors. Hepatic RNA-seq revealed 365 differentially expressed genes (DEGs) between the MCB and CON groups, with 229 up- and 136 down-regulated DEGs in the MCB group. Between the MCB and ANT groups, 407 DEGs were identified, including 299 up- and 108 down-regulated genes in MCB group. Some DEGs in the MCB group related to oxidative stress and inflammatory responses such as Sod3, Tlr2a/b, and Il10, which were up-regulated, while Apoa1, Cyp7a1, Acsl1/5, Fasn, Ppar-γ, and Scd, which are involved in lipid metabolism, were down-regulated, indicating that these genes were responsive to dietary C. butyricum for the alleviation of corticosterone-induced hepatic injury. Toll-like receptor signaling, PI3K-Akt signaling pathway, cytokine-cytokine receptor interaction, peroxisome proliferator-activated receptor (PPAR) signaling pathway, adipocytokine and glycerophospholipid metabolism signaling pathway were significantly enriched in the MCB group. These findings indicate that C. butyricum intervention can protect Pekin ducks from corticosterone-induced liver injury by the modulation of immunoregulatory- and lipid metabolism-related genes and pathways.

Edaravone presents antidepressant-like activity in corticosterone model of depression in mice with possible role of Fkbp5, Comt, Adora1 and Slc6a15 genes

Chronic exposure to environmental-like stress leads to dysregulation of hypothalamic–pituitary–adrenal (HPA) axis and to appearance of oxidative stress, which is implicated in the development of depression-like behaviour. Edaravone (3-methyl-1-phenyl-2-pyrazoline-5-one) exhibits a neuroprotective effect attributed to the potent free radical scavenging. This study was designed to assess antidepressant-like activity of edaravone based on behavioural tests in the animal model of depression. Furthermore, to elucidate its mechanisms, the expression of Fkbp5, Comt, Adora and Slc6a15 genes involved in turnover of neurotransmitters was analysed. In order to evaluate the antioxidant features of edaravone, DNA's oxidative damage was determined. The mice were injected subcutaneously (sc) with 40 mg/kg corticosterone, chronically for 21 days. Paroxetine (10 mg/kg) (a selective serotonin reuptake inhibitor) and edaravone (10 mg/kg) were administered separately (ip) 30 min prior to the corticosterone injection. After 21-days of treatment with respective drugs, the mice were decapitated and the prefrontal cortex was rapidly dissected and used for determination of DNA's oxidative damage and the real-time PCR analysis. Edaravone ameliorated behavioural impairments in sucrose preference test (SPT) and forced swim test (FST). A possible role in Fkbp5, Comt, Adora1 and Slc6a15 genes' expression in mediating this effect is postulated. Both edaravone and paroxetine have no effect on corticosterone-induced DNA's oxidative damage.

Oleanolic acid decreases SGK1 in the hippocampus in corticosterone-induced mice

Our previous study has demonstrated that oleanolic acid produced an antidepressant-like effect in mice exposed to chronic stress. Considering that serine/threonine-protein kinase 1 (SGK1) is involved in stress response, the present study aimed to evaluate the involvement of SGK1 in the antidepressant-like effects of oleanolic acid in depression-like mice induced by long term corticosterone (CORT) injection. Behaviors, SGK1, brain-derived neurotrophic factor (BDNF) and its downstream targets were assessed after administration with oleanolic for three weeks. The results indicated that oleanolic acid increased the sucrose preference and decreased the immobility time. In addition, oleanolic acid decreased SGK1 and activated BDNF-AKT/mTOR signaling in the hippocampus of CORT-induced animals. However, we found that GSK650394, an inhibitor of SGK1 did not exert any effects on the behaviors, GR levels and BDNF signaling. The number of spines in hippocampal neurons was not changed by GSK650394 as well. Taken together, this study demonstrated that oleanolic acid produced the antidepressant-like effects, which might be related to the down-regulation of SGK1. However, inhibition of SGK1 directly lacks the effects in the treatment of depression.

SAT-358 Corticosterone Treatment during Sepsis Results in a Primary Adrenal Defect in Male Survivors

Abnormalities of adrenal gland function have been described in survivors of prolonged critical illness, but whether an acute inflammatory illness such as sepsis causes lasting changes in adrenal function is unknown. Critically ill patients with sepsis are often treated with high doses of corticosteroids for their vasoactive properties, which may also affect adrenal function. To examine the effect of sepsis and corticosteroid treatment on adrenal function, we used a naturalistic mouse model of sepsis, cecal ligation and puncture (CLP). Male and female C57Bl/6 mice (N = 20 per group, 10 male/10 female) underwent CLP or sham surgery and were treated with daily injections of either corticosterone (13 mg/kg) or vehicle for five days. Mice were maintained on a 14:10 light-dark cycle with lights on at 6 AM. Three weeks after surgery, mice were sacrificed at baseline (between 9:00 and 12:00) or after stress (6-minute swim) and blood collected for hormone measurements. Adrenal weights, adrenal gland histology, and gene expression analysis were performed on a subset of mice. The results showed that female mice had higher adrenal weights and higher plasma corticosterone, but lower plasma ACTH, when compared to males. Corticosterone and CLP had sex-dependent effects on adrenal function. Specifically, corticosterone-treated male sepsis survivors had higher morning ACTH/corticosterone ratios than the other groups without any difference in stress ACTH/corticosterone, and this group had heavier adrenal weights. These findings were not explained by adrenal histology. Gene expression analysis of male adrenals showed that corticosterone treatment increased adrenal expression of Sonic Hedgehog, Disabled-2, and COUP-TF in the sham mice, but this effect was absent in sepsis survivors. We conclude that corticosterone treatment during sepsis causes a defect in adrenal function after recovery only in males. The increased ACTH/corticosterone ratio suggests a compensatory increase in pituitary activity, while the gene expression analysis shows an absence of the normal recovery process from corticosterone treatment in the sepsis survivors. These novel findings could have clinical implications for the maintenance of appropriate adrenal function after corticosteroid treatment during acute illness. This work was supported by grants from the NIMH, NIDDK, Office of Naval Research, Hope for Depression Research Foundation, and the Brain and Behavior Research Foundation.

Melanin‐concentrating hormone‐R1 in the locus coeruleus may be involved in the regulation of depressive‐like behavior

BackgroundPrevious anatomical and behavioral studies have shown that melanin‐concentrating hormone (MCH) is involved in the modulation of emotional states. However, little is known about brain regions other than the dorsal raphe nucleus that relate the MCH‐ergic system to depressive states. Numerous studies have shown that the locus coeruleus (LC) is involved in the regulation of depression and sleep. Although direct physiological evidence is lacking, previous studies suggest that MCH release in the LC decreases neuronal discharge. However, remaining unclear is whether the MCH‐ergic system in the LC is related to depressive‐like behavior.MethodWe treated rats with an intra‐LC injection of MCH, intracerebroventricular injection of MCH, or chronic subcutaneous injections of corticosterone to induce different depressive‐like phenotypes. We then assessed the effects of the MCH receptor 1 antagonist SNAP‐94847 on depressive‐like behavior in the forced swim test (FST) and the sucrose preference test (SPT).ResultsThe intra‐LC and intracerebroventricular injections of MCH and chronic injections of corticosterone increased immobility time in the FST and decreased sucrose preference in the SPT. All of these depressive‐like behaviors were reversed by an intra‐LC microinjection of SNAP‐94847.ConclusionsThese results suggest that the MCH‐ergic system in the LC might play an important role in the regulation of depressive‐like behavior.Support or Funding InformationThis study was funded by grants from the National Natural Science Foundation of China (No. 81573407, 81872851, 81871038 and 81302746).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Acute corticosterone treatment elicits antidepressant-like actions on the hippocampal 5-HT and the immobility phenotype

Corticosterone (CORT) has long been shown to modulate 5-HT system, and to alter hippocampal functions in various physiological and pathological conditions. However, CORT-elicited changes in the hippocampal 5-HT transmission and the immobility phenotype had not been fully addressed. The current study sought to explore effects of acute CORT subcutaneously injected at 10, 20, 40 mg/kg on the extracellular 5-HT in the hippocampus and the immobility time in male CD-1 mice. Following an injection of CORT or vehicle, time course of the extracellular 5-HT in the hippocampal CA3 was determined using in vivo microdialysis. The immobility time was measured at 0 min, 60 min, 120 min, 180 min in the forced swimming test (FST) and the tail suspension test (TST), respectively. Results showed that the vehicle, used to dissolve CORT, did not affect the dialysate 5-HT, nor the immobility time, by comparing the pre- and post-injection. CORT was found to dose-dependently increase the dialysate 5-HT and decrease the immobility time when compared to their vehicle-treated controls. The peak increase in the dialysate 5-HT and the decrease in the immobility time were both obtained at the 120 min following the CORT injection. Furthermore, a negative correlation was detected between the immobility time and the peak increase in the dialysate 5-HT. Our results indicated that acute CORT injection elicits antidepressant-like actions on the hippocampal 5-HT and the immobility time. The study suggested that hippocampal 5-HT responses may be one of the neurochemical bases for the immobility phenotype following CORT injection.

Selective vulnerability of dorsal raphe-medial prefrontal cortex projection neurons to corticosterone-induced hypofunction.

Glucocorticoid hormones and serotonin (5-HT) are strongly associated with the development and treatment of depression, respectively. Glucocorticoids regulate the function of serotonergic neurons in the dorsal raphe nucleus (DR), which are the major source of 5-HT to the forebrain. DR 5-HT neurons are electrophysiologically heterogeneous, though whether this phenotypic variation aligns with specific brain functions or neuropsychiatric disease states is largely unknown. The goal of this work was to determine if chronic exogenous glucocorticoid administration differentially affects the electrophysiological profile of DR neurons implicated in the regulation of emotion versus visual sensation by comparing properties of cells projecting to medial prefrontal cortex (mPFC) versus lateral geniculate nucleus (LGN). Following retrograde tracer injection into mPFC or LGN, male Sprague-Dawley rats received daily injections of corticosterone (CORT) for 21days, after which whole-cell patch clamp recordings were made from retrogradely labeled DR neurons. CORT-treatment significantly increased the action potential half-width of LGN-projecting DR neurons, but did not significantly affect the firing frequency or excitatory postsynaptic currents of these cells. CORT-treatment significantly reduced the input resistance, evoked firing frequency, and spontaneous excitatory postsynaptic current frequency of mPFC-projecting DR neurons, indicating a concurrent reduction of both intrinsic excitability and excitatory drive. Our results suggest that the serotonergic regulation of cognitive and emotional networks in the mPFC may be more sensitive to the effects of glucocorticoid excess than visual sensory circuits in the LGN and that reduced 5-HT transmission in the mPFC may underlie the association between glucocorticoid excess and depression.

Red wine polyphenols reverse depressive-like behaviors in mice induced by repeated corticosterone treatment

The aim of this study was to investigate the antidepressant-like effect of red wine phenolic extracts in mouse model exposed to exogenous corticosterone. The results showed that 3-week corticosterone injections caused depression-like behavior in mice, as indicated by the significant decrease in sucrose consumption and increase immobility time in the forced swimming test (FST). Red wine phenolic extracts treatment significantly reduced serum corticosterone levels. Moreover, it was found that red wine phenolic extract increased the brain-derived neurotrophic factor protein (BNDF) and tropomyosin-related kinase B (TrkB) phosphorylation and cAMP-responsive element binding protein (CREB) phosphorylation levels in the hippocampus and prefrontal cortex. However, K252a, an inhibitor of TrkB, completely abolished those antidepressant-like effects. These results suggested that the red wine phenolic extracts produce an antidepressant-like effect in corticosteronetreated mice, at least in part, which is possibly mediated by modulating hypothalamic-pituitary-adrenal (HPA) axis, BDNF, TrkB and CREB phosphorylation levels in the brain region of mice.