Sex,stress, and epigenetics: regulation of behavior in animal models of mood disorders

Stress-related psychiatric disorders, such as unipolar depression and post-traumatic stress disorder (PTSD), occur more frequently in women than in men. Emerging research suggests that sex differences in receptors for the stress hormones, corticotropin releasing factor (CRF) and glucocorticoids, contribute to this disparity. For example, sex differences in CRF receptor binding in the amygdala of rats may predispose females to greater anxiety following stressful events. Additionally, sex differences in CRF receptor signaling and trafficking in the locus coeruleus arousal center combine to make females more sensitive to low levels of CRF, and less adaptable to high levels. These receptor differences in females could lead to hyperarousal, a dysregulated state associated with symptoms of depression and PTSD. Similar to the sex differences observed in CRF receptors, sex differences in glucocorticoid receptor (GR) function also appear to make females more susceptible to dysregulation after a stressful event. Following hypothalamic pituitary adrenal axis activation, GRs are critical to the negative feedback process that inhibits additional glucocorticoid release. Compared to males, female rats have fewer GRs and impaired GR translocation following chronic adolescent stress, effects linked to slower glucocorticoid negative feedback. Thus, under conditions of chronic stress, attenuated negative feedback in females would result in hypercortisolemia, an endocrine state thought to cause depression. Together, these studies suggest that sex differences in stress-related receptors shift females more easily into a dysregulated state of stress reactivity, linked to the development of mood and anxiety disorders. The implications of these receptor sex differences for the development of novel pharmacotherapies are also discussed.     

Relevance of stress and female sex hormones for emotion and cognition

There are clear sex differences in incidence and onset of stress-related and other psychiatric disorders in humans. Yet, rodent models for psychiatric disorders are predominantly based on male animals. The strongest argument for not using female rodents is their estrous cycle and the fluctuating sex hormones per phase which multiplies the number of animals to be tested. Here, we will discuss studies focused on sex differences in emotionality and cognitive abilities in experimental conditions with and without stress. First, female sex hormones such as estrogens and progesterone affect emotions and cognition, contributing to sex differences in behavior. Second, females respond differently to stress than males which might be related to the phase of the estrous cycle. For example, female rats and mice express less anxiety than males in a novel environment. Proestrus females are less anxious than females in the other estrous phases. Third, males perform in spatial tasks superior to females. However, while stress impairs spatial memory in males, females improve their spatial abilities, depending on the task and kind of stressor. We conclude that the differences in emotion, cognition and responses to stress between males and females over the different phases of the estrous cycle should be used in animal models for stress-related psychiatric disorders.     

Gender related differences in quality of life and affective status in patients with inflammatory bowel disease

According to the literature, quality of life has been shown to be reduced in females compared with males with Inflammatory Bowel Disease (IBD). Psychosocial factors are also playing an important role in IBD, especially emotional lability. The aims of study was to investigate the sex differences in general and specific health-related quality of life (HRQoL), anxiety and depression in IBD patients. Hundred and twelve outpatients of the Gastroenterology Division, Clinical Hospital Centre Rijeka, were enrolled in our study and divided in two groups: 50 females (31 with ulcerative colitis, UC and 19 with Crohn disease, CD) and 62 males (30 with UC and 32 with CD), age range 19 to 74 (M = 41.46; SD = 13.06). Most patients have been in long clinical remission or with mild disease according to Clinical Disease Activity Index (CDAI) score for CD and Clinical Activity Index (CAI) score for UC. There were significant differences in physical (F = 13.96, p < .0001) and mental (F = 9.44, p < .001) component of the general HRQoL, emotional domain ((F = 9.26, p < .001) and bowel symptoms (F = 7.04, p < .001) of the Inflammatory Bowel Disease Quality of life (IBDQoL), as well as, in anxiety (F = 7.03, p < .001) and depression (F = 12.09, p < .0001) between men and women with IBD. Women have expressed significantly lower level of the general HRQoL and more emotional disturbances connected with their disease as well as more frequent bowel symptoms compared with men. Effect sizes of those differences were large. Results of this study confirm that women with IBD are more prone to the negative impact of the disease on their HRQoL than men. Women with higher level of depression and anxiety experienced more emotional disturbances, bowel and systemic symptoms and lower general HRQoL. These results should deserve more considerations in the clinical treatment of IBD patients.     

Anxiety symptomatology,sex and chronotype: The mediational effect of diurnal sleepiness

ABSTRACT

Diurnal subjective sleepiness has been associated with a large number of negative outcomes, such as increased risk of accidents and development of mental disorders as depression and anxiety. However, the role of the diurnal subjective sleepiness as a mediator is poorly understood. The goal of the present study was to examine the role of diurnal subjective sleepiness as a mediator of the relationship between sex, chronotype and anxiety symptoms in healthy young adults. Four-hundred and sixty-seven healthy young adults (64.8% females, age range 18–32 years, mean 20.7, ±2.3) were evaluated with validated and widely used scales for the measurement of diurnal sleepiness, anxiety symptoms and morningness–eveningness preference. We have found that diurnal subjective sleepiness correlated with anxiety symptoms when evaluated both in the total sample and within chronotypes. This association was more important in females than in males (p < 0.0001). Regarding chronotype, only for morning-types, diurnal subjective sleepiness was a significant mediator of the relationship between sex and anxiety symptoms. This is the first study that examines the mediator role of diurnal subjective sleepiness in the known relationship between sex and anxiety symptoms, and adds new evidence about the effect of the chronotype on sleep problems and mental health. Although future work is required, our results have important implications for clinical settings and public health interventions.     

A behavioral comparison of male and female adults with high functioning autism spectrum conditions

Autism spectrum conditions (ASC) affect more males than females in the general population. However, within ASC it is unclear if there are phenotypic sex differences. Testing for similarities and differences between the sexes is important not only for clinical assessment but also has implications for theories of typical sex differences and of autism. Using cognitive and behavioral measures, we investigated similarities and differences between the sexes in age- and IQ-matched adults with ASC (high-functioning autism or Asperger syndrome). Of the 83 (45 males and 38 females) participants, 62 (33 males and 29 females) met Autism Diagnostic Interview-Revised (ADI-R) cut-off criteria for autism in childhood and were included in all subsequent analyses. The severity of childhood core autism symptoms did not differ between the sexes. Males and females also did not differ in self-reported empathy, systemizing, anxiety, depression, and obsessive-compulsive traits/symptoms or mentalizing performance. However, adult females with ASC showed more lifetime sensory symptoms (p = 0.036), fewer current socio-communication difficulties (p = 0.001), and more self-reported autistic traits (p = 0.012) than males. In addition, females with ASC who also had developmental language delay had lower current performance IQ than those without developmental language delay (p<0.001), a pattern not seen in males. The absence of typical sex differences in empathizing-systemizing profiles within the autism spectrum confirms a prediction from the extreme male brain theory. Behavioral sex differences within ASC may also reflect different developmental mechanisms between males and females with ASC. We discuss the importance of the superficially better socio-communication ability in adult females with ASC in terms of why females with ASC may more often go under-recognized, and receive their diagnosis later, than males.     

Stress experienced in utero reduces sexual dichotomies in neurogenesis, microenvironment, and cell death in the adult rat hippocampus

Hippocampal function and plasticity differ with gender, but the regulatory mechanisms underlying sex differences remain elusive and may be established early in life. The present study sought to elucidate sex differences in hippocampal plasticity under normal developmental conditions and in response to repetitive, predictable versus varied, unpredictable prenatal stress (PS). Adult male and diestrous female offspring of pregnant rats exposed to no stress (control), repetitive stress (PS-restraint), or a randomized sequence of varied stressors (PS-random) during the last week of pregnancy were examined for hippocampal proliferation, neurogenesis, cell death, and local microenvironment using endogenous markers. Regional volume was also estimated by stereology. Control animals had comparable proliferation and regional volume regardless of sex, but females had lower neurogenesis compared to males. Increased cell death and differential hippocampal precursor kinetics both appear to contribute to reduced neurogenesis in females. Reduced local interleukin-1beta (IL-1beta) immunoreactivity (IR) in females argues for a mechanistic role for the anti-apoptotic cytokine in driving sex differences in cell death. Prenatal stress significantly impacted the hippocampus, with both stress paradigms causing robust decreases in actively proliferating cells in males and females. Several other hippocampal measures were feminized in males such as precursor kinetics, IL-1beta-IR density, and cell death, reducing or abolishing some sex differences. The findings expand our understanding of the mechanisms underlying sex differences and highlight the critical role early stress can play on the balance between proliferation, neurogenesis, cell death, and hippocampal microenvironment in adulthood.     

Sex differences and sex hormones in anxiety-like behavior of aging rats

Sex differences in the prevalence of affective disorders might be attributable to different sex hormone milieu. The effects of short-term sex hormone deficiency on behavior, especially on anxiety have been studied in numerous animal experiments, mainly on young adult rats and mice. However, sex differences in aged animals and the effects of long-term hypogonadism are understudied. The aim of our study was to analyze sex differences in anxiety-like behavior in aged rats and to prove whether they can be attributed to endogenous sex hormone production in males. A battery of tests was performed to assess anxiety-like behavior in aged female, male and gonadectomized male rats castrated before puberty. In addition, the aged gonadectomized male rats were treated with a single injection of estradiol or testosterone or supplemented with estradiol for two-weeks. Female rats displayed a less anxious behavior than male rats in most of the conducted behavioral tests except the light-dark box. Long-term androgen deficiency decreased the sex difference in anxiety either partially (open field, PhenoTyper cage) or completely (elevated plus maze). Neither single injection of sex hormones, nor two-week supplementation of estradiol in gonadectomized aged male rats significantly affected their anxiety-like behavior in the elevated plus maze. In conclusion, our results confirm sex differences in anxiety in aged rats likely mediated by endogenous testosterone production in males. Whether long-term supplementation with exogenous sex hormones could affect anxiety-like behavior in elderly individuals remains to be elucidated.     

Maternal glucocorticoid hormones as a factor mediating the effect of prenatal stress on offspring anxiety

The plus-maze behavior was studied in offsprings of female rats subjected to immobilization stress on the 15-18 days of pregnancy. Prenatal stress decreased the level of anxiety in males and increased in females. The blockade of the mother's stress-induced glucocorticoid secretion by prior adrenalectomy and subsequent corticosterone injection during immobilization in a low dose (0.3 mg/kg) prevented the behavioral disorders in offsprings. In case of a higher dose of corticosterone (3 mg/kg) injection, the behavior of offsprings was the same as that of offsprings of the intact mothers subjected to immobilization. The results suggest that the stress-induced increase in maternal glucocorticoid level may be the mechanism by which prenatal stress impairs the development of sex differences in rat anxiety behavior.     

Changes in the neuroendocrine regulation of adaptive behavior in rats subjected to stress in the late prenatal ontogenesis]

Female rats were subjected from the 14th to 17th day of pregnancy to immobilisation under conditions of 1-hour daily bright illumination. On the 20th day, contents of testosterone and estradiol was decreased with no sex difference in their level in the pregnant female rats' blood and in the amniotic fluid. Sex differences were flattened in 1-month litter both in the androgen and oestrogen contents and in adaptive behaviour. In prenatally stressed males, motor activity was inhibited and anxiety was enhanced as compared with the control. At one and a half months of age, the consequences of the prenatal stress disappeared and then reappeared after sexual maturation but with an opposite trend. Adaptive behaviour of adult males was less flexible and revealed no age-dependent oscillations inherent in the control animals. Prenatal stress while preventing the maximal raise of sex steroids in the blood shifts sex differentiation of the adaptive behaviour toward demasculinization.     

Sex, glia, and development: Interactions in health and disease

This article is part of a Special Issue "Neuroendocrine-Immune Axis in Health and Disease." Microglia and astrocytes are the primary immune cells within the central nervous system. Microglia influence processes including neural development, synaptic plasticity and cognition; while their activation and production of immune molecules can induce stereotyped sickness behaviors or pathologies including cognitive dysfunction. Given their role in health and disease, we propose that glia may also be a critical link in understanding the etiology of many neuropsychiatric disorders that present with a strong sex-bias in their symptoms or prevalence. Specifically, males are more likely to be diagnosed with disorders that have distinct developmental origins such as autism or schizophrenia. In contrast, females are more likely to be diagnosed with disorders that present later in life, after the onset of adolescence, such as depression and anxiety disorders. In this review we will summarize the evidence suggesting that sex differences in the colonization and function of glia within the normal developing brain may contribute to distinct windows of vulnerability between males and females. We will also highlight the current gaps in our knowledge as well as the future directions and considerations of research aimed at understanding the link between neuroimmune function and sex differences in mental health disorders.     

Psychosocial effects of radiotherapy after mastectomy.

Psychosocial morbidity was measured in 47 patients who received postoperative radiotherapy and in 38 who received no further treatment after mastectomy. Roughly one third of all patients experienced depression or anxiety. One month after operation, before radiotherapy, there were no significant differences between the two groups in any of the measures of psychosocial morbidity. Knowledge of impending treatment did not seem to influence morbidity. At three months patients who had completed radiotherapy had significantly more somatic symptoms and social dysfunction than those not so treated. At six months the radiotherapy group continued to show more somatic symptoms, but a year after operation there were no significant differences between the groups. Although several patients who received radiotherapy were upset by their treatment, the study failed to confirm that depression and anxiety were commoner among those given radiotherapy than among patients given no further treatment.     

Sex differences in behavioral and corticosterone responses to mild stressors in ICR mice are altered by ovariectomy in peripubertal period

Among rodents, females are generally considered to be highly responsive in terms of emotionality under stressful conditions, and have higher corticosterone levels and activity. In this study, we examined sex differences in mice by evaluating anxiety behaviors and corticosterone responses to mild stressors. In our first experiment, we analyzed the behavioral and corticosterone responses to the elevated plus-maze test and open-field test in male and female mice, and compared sex differences. Principal component analysis (PCA) was used to investigate the correlation of these responses between males and females. The corticosterone level was higher in females under both basal and stressed conditions. In the behavioral response, higher locomotor activity was seen in females in the elevated plus-maze test. PCA showed little association among anxiety behavior, locomotor activity, and corticosterone secretion. In our second experiment, we examined the activational effects of sex steroids on the corticosterone response to the elevated plus-maze test by gonadectomizing male and female mice and using testosterone or estrogen capsules as hormonal replacements. Sex differences at the basal corticosterone level were not altered by the hormonal milieu in adults, however the higher corticosterone level of females in response to stress was diminished by ovariectomy, although replacement with neither testosterone nor estrogen had any effect. These results suggest that the sex difference in novelty exposure observed in the form of a greater hypothalamic-pituitary-adrenal (HPA) axis response in female ICR mice is controlled by ovary-derived factors in adults.     

Sex differences in the response to influenza virus infection: modulation by stress

Influenza virus infection is a significant public health problem; however factors affecting the incidence and severity of disease have not been fully elucidated. The present study sought to examine the role of sex and stress in mediating susceptibility to an influenza viral infection in mice. Male and female mice underwent repeated cycles of restraint (RST) stress, followed by an influenza A/PR8 virus infection. Following these manipulations, levels of circulating corticosterone, lung proinflammatory cytokine gene expression and sickness behavior were examined. The data indicate sex differences in several aspects of the response to the A/PR8 virus infection. The kinetics of lung interleukin-1β mRNA expression were faster in infected males compared to females, while circulating corticosterone levels were elevated in infected females, but not in males. Anorexia and reduced saccharin consumption began earlier and symptoms were more pronounced in infected males than in females. In addition, RST modulated the response to the A/PR8 virus infection. Proinflammatory cytokine gene expression in response to infection was enhanced and sickness behavior was modulated by RST in both males and females. These data suggest that males mount more vigorous immune and behavioral responses to influenza viral infection compared to females, and stress exacerbates the response in both males and females. In conclusion, complex interactions between biological and behavioral factors are involved in mediating individual differences in health and disease. Additional studies may help uncover some of the factors contributing to the individual differences in susceptibility to influenza infection.     

Stress amplifies sex differences in primate prefrontal profiles of gene expression

Background

Stress is a recognized risk factor for mood and anxiety disorders that occur more often in women than men. Prefrontal brain regions mediate stress coping, cognitive control, and emotion. Here, we investigate sex differences and stress effects on prefrontal cortical profiles of gene expression in squirrel monkey adults.

Methods

Dorsolateral, ventrolateral, and ventromedial prefrontal cortical regions from 18 females and 12 males were collected after stress or no-stress treatment conditions. Gene expression profiles were acquired using HumanHT-12v4.0 Expression BeadChip arrays adapted for squirrel monkeys.

Results

Extensive variation between prefrontal cortical regions was discerned in the expression of numerous autosomal and sex chromosome genes. Robust sex differences were also identified across prefrontal cortical regions in the expression of mostly autosomal genes. Genes with increased expression in females compared to males were overrepresented in mitogen-activated protein kinase and neurotrophin signaling pathways. Many fewer genes with increased expression in males compared to females were discerned, and no molecular pathways were identified. Effect sizes for sex differences were greater in stress compared to no-stress conditions for ventromedial and ventrolateral prefrontal cortical regions but not dorsolateral prefrontal cortex.

Conclusions

Stress amplifies sex differences in gene expression profiles for prefrontal cortical regions involved in stress coping and emotion regulation. Results suggest molecular targets for new treatments of stress disorders in human mental health.

     

Sex, stress, and mood disorders: at the intersection of adrenal and gonadal hormones

The risk for neuropsychiatric illnesses has a strong sex bias, and for major depressive disorder (MDD), females show a more than 2-fold greater risk compared to males. Such mood disorders are commonly associated with a dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis. Thus, sex differences in the incidence of MDD may be related with the levels of gonadal steroid hormone in adulthood or during early development as well as with the sex differences in HPA axis function. In rodents, organizational and activational effects of gonadal steroid hormones have been described for the regulation of HPA axis function and, if consistent with humans, this may underlie the increased risk of mood disorders in women. Other developmental factors, such as prenatal stress and prenatal overexposure to glucocorticoids can also impact behaviors and neuroendocrine responses to stress in adulthood and these effects are also reported to occur with sex differences. Similarly, in humans, the clinical benefits of antidepressants are associated with the normalization of the dysregulated HPA axis, and genetic polymorphisms have been found in some genes involved in controlling the stress response. This review examines some potential factors contributing to the sex difference in the risk of affective disorders with a focus on adrenal and gonadal hormones as potential modulators. Genetic and environmental factors that contribute to individual risk for affective disorders are also described. Ultimately, future treatment strategies for depression should consider all of these biological elements in their design.     

Sex differences in adrenal function in the lizard Cnemidophorus sexlineatus: II. Responses to acute stress in the laboratory.

Circulating concentrations of plasma corticosterone and gonadal steroids were measured in intact and gonadectomized male and female lizards (Cnemidophorus sexlineatus) following acute stress (handling) in the laboratory. There was a significant increase in plasma corticosterone after stress. Whereas intact females exhibited greater concentrations of corticosterone relative to intact males, ovariectomized females exhibited lower concentrations of corticosterone relative to castrated males. In addition to sex differences in corticosterone responses to gonadectomy, progesterone was elevated by stress in both intact and ovariectomized females but not in males. Corticosterone adjusted for castration and handling in males was negatively correlated with the plasma androgen level. The adrenal responsiveness of males to acute stress may be attenuated by androgens presumably secreted by the testis. Not only does adrenal function influence reproduction, but adrenal responses differ between males and females, and appear to be influenced by the gonadal axis. The sex differences in adrenal responses to stress likely reflect different reproductive strategies and nutritional requirements of males and females during the breeding season.     

Early Stress Causes Sex-Specific,Life-Long Changes in Behaviour,Levels of Gonadal Hormones,and Gene Expression in Chickens

Early stress can have long-lasting phenotypic effects. Previous research shows that male and female chickens differ in many behavioural aspects, and respond differently to chronic stress. The present experiment aimed to broadly characterize long-term sex differences in responses to brief events of stress experienced during the first weeks of life. Chicks from a commercial egg-laying hybrid were exposed to stress by inducing periods of social isolation during their first three weeks of life, followed by a broad behavioural, physiological and genomic characterization throughout life. Early stressed males, but not females, where more anxious in an open field-test, stayed shorter in tonic immobility and tended to have delayed sexual maturity, as shown by a tendency for lower levels of testosterone compared to controls. While early stressed females did not differ from non-stressed in fear and sexual maturation, they were more socially dominant than controls. The differential gene expression profile in hypothalamus was significantly correlated from 28 to 213 days of age in males, but not in females. In conclusion, early stress had a more pronounced long-term effect on male than on female chickens, as evidenced by behavioral, endocrine and genomic responses. This may either be attributed to inherent sex differences due to evolutionary causes, or possibly to different stress related selection pressures on the two sexes during commercial chicken breeding.     

Association of gender with clinical expression, quality of life, disability, and depression and anxiety in patients with systemic sclerosis

Objectives

To assess the association of gender with clinical expression, health-related quality of life (HRQoL), disability, and self-reported symptoms of depression and anxiety in patients with systemic sclerosis (SSc).

Methods

SSc patients fulfilling the American College of Rheumatology and/or the Leroy and Medsger criteria were assessed for clinical symptoms, disability, HRQoL, self-reported symptoms of depression and anxiety by specific measurement scales.

Results

Overall, 381 SSc patients (62 males) were included. Mean age and disease duration at the time of evaluation were 55.9 (13.3) and 9.5 (7.8) years, respectively. One-hundred-and-forty-nine (40.4%) patients had diffuse cutaneous SSc (dcSSc). On bivariate analysis, differences were observed between males and females for clinical symptoms and self-reported symptoms of depression and anxiety, however without reaching statistical significance. Indeed, a trend was found for higher body mass index (BMI) (25.0 [4.1] vs 23.0 [4.5], p = 0.013), more frequent dcSSc, echocardiography systolic pulmonary artery pressure >35 mmHg and interstitial lung disease in males than females (54.8% vs 37.2%, p = 0.010; 24.2% vs 10.5%, p = 0.003; and 54.8% vs 41.2%, p = 0.048, respectively), whereas calcinosis and self-reported anxiety symptoms tended to be more frequent in females than males (36.0% vs 21.4%, p = 0.036, and 62.3% vs 43.5%, p = 0.006, respectively). On multivariate analysis, BMI, echocardiography PAP>35 mmHg, and anxiety were the variables most closely associated with gender.

Conclusions

In SSc patients, male gender tends to be associated with diffuse disease and female gender with calcinosis and self-reported symptoms of anxiety. Disease-associated disability and HRQoL were similar in both groups.