Corticosterone Research Articles

Environmental pollution and nutritional quality modulate immune response of the wood mouse (Apodemus sylvaticus) through hormonal disturbances

Cadmium (Cd) and lead (Pb) are known to enhance immune cell damages and to decrease cellular immunity, promoting higher susceptibility to infectious diseases. Selenium (Se) is an essential element involved in immunity and reactive oxygen species scavenging. This study aimed at evaluating how Cd and Pb and low nutritional (Se) quality modulate immune response to a bacterial lipopolysaccharide (LPS) challenge in wood mice (Apodemus sylvaticus). Mice were trapped near a former smelter in northern France in sites of High or Low contamination. Individuals were challenged immediately after capture or after five days of captivity, fed a standard or a Se-deficient diet. Immune response was measured with leukocyte count and plasma concentration of TNF-α, a pro-inflammatory cytokine. Faecal and plasma corticosterone (CORT), a stress-hormone involved in anti-inflammatory processes, was measured to assess potential endocrine mechanisms. Higher hepatic Se and lower faecal CORT were measured in free-ranging wood mice from High site. LPS-challenged individuals from High site showed steeper decrease of circulating leukocytes of all types, higher TNF-α concentrations, and a significant increase of CORT, compared to individuals from Low site. Challenged captive animals fed standard food exhibited similar patterns (decrease of leukocytes, increase of CORT, and detectable levels of TNF-α), with individuals from lowly contaminated site having higher immune responses than their counterparts from highly polluted site. Animals fed Se-deficient food exhibited lymphocytes decrease, no CORT variation, and average levels of TNF-α. These results suggest (i) a higher inflammatory response to immune challenge in free-ranging animals highly exposed to Cd and Pb, (ii) a faster recovery of inflammatory response in animals lowly exposed to pollution when fed standard food than more exposed individuals, and (iii) a functional role of Se in the inflammatory response. The role of Se and mechanisms underlying the relationship between glucocorticoid and cytokine remain to be elucidated.

PI3K-AKT-mTOR signaling pathway regulates autophagy of hippocampal neurons in diabetic rats with chronic unpredictable mild stress

It is reported that the co-morbidities of diabetes and depression will be a new challenge for humanity. However, the underlying mechanism is not clear. The present study investigated the histopathology, autophagy of hippocampal neurons, and the PI3K-AKT- mTOR signaling pathway in type 2 diabetes with depression（T2DD） rats. The results showed that, the chronic unpredictable mild stress (CUMS), Type 2 diabetes mellitus (T2DM) and T2DD in rats were induced successfully. Compared with the CUMS and T2DM groups, the T2DD group performed significantly fewer autonomic activities in the open-field test, and longer immobile in the force swimming test, and increasing of Corticosterone (CORT) in blood. The number of pyknotic neurons at cornu ammonis 1 (CA1) and dentate gyrus (DG) of the hippocampus in T2DD was significantly increased compared with CUMS and T2DM groups. Moreover, compared with the CUMS and T2DM groups, the mitochondrial autophagosomes were most abundant in the T2DD group. As shown in western blot and immunofluorescence, compared with the control group, in the CUMS, T2DM and T2DD groups, significantly increased expression of Beclin-1 and LC3B and decreased P62 were detected. In the PC12 cells, the relative amount of parkin and LC3B in the CORT+HG group was significantly higher than that in the CORT and HG groups. Compared with the control group, p-AKT/AKT and p-mTOR/mTOR in CUMS, T2DM and T2DD groups were significantly decreased. Compared with the CUMS group, p-AKT/AKT, p-PI3K/PI3K and p-mTOR/mTOR in the T2DD group exhibited further decrease. Similar results were obtained in PC12 cells in vitro. It is suggests that memory and cognitive impairment in rats with co-morbidities of diabetes and depression might be related with hippocampal neuronal damage and autophagy increase, which was involved in the PI3K-AKT-mTOR signaling pathway.

The effects of pre-hatch elevated corticosterone and post-hatch restrictive food availability on the HPA axis development of mallard ducks (Anas platyrhynchos)

Environmental changes can be stressors (altered habitat and food supply, climate change, etc.) to wild animals. Stressors trigger the hypothalamic pituitary adrenal (HPA) axis to release corticosterone (CORT) which modifies energy homeostasis. During nesting, stressed females can deposit increased concentrations of CORT into eggs, altering egg viability and offspring characteristics, constituting a significant mechanism regulating population productivity in subsequent generations. In this study, increased maternal disposition of CORT was mimicked through a 15 ng/g in ovo injection of CORT into mallard duck eggs. Growth and HPA axis function were measured during post-hatch development. For growth, changes in mass were compared at hatch, 7 weeks and 11 weeks. The HPA axis was assessed at seven weeks by measuring CORT at baseline, followed by restraint stress, dexamethasone (negative feedback) and ACTH (maximal adrenal capacity) challenges. At eleven weeks of age, ducks were subjected to a 6-day 25% feed reduction to simulate a poor quality environment to evaluate response to a chronic stressor by comparing CORT at baseline and after restraint stress. Growth and CORT concentration did not differ between treatments at seven weeks or after feed restriction (11 weeks). The CORT dosage administered did not appear to affect HPA axis development in ducklings. Mallards are a highly adaptable species and may have overcome any early alterations to their phenotype. Further research is needed to determine the effects of increased maternal CORT on growth and the development of the HPA axis in ducks. Summary statementThis study examines how maternal stress (simulated through elevated corticosterone in ovo) and post-hatch chronic stressors (food restriction) affect the development of the HPA axis in a precocial bird.

Loss of epidermal glucocorticoid receptor protects against whole body metabolic dysfunction upon chronic corticosterone treatment

ObjectiveGlucocorticoid (GC) excess contributes to the development of metabolic syndrome, defined by visceral obesity, abnormal glucose tolerance, and dyslipidemia. While it is accepted that loss of metabolic control is causative of cutaneous diseases, the systemic effects of epidermal dysfunction have received limited attention. Importantly, independent of GC blood levels, skin synthesis of these hormones can provide tissue-specific variations that may affect global homeostasis. We aimed to assess whether the epidermal-specific loss of the GC receptor (GR) had an impact on the dermal white adipose tissue (dWAT), a specialized fat depot functionally different from other fat pads, as well as on whole body homeostasis. MethodsGR epidermal KO (GREKO) and control female mice were treated with oral corticosterone (CORT) for 4 weeks, a protocol inducing metabolic dysfunction. Metabolic parameters including body weight, visceral and hepatic fat accumulation, blood glucose and insulin levels, glucose tolerance tests upon fasting, and triglycerides levels, were determined. Systemic alterations of soluble factors with known roles in immunity and inflammation were also assessed by a multiplex antibody array system containing selected cytokines, chemokines, and growth factors. The levels of cutaneous GCs and the profile of skin-secreted factors were determined in tissue explants by ELISA and the multiplex array system. Morphometric studies quantitated changes in dWAT thickness and adipocyte size in both genotypes, basally and at the end of CORT treatment. The expression of adipocyte markers was assessed in purified dermal adipocytes in vehicle and CORT-treated GREKOvs controls. ResultsDespite similar circulating levels of GCs, GREKO mice were highly resistant to CORT-induced systemic metabolic anomalies including body weight gain, visceral and hepatic fat, hyperglycemia, insulinemia, and elevated levels of plasma triglycerides, leptin, FGF-21, PAI-1, and CCL11. GREKO mice featured constitutively enhanced levels of cutaneous GCs relative to controls at least partially due to keratinocyte-specific increased expression of the critical steroidogenic enzyme Cyp11b1. Also, the higher ratio of skin-secreted protective vs inflammatory adipokines in GREKOvs controls, correlated with higher capacity of adipogenic conversion in experiments using conditioned media from tissue explants. Following CORT treatment, relative to controls, GREKO mice featured reduced dWAT hyperplasia and adipocyte hypertrophy, with increased Adipoq and decreased Lipocalin 2 expression in purified dermal adipocytes. ConclusionsOverall data suggest that epidermal GR loss results in paracrine actions on dermal adipocytes as well as endocrine actions on key metabolic tissues that significantly improve the whole body metabolism in a mouse model of metabolic dysfunction.

Contrasting effects of transdermal and implant corticosterone treatments in the American bullfrog wound healing.

Glucocorticoid (GC) release is triggered by adverse stimuli that activate the hypothalamus-pituitary-adrenal/interrenal axis. Glucocorticoids may enhance or suppress immune functions depending on the level of elevation. In this study, we investigated the effects of transient and chronic increase of corticosterone (CORT) on the wound healing of the American bullfrog. Frogs were submitted to a daily transdermal hormonal application that acutely elevated CORT plasma levels, or vehicle as a control. Other frogs were surgically implanted with a silastic tube filled with CORT that resulted in chronic elevation of CORT plasma levels or received empty implants as a control. A dermal biopsy was performed to create a wound and was photographed every 3 days. Individuals treated with transdermal CORT started healing faster than their control 32 days after the biopsy. Frogs that received CORT implants tended to heal slower than control subjects. Plasma bacterial killing ability was not affected by treatment, which reinforces the constitutive nature of this innate immune trait. By the end of the experiment, frogs from the acute CORT treatment had smaller wounds compared with those receiving the CORT-filled implants, highlighting the differential effects of acute (immunoenhancing) and chronic (immunosuppressive) elevation of CORT plasma levels. This article is part of the theme issue 'Amphibian immunity: stress, disease and ecoimmunology'.

Testosterone immunomodulation in free-living and captive Rhinella icterica male toads.

Testosterone (T) regulates immune function, with both immunostimulatory and immunosuppressive effects on several vertebrates. We investigated the covariation between plasma T and corticosterone (CORT) levels and immunity (plasma bacterial killing ability (BKA), and neutrophil to lymphocyte ratio (NLR)) in free-living Rhinella icterica male toads inside and outside the reproductive season. We found an overall positive correlation between steroids and immune traits, with toads during the reproductive season displaying increased T, CORT and BKA. We also investigated the T transdermal application effects on T, CORT, phagocytosis of blood cells, BKA and NLR in captive toads. Toads were treated with T (1, 10 or 100 µg) or vehicle (sesame oil) for eight consecutive days. Animals were bled on the first and eighth days of treatment. Increased plasma T was observed on the first and last day of T-treatment, while increased BKA was observed following all T doses on the last day, with a positive correlation between T and BKA. Plasma CORT, NLR and phagocytosis increased on the last day for all T-treated and vehicle groups. Overall, we demonstrated a positive covariation between T and immune traits in the field and T-induced augmented BKA in captive toads, indicating a T immunoenhancing effect in R. icterica males. This article is part of the theme issue 'Amphibian immunity: stress, disease and ecoimmunology'.

Fluoxetine Can Cause Epileptogenesis and Aberrant Neurogenesis in Male Wild-Type Mice

Antidepressants in general, and fluoxetine in particular, increase adult hippocampal neurogenesis (AHN) in mice. Here we asked how the antidepressant fluoxetine affects behavior and AHN in a corticosterone model of depression. In three groups of adult male C57BL/6j mice, we administered either vehicle (VEH), corticosterone (CORT) treatment to induce a depression-like state, or corticosterone plus a standard dose of fluoxetine (CORT+FLX). Following treatment, mice performed the open field test, the novelty suppressed feeding (NSF) test, and the splash test. Neurogenesis was assessed by means of immunohistochemistry using BrdU and neuronal maturation markers. Unexpectedly, 42% of the CORT+FLX-treated mice exhibited severe weight loss, seizures, and sudden death. As expected, the CORT-treated group had altered behaviors compared to the VEH group, but the CORT+FLX mice that survived did not show any behavioral improvement compared to the CORT group. Antidepressants generally increase neurogenesis and here we also found that compared to CORT mice, CORT+FLX mice that survived had a significantly greater density of BrdU+, BrdU+DCX+, and BrdU+NeuN+ cells, suggesting increased neurogenesis. Moreover, the density of BrdU+NeuN+ cells was increased in an aberrant location, the hilus, of CORT+FLX mice, similar to previous studies describing aberrant neurogenesis following seizures. In conclusion, fluoxetine could induce considerable adverse effects in wild-type mice, including seizure-like activity. Fluoxetine-induced neurogenesis increases could be related to this activity; therefore, proneurogenic effects of fluoxetine and other antidepressants, especially in the absence of any behavioral therapeutic effects, should be interpreted with caution.

Association analysis of gut microbiota-metabolites-neuroendocrine changes in male rats acute exposure to simulated altitude of 5500 m

Hyperactivation of hypothalamic–pituitary–adrenal (HPA) axis and hypothalamic–pituitary–thyroid (HPT) axis were found in acute high altitude challenge, but the role of gut microbiota and metabolites is unknown. We utilized adult male Sprague–Dawley rats at a simulated altitude of 5500 m for 3 days in a hypobaric-hypoxic chamber. ELISA and metabolomic analyses of serum and 16S rRNA and metabolomic analyses of fecal samples were then performed. Compared with the normoxic group, serum corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), corticosterone (CORT), and thyroxine (tT4) were increased in the hypoxia group, whereas thyrotropin-releasing hormone (TRH) was decreased. Bacteroides, Lactobacillus,Parabacteroides,Butyricimonas,SMB53,Akkermansia,Phascolarctobacterium, and Aerococcus were enriched in hypoxia group, whereas [Prevotella], Prevotella,Kaistobacter,Salinibacterium, and Vogesella were enriched in normoxic group. Metabolomic analysis indicated that acute hypoxia significantly affected fecal and serum lipid metabolism. In addition, we found five fecal metabolites may mediate the cross-talk between TRH, tT4, and CORT with [Prevotella], Kaistobacter,Parabacteroides, and Aerococcus, and 6 serum metabolites may mediate the effect of TRH and tT4 on [Prevotella] and Kaistobacter by causal mediation analysis. In conclusion, this study provides new evidence that key metabolites mediate the cross-talk between gut microbiota with HPA and HPT axis under acute hypobaric hypoxia challenge.

The parabrachial nucleus elicits a vigorous corticosterone feedback response to the pro-inflammatory cytokine IL-1β

The central nervous system regulates systemic immune responses by integrating the physiological and behavioral constraints faced by an individual. Corticosterone (CS), the release of which is controlled in the hypothalamus by the paraventricular nucleus (PVN), is a potent negative regulator of immune responses. Using the mouse model, we report that the parabrachial nucleus (PB), an important hub linking interoceptive afferent information to autonomic and behavioral responses, also integrates the pro-inflammatory cytokine IL-1β signal to induce the CS response. A subpopulation of PB neurons, directly projecting to the PVN and receiving inputs from the vagal complex (VC), responds to IL-1β to drive the CS response. Pharmacogenetic reactivation of these IL-1β-activated PB neurons is sufficient to induce CS-mediated systemic immunosuppression. Our findings demonstrate an efficient brainstem-encoded modality for the central sensing of cytokines and the regulation of systemic immune responses.

Adult mice with noise-induced hearing loss exhibited temporal ordering memory deficits accompanied by microglia-associated neuroplastic changes in the medial prefrontal cortex

Acquired peripheral hearing loss in midlife is considered the primary modifiable risk factor for dementia, while the underlying pathological mechanism remains poorly understood. Excessive noise exposure is the most common cause of acquired peripheral hearing loss in modern society. This study was designed to investigate the impact of noise-induced hearing loss (NIHL) on cognition, with a focus on the medial prefrontal cortex (mPFC), a brain region that is involved in both auditory and cognitive processes and is highly affected in patients with cognitive impairment. Adult C57BL/6 J mice were randomly assigned to a control group and seven noise groups: 0HPN, 12HPN, 1DPN, 3DPN, 7DPN, 14DPN, and 28DPN, which were exposed to broadband noise at a 123 dB sound pressure level (SPL) for 2 h and sacrificed immediately (0 h), 12 h, or 1, 3, 7, 14, or 28 days post-noise exposure (HPN, DPN), respectively. Hearing assessment, behavioral tests, and neuromorphological studies in the mPFC were performed in control and 28DPN mice. All experimental animals were included in the time-course analysis of serum corticosterone (CORT) levels and mPFC microglial morphology. The results illustrated that noise exposure induced early-onset transient serum CORT elevation and permanent moderate-to-severe hearing loss in mice. 28DPN mice, in which permanent NIHL has been verified, exhibited impaired performance in temporal order object recognition tasks concomitant with reduced structural complexity of mPFC pyramidal neurons. The time-course immunohistochemical analysis in the mPFC revealed significantly higher morphological microglial activation at 14 and 28 DPN, preceded by a remarkably higher amount of microglial engulfed postsynaptic marker PSD95 at 7 DPN. Additionally, lipid accumulation in microglia was observed in 7DPN, 14DPN and 28DPN mice, suggesting a driving role of lipid handling deficits following excessive phagocytosis of synaptic elements in delayed and sustained microglial abnormalities. These findings provide fundamentally novel information concerning mPFC-related cognitive impairment in mice with NIHL and empirical evidence suggesting the involvement of microglial malfunction in the mPFC neurodegenerative consequences of NIHL.

Butein inhibits corticosterone-induced apoptosis of Neuro2A cells by maintaining MEK-ERK signaling.

Stress-induced overactivation of glucocorticoid signaling may contribute to mental illness by inducing neuronal death and dysfunction. We previously reported that pretreatment with the plant flavonoid butein inhibits corticosterone (CORT)-induced apoptosis of Neuro2A (N2A) cells. In the current study, we examined whether MEK-ERK and PI3K-AKT signaling pathways are involved in neuroprotection by butein. N2A cells were pre-incubated with serum-free DMEM containing 0.5μM butein for 30min, and then incubated with serum-free DMEM containing 0.5µM butein, 50µM CORT, 50µM LY294002, or 50µM PD98059 as indicated for 24h. We subsequently performed the MTT assay and the western blot analysis. As expected, CORT considerably reduced N2A cell viability and increased relative expression of the apoptosis effector cleaved caspase-3, whereas pretreatment with butein blocked these cytotoxic effects. Treatment with CORT alone also decreased both AKT and ERK protein phosphorylation. Butein pretreatment had no effect on AKT phosphorylation, and only partially reversed the reduction in phosphorylated ERK. However, cotreatment with butein and the PI3K inhibitor LY294002 during CORT exposure enhanced ERK phosphorylation, whereas cotreatment with butein and the ERK phosphorylation/activation inhibitor PD98059 enhanced AKT phosphorylation, suggesting that MEK-ERK negatively regulates AKT phosphorylation. Moreover, the protective efficacy of butein was blocked by PD98059 cotreatment but not LY294002 cotreatment. These findings suggest that butein protects neurons against glucocorticoid-induced apoptosis by sustaining ERK phosphorylation and downstream signaling.

Cinnamon oil solid self-microemulsion mediates chronic mild stress-induced depression in mice by modulating monoamine neurotransmitters, corticosterone, inflammation cytokines, and intestinal flora

Cinnamon oil (CO) is a classic Chinese medicine with excellent soothing effects on exhaustion, weakness and depression. Cinnamaldehyde is the main active ingredient of cinnamic oil. Although CO have antidepression-like effects, limited information is available. Furthermore, the disadvantages of CO, such as low oral availability and difficult portability, limit its development. In this study, a Cinnamon Oil Solid Self-Microemulsifying Drug Delivery System (CO-S-SME) was designed, prepared. In addition, we explored the effects and mechanisms of CO-S-SME on chronic unpredictable mild stress (CUMS)-induced depression-like behavior, monoamine neurotransmitters, inflammatory factors, intestinal flora in mice. Mice were subjected CUMS to establish the depression model. The antidepressant effect of CO-S-SME was evaluated by behavioral tests. In addition, the expression levels of neurotransmitters, corticosterone (CORT) and inflammatory factors in CUMS mice were analyzed by enzyme-linked immunosorbent assay. In addition, we explored the effects of CO-S-SME on the diversity and richness of intestinal flora of mice in each group. Behavioral tests showed that CO-S-SME could effectively improve depression-like behaviors in CUMS mice. Specifically, CO-S-SME treatment effectively increased neurotransmitter levels and reduced the expressions of corticosterone and inflammatory factors in CUMS mice. CO-S-SME also changed the intestinal flora composition, decreased the ratio of Firmicutes to Bacteroidetes, reduced relative abundances of Lactobacillus, modulated Alpha diversity and beta diversity. These results suggest that CO-S-SME an act as a good antidepressant, exhibiting effects via monoamine neurotransmitters, CORT, inflammation cytokines, and intestinal flora.

Effects of long-snake moxibustion on the HPA axis and liver 11β-HSD1 expression in rats with kidney yang deficiency: 长蛇灸对肾阳虚大鼠HPA轴及肝脏11β-HSD1的影响

ObjectiveTo observe the effects of long-snake moxibustion on the hypothalamic-pituitary-adrenocortical (HPA) axis and hepatic 11β-hydroxy steroid dehydrogenase type 1 (11β-HSD1) expression in rats with kidney yang deficiency to provide a basis for later in-depth exploration of the action mechanism of long-snake moxibustion on such rats. MethodsFifteen SPF-grade, male, SD rats were randomly divided into a blank control group, a model group, and a long-snake moxibustion treatment group, with five rats in each group. Hydrocortisone powder (30 mg/kg) was administered by gavage at a volume of 10 mL/kg to prepare the rat model of kidney yang deficiency. After successful modeling, the rats in the long-snake moxibustion treatment group underwent long-snake moxibustion treatment every other day (along the governor vessel from Dazhui (GV14) to Shenshu(BL23), for a period of 14 days. The remaining two groups were secured in the same way as the long-snake moxibustion treatment group, although they did not receive any treatment. The body weight, rectal temperature, and spontaneous activity count of the rats, as well as serum levels of corticotropin releasing hormone (CRH) and corticosterone (CORT) were detected by ELISA before modeling, after modeling, and after treatment. The amount of 11β-HSD1 protein in rat liver was determined by immunohistochemistry and Western blot analysis. ResultsCompared with the rats in the blank control group, those in the model group exhibited a significant decrease in the trend of body weight growth and in rectal temperature (P <0.05), as well as a slight yet non-significant decrease in spontaneous activity count (P >0.05); compared with the rats in the model group, the rats in the treatment group exhibited a significant increase in rectal temperature (P <0.05) and in spontaneous activity count (P <0.05). Moreover, after 14 days of treatment, compared with the rats in the blank, the rats in the model group exhibited a significant decrease in serum CORT content (P <0.05) and in the expression of 11β-HSD1 in the liver (P <0.05), as well as a slight yet non-significant decrease in serum CRH content (P >0.05); compared with the rats in the model group, the rats in the treatment group exhibited a significant increase in serum CRH content (P <0.05) and in the expression of 11β-HSD1 in the liver (P <0.05), as well as a slight yet non-significant increase in serum CORT content (P >0.05). ConclusionLong-snake moxibustion can increase the rectal temperature and spontaneous activity count of rats with kidney yang deficiency, improve the function of the HPA axis, and increase the expression of 11β-HSD1 in the liver.

Areca catechu L. ameliorates chronic unpredictable mild stress-induced depression behavior in rats by the promotion of the BDNF signaling pathway

ObjectivesIn this study, we have investigated the anti-depressant effects of the fruit Areca catechu L. (ACL) and elucidated its potential underlying mechanism using a rat model of chronic unpredictable mild stress (CUMS). MethodsCUMS was induced in rats to establish a depression animal model for 28 days. According to the baseline sucrose preference, the male rats were divided into 6 different groups. They were treated with paroxetine hydrochloride, ACL, and water once a day until the behavioral tests were performed. The levels of corticosterone (CORT), malondialdehyde (MDA), catalase (CAT), and total superoxide dismutase (T-SOD) in serum were detected using a commercial kit, and the concentrations of 5-hydroxytryptamine (5-HT) and dopamine (DA) monoamine neurotransmitters in the brain tissues were detected by liquid chromatography-tandem mass spectrometry. doublecortin (DCX) expression in the hippocampal dentate gyrus (DG) was determined by immunofluorescence, and the relative abundance of brain-derived neurotrophic factor (BDNF), TrkB, PI3K, p-AKT/AKT, PSD-95, and p-GSK-3β/GSK-3β of brain tissues were assayed by western blot. ResultsACL markedly increased sucrose preference, decreased the immobility time, and shortened the feeding latency of CUMS-induced rats. CUMS induction resulted in marked changes in the contents of the monoamine neurotransmitters (5-HT and DA) in the hippocampus and cortex of brain tissues and the levels of CORT, MDA, CAT, and T-SOD in serum, whereas ACL administration alleviated these considerable changes. ACL promoted DCX expression in DG and increased the protein levels of BDNF, TrkB, PI3K, p-AKT/AKT, PSD-95, and p-GSK-3β/GSK-3β in the brains of CUMS-induced rats. ConclusionsOur results indicated that ACL may improve depression-like behaviors in CUMS-induced rats by decreasing the hyperfunction and oxidative stress of the hypothalamic–pituitary–adrenal axis, stimulating hippocampal neurogenesis, and activating the BDNF signaling pathway.

Reproductive cycles of alligator snapping turtles (Macrochelys temminckii)

The alligator snapping turtle (Macrochelys temminckii) is a species for which captive propagation and reintroduction programs are well established; however, little is known about its reproductive behavior and physiology. In this study, we measured monthly plasma sex steroid hormone concentrations of androgen (T + DHT) estradiol-17B (E2), and progesterone (P4), and used ultrasonography to monitor annual reproductive cycles of a captive population of alligator snapping turtles that is maintained under semi-natural conditions in southeastern Oklahoma. Concurrently, we used automated radio telemetry to measure the relative activity levels of male and female alligator snapping turtles and examine these activity patterns in the context of their reproductive cycles. We also measured monthly concentrations of the glucocorticoid (GC) corticosterone (CORT). Seasonal variation was only detected for T in males, but was observed for T, E2, and P4 in females. Vitellogenesis began in August and ended in April and coincided with elevated E2. Ovulation took place 10–29 April and the nesting period lasted from 11 May – 3 June. Males exhibited greater relative activity levels than females in the fall, winter, and early spring, which coincided with the period when mature sperm would be available for mating. Females were more active than males during the peri-nesting period in the spring. Seasonal changes in CORT were detected and did not differ between males and females. CORT concentrations were elevated in the late spring and summer, coincident with the foraging season, and depressed in the fall, and winter, and at their nadir in the early spring.

Characterization of 2 Novel Phosphodiesterase 2 Inhibitors Hcyb1 and PF-05180999 on Depression- and Anxiety-Like Behavior.

Phosphodiesterase 2A (PDE2A) represents a novel target for new therapies addressing psychiatric disorders. To date, the development of PDE2A inhibitors suitable for human clinical evaluation has been hampered by the poor brain accessibility and metabolic stability of the available compounds. Corticosterone (CORT)-induced neuronal cell lesion and restraint stress mouse model were used to measure the neuroprotective effect in cells and antidepressant-like behavior in mice. The cell-based assay showed that both Hcyb1 and PF were potent in protecting cells against stress hormone CORT insults by stimulating cAMP and cGMP signaling in hippocampal cells (HT-22). Administration of both compounds before treatment of CORT to cells increased cAMP/cGMP, VASP phosphorylation at Ser239 and Ser157, cAMP response element binding protein phosphorylation at Ser133, and brain derived neurotrophic factor BDNF expression. Further in vivo study showed that both Hcyb1 and PF displayed -antidepressant- and anxiolytic-like effects against restraint stress as indicated by reduced immobility time in the forced swimming and tail suspension tasks as well as increased open arm entries and time spent in open arms and holes visit in elevated plus maze and hole-board tests, respectively. The biochemical study confirmed that these antidepressant- and anxiolytic-like effects of Hcyb1 and PF were related to cAMP and cGMP signaling in the hippocampus. The results extend the previous studies and validate that PDE2A is a tractable target for drug development in the treatment of emotional disorders such as depression and anxiety.

Reducing lipid peroxidation attenuates stress-induced susceptibility to herpes simplex virus type 1.

Psychological stress increases the susceptibility to herpes simplex virus type 1 (HSV-1) infection. There is no effective intervention due to the unknown pathogenesis mechanisms. In this study we explored the molecular mechanisms underlying stress-induced HSV-1 susceptibility and the antiviral effect of a natural compound rosmarinic acid (RA) in vivo and in vitro. Mice were administered RA (11.7, 23.4 mg·kg-1·d-1, i.g.) or acyclovir (ACV, 206 mg·kg-1·d-1, i.g.) for 23 days. The mice were subjected to restraint stress for 7 days followed by intranasal infection with HSV-1 on D7. At the end of RA or ACV treatment, mouse plasma samples and brain tissues were collected for analysis. We showed that both RA and ACV treatment significantly decreased stress-augmented mortality and alleviated eye swelling and neurological symptoms in HSV-1-infected mice. In SH-SY5Y cells and PC12 cells exposed to the stress hormone corticosterone (CORT) plus HSV-1, RA (100 μM) significantly increased the cell viability, and inhibited CORT-induced elevation in the expression of viral proteins and genes. We demonstrated that CORT (50 μM) triggered lipoxygenase 15 (ALOX15)-mediated redox imbalance in the neuronal cells, increasing the level of 4-HNE-conjugated STING, which impaired STING translocation from the endoplasmic reticulum to Golgi; the abnormality of STING-mediated innate immunity led to HSV-1 susceptibility. We revealed that RA was an inhibitor of lipid peroxidation by directly targeting ALOX15, thus RA could rescue stress-weakened neuronal innate immune response, thereby reducing HSV-1 susceptibility in vivo and in vitro. This study illustrates the critical role of lipid peroxidation in stress-induced HSV-1 susceptibility and reveals the potential for developing RA as an effective intervention in anti-HSV-1 therapy.

Role of PGC-1α mediated synaptic plasticity, mitochondrial function, and neuroinflammation in the antidepressant effect of Zi-Shui-Qing-Gan-Yin.

Depression is the most prevalent psychiatric disorder, which needs deeper mechanism research studies and effective therapy. Zi-Shui-Qing-Gan-Yin (ZSQGY) is a traditional Chinese medicine decoction that has been widely used in China in the treatment of depressive symptoms. The aim of the study was to examine the anti-depressive effects of ZSQGY and the possible mechanism of action in the monosodium glutamate (MSG)-induced depressive model and the corticosterone (CORT)-induced PC12 cell model. Liquid chromatography-mass spectrometry (LC-MS) was performed to determine the major compounds in the water extract of ZSQGY. The depressive behaviors were evaluated by the field swimming test (FST), the sucrose preference test (SPT), and the open field test (OFT). Golgi staining and transmission electron microscopy (TEM) were performed to display the alterations of synaptic ultrastructure. The mitochondrion function and inflammatory factors were also quantified. The changes in peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α) expression were evaluated. The results of this study demonstrated that ZSQGY significantly improved depressive behaviors. ZSQGY also reversed the changes in synaptic plasticity, improved mitochondrion function, and reduced the levels of inflammatory factors. The neuroprotective effects were accompanied by the increased expression of PGC-1α. However, the beneficial changes were reversed after the inhibition of PGC-1α. These results indicated that ZSQGY effectively could improve depressive behaviors via the mechanisms that regulate synaptic structural plasticity, improve mitochondrion function, and alleviate neuroinflammation, which could, or partly, attribute to the regulation of PGC-1α.

Hippocampal BAIAP2 prevents chronic mild stress-induced depression-like behaviors in mice.

The pathogenesis of depression is closely related to changes in hippocampal synaptic plasticity; however, the underlying mechanism is still unclear. Brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2), a postsynaptic scaffold protein in excitatory synapses important for synaptic plasticity, is highly expressed in the hippocampus and has been implicated in several psychiatric disorders. However, the role of BAIAP2 in depression remains poorly understood. In the present study, a mouse model of depression was established via exposure to chronic mild stress (CMS). An adeno-associated virus (AAV) vector expressing BAIAP2 was injected into the hippocampal brain region of mice and a BAIAP2 overexpression plasmid was transfected into HT22 cells to upregulate BAIAP2 expression. Depression- and anxiety-like behaviors and dendritic spine density were examined in mice using behavioral tests and Golgi staining, respectively. In vitro, hippocampal HT22 cells were treated with corticosterone (CORT) to simulate the stress state, and the effect of BAIAP2 on CORT-induced cell injury was explored. Reverse transcription-quantitative PCR and western blotting were employed to determine the expression levels of BAIAP2 and those of the synaptic plasticity-related proteins glutamate receptor ionotropic, AMPA 1 (GluA1), and synapsin 1 (SYN1). Mice exposed to CMS exhibited depression- and anxiety-like behaviors accompanied by decreased levels of BAIAP2 in the hippocampus. In vitro, the overexpression of BAIAP2 increased the survival rate of CORT-treated HT22 cells and upregulated the expression of GluA1 and SYN1. Consistent with the in vitro data, the AAV-mediated overexpression of BAIAP2 in the hippocampus of mice significantly inhibited CMS-induced depression-like behavior, concomitant with increases in dendritic spine density and the expression of GluA1 and SYN1 in hippocampal regions. Our findings indicate that hippocampal BAIAP2 can prevent stress-induced depression-like behavior and may be a promising target for the treatment of depression or other stress-related diseases.

Chronic corticosterone improves perseverative behavior in mice during sequential reversal learning

BackgroundStressful life events can both trigger development of psychiatric disorders and promote positive behavioral changes in response to adversities. The relationship between stress and cognitive flexibility is complex, and conflicting effects of stress manifest in both humans and laboratory animals. ObjectiveTo mirror the clinical situation where stressful life events impair mental health or promote behavioral change, we examined the post-exposure effects of stress on cognitive flexibility in mice. MethodsWe tested female C57BL/6JOlaHsd mice in the touchscreen-based sequential reversal learning test. Corticosterone (CORT) was used as a model of stress and was administered in the drinking water for two weeks before reversal learning. Control animals received drinking water without CORT. Behaviors in supplementary tests were included to exclude non-specific confounding effects of CORT and improve interpretation of the results. ResultsCORT-treated mice were similar to controls on all touchscreen parameters before reversal. During the low accuracy phase of reversal learning, CORT reduced perseveration index, a measure of perseverative responding, but did not affect acquisition of the new reward contingency. This effect was not related to non-specific deficits in chamber activity. CORT increased anxiety-like behavior in the elevated zero maze test and repetitive digging in the marble burying test, reduced locomotor activity, but did not affect spontaneous alternation behavior. ConclusionCORT improved cognitive flexibility in the reversal learning test by extinguishing prepotent responses that were no longer rewarded, an effect possibly related to a stress-mediated increase in sensitivity to negative feedback that should be confirmed in a larger study.