Stress In Female Mice Research Articles

Fighting Females: Neural and Behavioral Consequences of Social Defeat Stress in Female Mice

BackgroundDespite the twofold higher prevalence of major depressive and posttraumatic stress disorders in women compared with men, most clinical and preclinical studies have focused on male subjects. We used an ethological murine model to study several cardinal symptoms of affective disorders in the female targets of female aggression. MethodsIntact Swiss Webster (CFW) female resident mice were housed with castrated male mice and tested for aggression toward female intruders. For 10 days, aggressive CFW female residents defeated C57BL/6J (B6) female intruders during 5-minute encounters. Measures of corticosterone, c-Fos activation in hypothalamic and limbic structures, and species-typical behaviors were collected from defeated and control females. Ketamine (20 mg/kg) was tested for its potential to reverse stress-induced social deficits. ResultsHoused with a castrated male mouse, most intact resident CFW females readily attacked unfamiliar B6 female intruders, inflicting >40 bites in a 5-minute encounter. Compared with controls, defeated B6 females exhibited elevated plasma corticosterone and increased c-Fos activation in the medial amygdala, ventral lateral septum, ventromedial hypothalamus, and hypothalamic paraventricular nucleus. Chronically defeated females also showed vigilance-like behavior and deficits in social interactions, novel object investigation, and nesting. The duration of social interactions increased 24 hours after chronically defeated female mice received a systemic dose of ketamine. ConclusionsThese findings demonstrate that CFW female mice living with male conspecifics can be used as aggressive residents in an ethological model of female social defeat stress. These novel behavioral methods will encourage further studies of sex-specific neural, physiological, and behavioral adaptations to chronic stress and the biological bases for interfemale aggression.

SAT-407 Evidence for Impaired Kisspeptin Signaling During Metabolic Stress in Female Mice

Stress impairs reproduction, at least in part, by suppressing gonadotropin secretion. One common metabolic stressor is hypoglycemia, which occurs in a variety of pathologies and in healthy people, particularly athletes. Insulin-induced hypoglycemia (IIH) is a repeatable, reliable, and quantifiable acute model of metabolic stress that inhibits pulsatile luteinizing hormone (LH) secretion, though little is known about the underlying mechanism. We have observed that IIH robustly suppresses LH pulses in female mice, which could be mediated by either a pituitary or hypothalamic effect. In the present study, we performed a kisspeptin challenge to determine whether downstream cells involved in LH pulsatility are impaired during IIH. Adult mice (C57/BL6, n = 8/group) were ovariectomized and acclimated to handling for tail-tip blood collection and i.p. injection. On the day of each challenge, mice were fasted for 5 hr and then received an i.p. injection of either saline or insulin (0.75mU/kg). All animals then received an injection of kisspeptin (2μg/g), 45 min later. This time point represents a consistent period of LH pulse suppression following IIH. Frequent blood samples were collected for 30 min before and after kisspeptin injection. Two-weeks later, the experiment was repeated with each mouse receiving the alternate treatment (i.e. insulin or saline) in a cross-over design. Mean LH concentrations were significantly increased after kisspeptin injection in animals treated with saline (saline, pre: 3.8 ± 0.6 vs. post: 7.8 ± 0.5 ng/ml). Interestingly, the LH response to kisspeptin in animals treated with insulin was also markedly increased (insulin, pre: 3.2 ± 0.6 vs. post: 6.4 ± 0.3 ng/ml), but not significantly different from animals treated with saline. We conclude from this study that impaired GnRH or gonadotrope cell function is not the primary cause of reduced LH secretion in this model of metabolic stress. Since kisspeptin neurons in the arcuate nucleus likely form the GnRH/LH pulse generator, we next determined whether arcuate kisspeptin cells were inhibited during IIH. For this purpose, we used a mouse model expressing GFP in kisspeptin cells (Kiss1-Cre-GFP). Mice were fasted and injected with insulin or saline, as above, and fixed neural tissue was collected for assessment of c-Fos immunoreactivity in arcuate Kiss1 cells. Two hours following saline injection ~20% of Kiss1 neurons contained c-Fos. In contrast, only 6.6 ± 0.5% of Kiss1 neurons contained c-Fos in animals treated with insulin. Thus, reduced gonadotropin secretion in IIH may be mediated by an inhibition of the ARC kisspeptin cells. Together these data support the hypothesis that inhibition of LH pulses by metabolic stress is mediated by neural factors including arcuate kisspeptin cells. Future work will investigate kisspeptin cell afferents that convey the inhibitory signal initiated by metabolic stressors.

Selenium Nanoparticles Attenuate Gentamycin-Induced Nephrotoxicity and Hematotoxicity in Female Swiss Albino Mice

Gentamycin (GM) is a widely used antibiotic for the treatment of Gram-negative bacterial infections, but nephrotoxic effects limit its use. Selenium nanoparticles (SeNPs) have attracted worldwide research interest due to their high bioavailability and potential antioxidant property. This study was, therefore, designed to examine the protective effect of SeNPs on GM-induced changes in body and kidney weights, blood hematology, serum biochemistry parameters, and renal tissue markers of oxidative stress in female mice. GM was administered intraperitoneally (100 mg/kgb.w) and SeNPs were given by oral gavage (2 mg/kg b.w) for 10 consecutive days. GM treatment caused significant changes in the body and relative kidney weights and significant renal damage, evidenced by increased serum levels of urea, uric acid, creatinine, total proteins, and blood urea nitrogen (BUN), along with noteworthy histopathological alterations. A marked decrease in serum sodium and potassium ions, and kidney tissue antioxidative defense system (reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT)) was observed in GM-treated mice when compared with the normal mice. Furthermore, significant decrease in total white blood corpuscles (WBC) count, total platelets count (PLT), total red blood corpuscles (RBC) count, hemoglobin concentration (Hgb), and packed cell volume (PCV) was also revealed in GM-treated group. However, GM + SeNPs group had effectively reversed GM-induced alteration of both biochemical and renal histological structures. Our results suggested for the first time that SeNPs are potent antioxidant candidate against GM-induced oxidative kidney toxicity and hematoxicity in mice.

Chronic restraint stress disturbs meiotic resumption through APC/C-mediated cyclin B1 excessive degradation in mouse oocytes

ABSTRACT Psychological stress, which exerts detrimental effects on human reproduction, may compromise the meiotic competence of oocytes. Meiotic resumption, germinal vesicle breakdown (GVBD), is the first milestone to confer meiotic competence to oocytes. In the practice of assisted reproductive technology (ART), the timing for GVBD is associated with the rates of cleavage and blastocyst formation. However, whether chronic stress compromises oocyte competence by influencing GVBD and the underlying mechanisms are unclear. In the present study, a chronic restraint stress (CRS) mouse model was used to investigate the effects of stress on oocyte meiotic resumption, as well as the mechanisms. Following a 4-week chronic restraint stress in female mice, the percentage of abnormal bipolar spindles increased and indicated compromised oocyte competence in the CRS group. Furthermore, we identified a decreased percentage of GVBD and prolonged time of GVBD in the CRS mouse oocytes compared with the control group. CRS simultaneously reduced the expression of cyclin B1 (CCNB1), which represents a regulatory subunit of M-phase/mature promoting factor (MPF). However, MG132, an inhibitor of anaphase-promoting complex/cyclosome (APC/C), could rescue the prolonged time of GVBD and increase the expression level of CCNB1 of oocytes from the CRS mice. Collectively, our results demonstrated that stress disturbed meiotic resumption through APC/C-mediated CCNB1 degradation, thus providing a novel understanding for stress-related oocyte quality decline; moreover, it may provide a non-invasive approach to select high-quality gametes and novel targets for molecular therapy to treat stress-related female infertility.

Learning to actively cope with stress in female mice

Repeated exposure to a same-sex resident stranger enhances subsequent indications of active coping that generalize across multiple contexts in intruder male mice. Here we investigate female mice for comparable learning to cope training effects. Stress coping research focused on females is important because stress related mood and anxiety disorders are more prevalent in women than men. Female mice were monitored for coping behavior in open-field, object-exploration, and tail-suspension tests conducted after repeated exposure to a same-sex resident stranger. During repeated exposure sessions of training staged in the resident’s home cage, behavioral measures of aggression and risk assessment were collected and plasma measures of the stress hormone corticosterone were obtained from separate samples of mice. Repeated exposure to a same-sex resident stranger subsequently enhanced active coping behavior exemplified by diminished freezing and increased center entries in the open-field, shorter object-exploration latencies, and a tendency toward decreased immobility on tail-suspension tests. Open-field locomotion considered as an index of non-specific activity was not increased by repeated sessions of exposure and did not correlate significantly with any measure of active coping. During repeated sessions of exposure to a same-sex resident stranger, risk assessment behavior and consistent but limited aggression occurred and corticosterone responses increased over repeated sessions. Exposure to a same-sex resident stranger is mildly stressful and promotes learning to actively cope in mice assessed in three different contexts.

What is stressful for females? Differential effects of unpredictable environmental or social stress in CD1 female mice

Stressful life events are a major factor in the etiology of several diseases, such as cardiovascular, inflammatory and psychiatric disorders (i.e., depression and anxiety), with the two sexes greatly differing in vulnerability. In humans and other animals, physiological and behavioral responses to stress are strongly dependent on gender, and conditions that are stressful for males are not necessarily stressful for females. Hence the need of an animal model of social chronic stress specifically designed for females. In the present study we aimed to compare the effects of two different chronic stress procedures in female mice, by investigating the impact of 4weeks of nonsocial unpredictable, physical stress by the Chronic Mild Stress paradigm (CMS; Exp.1) or of Social Instability Stress (SIS; Exp.2) on physiological, endocrine and behavioral parameters in adult female mice. CMS had a pronounced effect on females' response to novelty (i.e., either novel environment or novel social stimulus), body weight growth and hormonal profile. Conversely, 4weeks of social instability did not alter females' response to novelty nor hormonal levels but induced anhedonia. Our findings thus showed that female mice were more sensitive to nonsocial stress due to unpredictable physical environment than to social instability stressors. Neither of these stress paradigms, however, induced a consistent behavioral and physiological stress response in female mice comparable to that induced by chronic stress procedures in male mice, thus confirming the difficulties of developing a robust and validated model of chronic psychosocial stress in female mice.

A Novel Method for Chronic Social Defeat Stress in Female Mice.

Historically, preclinical stress studies have often omitted female subjects, despite evidence that women have higher rates of anxiety and depression. In rodents, many stress susceptibility and resilience studies have focused on males as one commonly used paradigm-chronic social defeat stress-has proven challenging to implement in females. We report a new version of the social defeat paradigm that works in female mice. By applying male odorants to females to increase resident male aggressive behavior, we find that female mice undergo repeated social defeat stress and develop social avoidance, decreased sucrose preference, and decreased time in the open arms of the elevated plus maze relative to control mice. Moreover, a subset of the female mice in this paradigm display resilience, maintaining control levels of social exploration and sucrose preference. This method produces comparable results to those obtained in male mice and will greatly facilitate studying female stress susceptibility.

Expression of the PPM1F Gene Is Regulated by Stress and Associated With Anxiety and Depression

BackgroundMolecular mechanisms underlying psychological sequelae of exposure to stressful experiences, such as posttraumatic stress disorder (PTSD) and depression, are not well understood. MethodsUsing convergent evidence from animal and human transcriptomic and genomic studies, we aimed to identify genetic mechanisms underlying depression and anxiety after traumatic experiences. ResultsFrom a transcriptome-wide analysis in mice, we found the Ppm1f gene to be differentially expressed in the amygdala and medial prefrontal cortex (mPFC) a week after immobilization stress. Next, we found that PPM1F messenger RNA levels in human blood were downregulated in cases with symptoms of comorbid PTSD and depression and consistently in cases with anxiety symptoms in a separate human dataset. Furthermore, we showed that a genetic variant of PPM1F, rs17759843, was associated with comorbid PTSD and depression and with PPM1F expression in both human brain and blood. Given prior reported mechanistic links between PPM1F and CAMK2 (CAMKII), we examined blood messenger RNA level of CAMK2G in humans and found it to be lower in cases with comorbid PTSD and depression. We also found that PPM1F protein levels and colocalization with CAMK2G were altered in amygdala and mPFC of male mice. Additionally, we found that a systemic dose of corticosterone blocked the depressive-like phenotype elicited by stress in female mice. Lastly, corticosterone rescued the anxiety-like phenotype and messenger RNA levels of Ppm1f in amygdala and mPFC in male mice and in mPFC of female mice. ConclusionsTaken together, our data suggest a mechanistic pathway involving PPM1F and CAMK2G in stress- and trauma-related manifestation of anxiety and depression across species.

Reduced hippocampal IL-10 expression, altered monoaminergic activity and anxiety and depressive-like behavior in female mice subjected to chronic social instability stress

Evidence indicates that release of pro-inflammatory cytokines induced by social stress contributes to affective disorders. Additionally, there are known sex differences in both the stress response and the stressors that can elicit this response. In this regard, the chronic social instability (CSI) rodent model of stress appears to be the best fit for the social nature of females. This study analyzed the effects of CSI on female mouse behavior, hippocampal cytokine expression, tryptophan metabolism and monoaminergic activity. The activity of hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes were also measured. Results showed a decrease in sucrose consumption in stressed subjects, indicative of anhedonic behavior and an increase in climbing activity in the forced swimming test (FST) and in whisking behavior, which have been associated with anxiety. Decreased interleukin-10 (IL-10) expression was found in the hippocampus of the stressed mice, while no differences in pro-inflammatory cytokine expression and tryptophan (TRYP), kynurenine (KYN) or 3-hydroxy kynurenine (3-HK) levels were found. Increased hippocampal serotoninergic and noradrenergic activity was observed in stressed mice. The higher plasma corticosterone and lower hypothalamic glucocorticoid receptor (GR) expression levels showed an increase in HPA activity after CSI. No differences were found in the plasma estradiol levels or the central estrogen receptors (ERα and ERβ) expression levels. These data indicate that the CSI stress-induced behavioral and physiological changes associated with anxiety and depressive disorders. Although additional studies are warranted, the results suggest an involvement of anti-inflammatory cytokines in the biobehavioral effects of social stress in female mice.

INHIBITING GLUCOCORTICOID RECEPTOR DIMERIZATION BLOCKS EFFECTS OF ACUTE STRESS ON Aβ IN FEMALE MICE

Results from both human and animal studies over the last decade have identified a clear increase in the rate of Alzheimer's disease (AD) in women. Sex differences in the prevalence or severity of many diseases are well recognized. A common underlying feature of disorders more prevalent in females is an association with stress, such as in anxiety and depression. Stress increases glucocorticoids (GC) in the brain, and the link between GCs and AD has been confirmed by several studies. We previously found that acute stress rapidly increases levels of Aβ in the mouse brain. GCs function through a nuclear GC receptor (GR) that acts as a dimer to facilitate transactivation or as a monomer to repress transcription (transrepression). The sex-related differences in transactivation versus transrepression remain unclear and the influence of either pathway on AD pathology has not been defined. Using microdialysis, Aβ levels in the interstitial fluid (ISF) of the hippocampus were measured in male and female APP/PS1 mice (3–4 months old). Samples were collected every hour for a baseline period, 3-hour restraint stress, and 12-hour post stress period. To evaluate the effects of blocking the transactivation arm of GR signaling through GR dimerization, we crossed APP/PS1 mice with the glucocorticoid receptor dimerization deficient mouse model (GRdim), to create GRdim APP mice. We also studied the effects of pharmacologically blocking GR dimerization using Compound A, administered via reverse microdialysis before restraint stress. We observed a significant difference between male and female mice in the percent increase in ISF Aβ during acute stress, with female mice having a much greater and sustained increase in ISF Aβ compared to males. ISF Aβ levels in female GRdim APP mice did not rise dramatically during acute stress, and stayed near baseline during the post stress period. Compound A completely blocked the increase in ISF Aβ induced by restraint stress in female mice. These results suggest that females are more sensitive to stress-induced increases in Aβ, and that acute stress increases Aβ in female mice through a GR dimerization dependent mechanism.

Abstract # 1734 Effect of chronic social instability stress on behavior, cytokine and GR receptor expression and monoaminergic brain activity in female mice

Studies show that women are at greater risk of developing stress related disorders such as depression or anxiety. It is also known that sex differences exist in the inflammatory response and that altered inflammatory signaling in the brain is involved in the development of affective disorders, possibly through its effect on neurotransmitter metabolism. This study analyzes changes in pro and anti-inflammatory cytokine expression and monoaminergic activity in the hippocampus, as well as changes in the HPA axis and behavior after exposure to chronic social instability stress in female mice. Results indicate increased HPA axis activity in stressed mice, manifested by higher plasma corticosterone levels and lower GR expression levels in the hypothalamus. No differences were found in hippocampal Il-6 and TNF-alpha proinflammatory cytokines, although a reduction was observed in IL-10 expression, accompanied by increased serotoninergic and noradrenergic activity. Stressed mice also showed a decrease in sucrose consumption, supporting the idea that in addition to proinflammatory cytokines, depressive behavior may also be influenced independently by the suppression of anti-inflammatory agents. Nevertheless, in the forced swimming test only was observed an increase in climbing behavior. This finding, alongside the increased noradrenergic and serotoninergic activity observed, may be indicative of anxiety. Data suggest that the social instability model may be useful to study different mechanisms involved in the development of stress-related psychopathologies in females.

Temporary amygdala inhibition reduces stress effects in female mice

The current study investigated the effect of temporary inhibition of amygdala in response to metabolic changes caused by stress in female mice. Unilateral and bilateral amygdala cannulation was carried out, and after a week of recovery, 2% lidocaine hydrochloride was injected into the mice amygdalae five minutes before the induction of stress. A communication box was employed to induce stress for four consecutive days and plasma corticosterone, food and water intake, weight changes, and anorexia were measured as stress-induced metabolic changes. Results demonstrated that stress, increases stress, increased plasma corticosterone concentrations, weight, food, and water intake. Temporary inhibition of the amygdala slightly decreased plasma corticosterone concentrations, but did not fully reduce the effect of stress. The bilateral injection of lidocaine hydrochloride to the amygdala reduced the effect of stress and reduced water intake and weight. Unilateral injection of lidocaine hydrochloride into the left and right amygdala reduced food intake. In conclusion, the present study demonstrated that the left side and right side of amygdala nuclei play a different role in metabolic responses in stress.

Prenatal SSRI alters the hormonal and behavioral responses to stress in female mice: Possible role for glucocorticoid resistance

Life time prevalence of major depression disorder (MDD) is higher in women compared to men especially during the period surrounding childbirth. Women suffering from MDD during pregnancy use antidepressant medications, particularly Selective Serotonin Reuptake Inhibitors (SSRI). These drugs readily cross the placental barrier and impact the developing fetal brain. The present study assessed the effects of prenatal exposure to fluoxetine (FLX), an SSRI antidepressant drug, on corticosterone and behavioral responses to stress in female mice. In young females, prenatal FLX significantly elevated corticosterone response to continuous stress. In adults, prenatal FLX augmented corticosterone response to acute stress and suppressed the response to continuous stress. Additionally, prenatal FLX significantly augmented stress-induced increase in locomotion and reduced anxiety- and depressive-like behaviors in adult, but not young mice. The dexamethasone suppression test revealed that prenatal FLX induced a state of glucocorticoid resistance in adult females, indicating that the negative feedback control of the hypothalamic-pituitary-adrenal axis response to stress was disrupted. These findings provide the first indication of altered hormonal and behavioral responses to continuous stress and suggest a role for the development of glucocorticoid resistance in these effects. According to these findings, prenatal environment may have implications for stress sensitivity and responsiveness to life challenges. Furthermore, this study may assist in understanding the limitations and precautions that should be taken in the use of SSRIs during pregnancy.

Sex Differences in Airway Remodeling in a Mouse Model of Chronic Obstructive Pulmonary Disease.

After adjustment for the amount of smoking, women have a 50% increased risk of chronic obstructive pulmonary disease (COPD) compared with men. The anatomic basis and/or mechanism(s) of these sex-related differences in COPD are unknown. To characterize the impact of female sex hormones on chronic cigarette smoke-induced airway remodeling and emphysema in a mouse model of COPD. Airway remodeling and emphysema were determined morphometrically in male, female, and ovariectomized mice exposed to 6 months of cigarette smoke. Antioxidant- and transforming growth factor (TGF)-β-related genes were profiled in airway tissues. The selective estrogen receptor modulator tamoxifen was also administered during smoke exposure in a short-term model. Airway wall thickness of male and female human smokers at risk of or with mild COPD was measured using optical coherence tomography. Small airway wall remodeling was increased in female but not male or ovariectomized mice and was associated with increased distal airway resistance, down-regulation of antioxidant genes, increased oxidative stress, and activation of TGF-β1. These effects were prevented by ovariectomy. Use of tamoxifen as a therapeutic intervention mitigated smoke-induced increase in oxidative stress in female mice. Compared with male human smokers, female human smokers had significantly thicker airway walls. The excess risk of small airway disease in female mice after chronic smoke exposure was associated with increased oxidative stress and TGF-β1 signaling and also was related to the effects of female sex hormones. Estrogen receptor antagonism might be of value in reducing oxidative stress in female smokers.

Effects of Mineralocorticoid Receptor Overexpression on Anxiety and Memory after Early Life Stress in Female Mice.

Early-life stress (ELS) is a risk factor for the development of psychopathology, particularly in women. Human studies have shown that certain haplotypes of NR3C2, encoding the mineralocorticoid receptor (MR), that result in gain of function, may protect against the consequences of stress exposure, including childhood trauma. Here, we tested the hypothesis that forebrain-specific overexpression of MR in female mice would ameliorate the effects of ELS on anxiety and memory in adulthood. We found that ELS increased anxiety, did not alter spatial discrimination and reduced contextual fear memory in adult female mice. Transgenic overexpression of MR did not alter anxiety but affected spatial memory performance and enhanced contextual fear memory formation. The effects of ELS on anxiety and contextual fear were not affected by transgenic overexpression of MR. Thus, MR overexpression in the forebrain does not represent a major resilience factor to early life adversity in female mice.

Pituitary CRH-binding protein and stress in female mice

The CRH-binding protein (CRH-BP) binds CRH with very high affinity and inhibits CRH-mediated ACTH release from anterior pituitary cells in vitro, suggesting that the CRH-BP functions as a negative regulator of CRH activity. Our previous studies have demonstrated sexually dimorphic expression of CRH-BP in the murine pituitary. Basal CRH-BP expression is higher in the female pituitary, where CRH-BP mRNA is detected in multiple anterior pituitary cell types. In this study, we examined stress-induced changes in CRH-BP mRNA and protein expression in mouse pituitary and assessed the in vivo role of CRH-BP in modulating the stress response. Pituitary CRH-BP mRNA was greater than 200-fold more abundant in females than males, and restraint stress increased pituitary CRH-BP mRNA by 11.8-fold in females and 3.2-fold in males as assessed by qRT-PCR. In females, restraint stress increased CRH-BP mRNA levels not only in POMC-expressing cells, but also in PRL-expressing cells. The increase in female pituitary CRH-BP mRNA following stress resulted in significant increases in CRH-BP protein 4–6h after a 30-minute restraint stress as detected by [125I]-CRH:CRH-BP cross-linking analyses. Based on this temporal profile, the physiological role of CRH-BP was assessed using a stressor of longer duration. In lipopolysaccharide (LPS) stress studies, female CRH-BP-deficient mice showed elevated levels of stress-induced corticosterone release as compared to wild-type littermates. These studies demonstrate a role for the pituitary CRH-BP in attenuating the HPA response to stress in female mice.

Lower susceptibility of female mice to acetaminophen hepatotoxicity: Role of mitochondrial glutathione, oxidant stress and c-jun N-terminal kinase

Acetaminophen (APAP) overdose causes severe hepatotoxicity in animals and humans. However, the mechanisms underlying the gender differences in susceptibility to APAP overdose in mice have not been clarified. In our study, APAP (300mg/kg) caused severe liver injury in male mice but 69–77% lower injury in females. No gender difference in metabolic activation of APAP was found. Hepatic glutathione (GSH) was rapidly depleted in both genders, while GSH recovery in female mice was 2.6 fold higher in the mitochondria at 4h, and 2.5 and 3.3 fold higher in the total liver at 4h and 6h, respectively. This faster recovery of GSH, which correlated with greater induction of glutamate-cysteine ligase, attenuated mitochondrial oxidative stress in female mice, as suggested by a lower GSSG/GSH ratio at 6h (3.8% in males vs. 1.4% in females) and minimal centrilobular nitrotyrosine staining. While c-jun N-terminal kinase (JNK) activation was similar at 2 and 4h post-APAP, it was 3.1 fold lower at 6h in female mice. However, female mice were still protected by the JNK inhibitor SP600125. 17β-Estradiol pretreatment moderately decreased liver injury and oxidative stress in male mice without affecting GSH recovery. Conclusion: The lower susceptibility of female mice is achieved by the improved detoxification of reactive oxygen due to accelerated recovery of mitochondrial GSH levels, which attenuates late JNK activation and liver injury. However, even the reduced injury in female mice was still dependent on JNK. While 17β-estradiol partially protects male mice, it does not affect hepatic GSH recovery.

Schizophrenia‐like behaviors in the offspring after maternal stress and prenatal NMDA receptor hypofunction (1144.9)

Pharmacological animal models have been developed and used to study the neurobiological deficits most commonly associated with schizophrenia. Evidence suggests that NMDA receptor (NMDAR) activity is an integral component in the pathophysiology of the disease, because antagonizing this receptor leads to schizophrenic‐like neurophysiological alterations and behaviors. In this study we sought to determine the influence of maternal NMDAR hypofunction combined with stress in the outcome of schizophrenia‐like behaviors of the offspring. After daily prenatal injections of MK‐801 and induction of stress in female mice, pregnancy was allowed to ensue and the litter was allowed to develop to P21‐P30. Analysis of schizophrenia‐like behaviors was performed on the offspring by measuring cognition as well as anxiety and other related behaviors. Our results suggest that maternal NMDAR dysfunction together with environmental stress impact the neurodevelopmental status of the offspring. These results not only strengthen the view that NMDAR function is involved in normal brain development, but also show that changes induced prenatally can affect the brains of the offspring.

Circulating and Urinary Adrenal Corticosterone, Progesterone, and Estradiol in Response to Acute Stress in Female Mice (Mus musculus)

In studies of stress, it can be difficult to obtain blood rapidly enough to avoid confounding steroid measures. Noninvasive urinary steroid measures may provide an alternative insofar as they reflect systemic steroids. In Experiment 1, we profiled urinary corticosterone, progesterone, and estradiol in ovariectomized female mice following 1 h on an elevated platform. This increased urinary corticosterone for 3 h and progesterone for 4 h. In Experiment 2, blood and urine samples were obtained at 0-6 h following stressor offset. Females showed increased serum corticosterone and progesterone immediately after stressor offset. Urinary corticosterone was increased at both 0 and 2 h post-stress, while an increase in progesterone 2-6 h after stressor offset was not significant. Estradiol was not influenced by this mild stressor. In Experiment 3, mice were exposed to a more severe 1 h stressor, a rat across a wire-mesh grid. In serum, both corticosterone and progesterone were elevated immediately after stressor offset and returned to baseline within 2 h. In urine, this severe stressor elevated corticosterone immediately and 2 h after stressor offset, and in progesterone 2 h after stressor offset. Estradiol in serum was not dynamic, but it was significantly elevated in urine 4 h after stressor offset. Urinary measures generally reflected systemic measures; however, with a different time course resulting in a longer return to baseline. We suggest that the relative value of serum or urinary steroid measures in mice depends upon the experimental design, and that estradiol may only respond when the stressor is severe.

A novel chronic social stress paradigm in female mice

Major depression is one of the most prevalent stress-related psychiatric diseases. Next to environmental influences such as chronic social stress, gender is among the strongest risk factors for major depression, with women having a twice as high risk to develop the disease compared to men. While there is abundant literature on the effects of chronic social stress in male rodents, there is a serious lack of information on gender-specific effects. Especially in mice, which due to the wide availability of transgenic lines offer a unique opportunity to study gene × environment interactions, there is no existing model of chronic social stress that is applicable to both sexes. We here describe the effects of chronic social stress based on the disruption of the social network in a group-housed situation in female mice, a model that was recently described and validated for male mice. In this model, the group composition of the mice is changed twice per week for a period of 7 weeks, covering the adolescent and early adulthood period. We observed that housing in an unpredictable social environment resulted in chronic stress in female mice. The observed effects, which included increased adrenal weight, decreased thymus weight, increased corticosterone levels, and increased anxiety-like behavior, were very similar to the described effects of this paradigm in male mice. In addition, we observed a distinct expression of stress system-related genes in female mice following chronic stress exposure. Our results validate this model as a suitable approach to study chronic social stress in female mice and open up the opportunity to use this model with transgenic or knockout mouse lines.