Coexistence of Anhedonia and anxiety-independent increased novelty-seeking behavior in the chronic mild stress model of depression

Previous research demonstrated excessive decreases in reward sensitivity and increases in harm avoidance in depressed individuals. These results straightly lead to a hypothesis that depressed patients should avoid novelty or express reduced novelty-seeking behavior. Nevertheless, literature in this regard is inconsistent. Furthermore, whether the potentially altered novelty-associated behavior is dependent on changed anxiety/fear or related to altered goal-directed approaching tendency is unclear. Here, we tested novel object-approaching behavior in a free-exploration paradigm in chronic mild stress (CMS)-induced anhedonic and stress-resistant rats respectively. Other CMS-induced, emotional behaviors were also examined in a battery of behavioral tests including novel cage, exploration, locomotor activity and elevated plus maze (EPM). We found that compared with controls, stress-resistant rats who consistently showed lower anxiety level in EPM (time in open arms) and, open-field (OF) test (time in central area) showed no sign of enhanced novel object approaching behavior. To the contrary, the anhedonic ones who did not express any sign of reduced anxiety showed paradoxically intensified novelty-approaching behavior. We concluded that reduced anxiety would not necessarily lead to enhanced novelty-seeking behavior; anhedonia coexists with anxiety-independent, increased novelty-seeking behavior. The salient paradox of coexistence of anhedonia and increased novelty-seeking behavior was critically discussed.     

Sex differences in depression and anxiety disorders: potential biological determinants

The phenomenon of higher rates of affective disorders in women illustrates many of the difficulties as well as promises of translating preclinical models to human disorders. Abnormalities in the regulation of the hypothalamic-pituitary adrenal axis and the sympathoadrenomedullary system have been identified in depression and anxiety disorders, and these disorders are clearly precipitated and exacerbated by stress. Despite the striking sex difference in the prevalence of depression and anxiety disorders, attempts to identify corresponding sex differences in stress response reactivity in animal models have met with limited success. Processes which may contribute to increased rates of affective disorders in women are greater fluxes in reproductive hormones across the life span, and increased sensitivity to catecholamine augmentation of emotional memory consolidation.     

Behavioral and neuroendocrine consequences of juvenile stress combined with adult immobilization in male rats

Exposure to stress during childhood and adolescence increases vulnerability to developing several psychopathologies in adulthood and alters the activity of the hypothalamic-pituitary-adrenal (HPA) axis, the prototypical stress system. Rodent models of juvenile stress appear to support this hypothesis because juvenile stress can result in reduced activity/exploration and enhanced anxiety, although results are not always consistent. Moreover, an in-depth characterization of changes in the HPA axis is lacking. In the present study, the long-lasting effects of juvenile stress on adult behavior and HPA function were evaluated in male rats. The juvenile stress consisted of a combination of stressors (cat odor, forced swim and footshock) during postnatal days 23–28. Juvenile stress reduced the maximum amplitude of the adrenocorticotropic hormone (ACTH) levels (reduced peak at lights off), without affecting the circadian corticosterone rhythm, but other aspects of the HPA function (negative glucocorticoid feedback, responsiveness to further stressors and brain gene expression of corticotrophin-releasing hormone and corticosteroid receptors) remained unaltered. The behavioral effects of juvenile stress itself at adulthood were modest (decreased activity in the circular corridor) with no evidence of enhanced anxiety. Imposition of an acute severe stressor (immobilization on boards, IMO) did not increase anxiety in control animals, as evaluated one week later in the elevated-plus maze (EPM), but it potentiated the acoustic startle response (ASR). However, acute IMO did enhance anxiety in the EPM, in juvenile stressed rats, thereby suggesting that juvenile stress sensitizes rats to the effects of additional stressors.     

Sex, hormones and affective arousal circuitry dysfunction in schizophrenia

Women with schizophrenia express affective disturbances disproportionately more than men. Brain regions implicated in the affective arousal circuitry also regulate the hypothalamic-pituitary-adrenal and -gonadal systems, which are dysfunctional in schizophrenia. This review will argue that understanding the etiology of affective arousal deficits in schizophrenia is intimately connected with characterizing the role of neuroendocrine dysfunction and sex effects in schizophrenia. Further, the etiology of these neuroendocrine deficits begins during fetal development, during a period of time that coincides with the sexual differentiation of the brain and the vulnerability for schizophrenia. Studying the links between deficits in neuroendocrine systems and the affective arousal system in schizophrenia will provide clues to understanding the development of sex differences in schizophrenia and thereby its etiology.     

Synergist effects of n-acetylcysteine and deferoxamine treatment on behavioral and oxidative parameters induced by chronic mild stress in rats

A growing body of evidence has pointed to a relationship between oxidative stress and depression. Thus, the present study was aimed at evaluating the effects of the antioxidants n-acetylcysteine (NAC), deferoxamine (DFX) or their combination on sweet food consumption and oxidative stress parameters in rats submitted to 40 days of exposure to chronic mild stress (CMS). Our results showed that in stressed rats treated with saline, there was a decrease in sweet food intake and treatment with NAC or NAC in combination with DFX reversed this effect. Treatment with NAC and DFX decreased the oxidative damage, which include superoxide and TBARS production in submitochondrial particles, and also thiobarbituric acid reactive substances (TBARS) levels and carbonyl proteins in the prefrontal cortex, amygdala and hippocampus. Treatment with NAC and DFX also increased the activity of the antioxidant enzymes, superoxide dismutase and catalase in the same brain areas. Even so, a combined treatment with NAC and DFX produced a stronger increase of antioxidant activities in the prefrontal cortex, amygdala and hippocampus. The results described here indicate that co-administration may induce a more pronounced antidepressant activity than each treatment alone. In conclusion, these results suggests that treatment with NAC or DFX alone or in combination on oxidative stress parameters could have positive effects against neuronal damage caused by oxidative stress in major depressive disorders.     

Maternal deprivation has sexually dimorphic long-term effects on hypothalamic cell-turnover, body weight and circulating hormone levels

Maternal deprivation (MD) has numerous outcomes, including modulation of neuroendocrine functions. We previously reported that circulating leptin levels are reduced and hypothalamic cell-turnover is affected during MD, with some of these effects being sexually dimorphic. As leptin modulates the development of hypothalamic circuits involved in metabolic control, we asked whether MD has long-term consequences on body weight, leptin levels and the expression of neuropeptides involved in metabolism. Rats were separated from their mother for 24 h starting on postnatal day (PND) 9 and sacrificed at PNDs 13, 35 and 75. In both sexes MD reduced body weight, but only until puberty, while leptin levels were unchanged at PND 35 and significantly reduced at PND 75. Adiponectin levels were also reduced at PND 75 in females, while testosterone levels were reduced in males. At PND 13, MD modulated cell-turnover markers in the hypothalamus of males, but not females and increased nestin, a marker of immature neurons, in both sexes, with males having higher levels than females and a significantly greater rise in response to MD. There was no effect of MD on hypothalamic mRNA levels of the leptin receptor or metabolic neuropeptides or the mRNA levels of leptin and adiponectin in adipose tissue. Thus, MD has long-term effects on the levels of circulating hormones that are not correlated with changes in body weight. Furthermore, these endocrine outcomes are different between males and females, which could be due to the fact that MD may have sexually dimorphic effects on hypothalamic development.     

Chronic stress effects on memory: sex differences in performance and monoaminergic activity

Increasing evidence suggests that the time course of advantageous versus deleterious effects of stress on physiologic function is also apparent in some brain functions, including learning and memory. This article reviews the effects of chronic stress on behavioral performance and, more importantly, shows that sex of the subject, as well as duration and intensity of stress, is an important determinant of the functional/behavioral, neurochemical, and anatomical consequences of the stress. Following chronic stress (7-28 days of restraint, 6 h/day), male and female rats were tested on a visual memory task (object recognition) and two spatial memory tasks (object placement and radial arm maze). At 21 days, stress impaired males on all tasks while females were either enhanced (spatial memory tasks) or not impaired (nonspatial memory tasks). Additionally, the influence of the hypothalamic-pituitary-adrenocortical axis in mediating the sex-specific responses to stress is considered. Behavioral and neurochemical assessments following chronic stress in ovariectomized females, with and without estradiol, suggest that estrogen exerts both organizational and activational influences on the observed sex differences in response to stress. Furthermore, stress differentially affected central transmitter levels in the frontal cortex, hippocampus, and amygdala depending on sex. The possible role of these sex-specific changes in neurotransmitter levels in mediating behavioral differences in response to stress is discussed. While these results are thus far limited to a few studies and require both further investigation and verification, chronic stress appears to be associated with distinct, sex-differentiated behavioral/cognitive and neurochemical responses. We conclude that sex differences must be taken into account when investigating or describing stress and associated sequalae.     

G(olf) protein levels in rat striatum are increased by chronic antidepressant administration and decreased by olfactory bulbectomy

There are many studies of the mechanisms of antidepressants; however, most of these studies were conducted on the hippocampus or frontal cortex. In the present study, we hypothesized that the nucleus accumbens and caudate/putamen might be major targets for antidepressant effects. Thus, we focused on G(olf) protein, a stimulant alpha-subunit of G protein that is coupled with the dopamine D1 receptor and specifically expressed in the striatum (nucleus accumbens, caudate/putamen and olfactory tubercle) in the rat brain. We examined the effects of chronic administration of imipramine, fluvoxamine, maprotiline and, as a negative control, cocaine on the level of G(olf) protein in the rat striatum. We also examined the effect of olfactory bulbectomy. Chronic imipramine treatment (10 mg/kg for 2 or 4 weeks) significantly increased the level of G(olf) in the striatum (by 17% or 18%, respectively), although this increase was not apparent after only 1 week of treatment. The time course of these changes corresponded well to that of the clinical efficacy of imipramine. Chronic fluvoxamine and maprotiline treatment (20 mg/kg for 2 weeks) also significantly increased the level of G(olf) (by 9% and 25%, respectively), but cocaine did not alter it significantly. Bulbectomy decreased the G(olf) protein level by 9%. The increases in G(olf) protein after chronic administration of these three different classes of antidepressants and the decrease after bulbectomy suggest that G(olf) protein may play an important role in the antidepressant effect.     

Behavioral and biochemical studies of total furocoumarins from seeds of Psoralea corylifolia in the chronic mild stress model of depression in mice

Depression is related to alterations of the monoamine oxidase (MAO), hypothalamic-pituitary-adrenal (HPA) axis, and oxidative systems, and some antidepressants achieve their therapeutic effects through alteration of following biochemical markers of depression: MAO-A and MAO-B activities, cortisol levels, superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels. The seeds of Psoralea corylifolia, otherwise known as Buguzhi, have long been used for treatments of various symptoms associated with aging in China. Furocoumarins are the most widespread secondary metabolites in this species. The present study was designed to evaluate the potential antidepressant-like activity of total furocoumarins of P. corylifolia (TFPC) in the chronic mild stress (CMS) model of depression. Mice subjected to CMS exhibited a reduction in sucrose intake. Conversely, brain MAO-A and MAO-B activities, plasma cortisol levels, and liver SOD activity and MDA levels were increased following CMS exposures. The time-course for reversal of CMS-induced deficits in sucrose consumption by TFPC was dose-dependent. Thus, the statistically significant effect of the higher dose of TFPC (50 mg/kg body wt.) was observed after 3 days of treatment, while 6 days of treatment were required in the group receiving a lower dose (30 mg/kg body wt.) of TFPC. TFPC reversed these biochemical changes. These results suggest that TFPC may possess potent and rapid antidepressant properties that are mediated via MAO, the HPA axis and oxidative systems and these antidepressant actions could make TFPC a potentially valuable drug for the treatment of depression in the elderly.     

Gender-specific effects of prenatal stress on emotional reactivity and stress physiology of goat kids

The aims of this study were to investigate the effects of maternal stress during pregnancy on the emotional reactivity, the hypothalamo-pituitary-adrenocortical (HPA) axis, and the sympatho-adrenomedullary (SAM) system of goat offspring according to their gender, and to investigate the role of maternal cortisol in prenatal stress effects. Goats were exposed to ten transports in isolation or ten ACTH injections (0.125 IU/kg body weight) during the last third of pregnancy. Control goats remained undisturbed. No effect of repeated transport during the last third of pregnancy was found on basal cortisol concentrations of the offspring. However, an increase in phenylethanolamine N-methyl transferase activity in the adrenals was observed in prenatally stressed kids compared to control kids (P = 0.031). In the presence of novelty, prenatally stressed female kids were more active (P = 0.049) than control females; they also showed more signs of arousal (P = 0.039) and tended to explore more of their environment (P = 0.053) in reaction to a startling stimulus. On the contrary, prenatally stressed male kids tended to be less active (P = 0.051) than control male kids but showed more signs of distress (P = 0.047) in the presence of novelty. Intermediate effects were found on the emotional reactivity to novelty of kids born from dams given injections of ACTH. In conclusion, transport stress in pregnant goats affects the sympatho-adrenomedullary system and the emotional reactivity of their offspring in a gender-specific manner. Moreover, the effects of prenatal transport and ACTH injections showed some similarities but differed in some critical details.     

Oxidative stress indicators and trace elements in the blue shark (Prionace glauca) off the east coast of the Mexican Pacific Ocean

Trace element concentrations and oxidative stress indicators (including production of reactive oxygen species (ROS), antioxidant enzyme activities and oxidative damage) were measured in muscle of blue sharks collected along the west coast of Baja California Sur to determine potential differences by sex and maturity cohorts. Mercury (Hg) concentration in muscle samples from larger sharks (>200 cm LT) exceeded the permissible limit (>1 ppm wet weight) for human consumption set by numerous international agencies. Significant differences were found in Hg concentrations (mature>immature; males>females), and in protein carbonyl concentrations (male>female); however, except for carbonyl protein levels, no significant differences by sex or maturity stage were found in the oxidative stress indicators. Differences between sexes and maturity stages in trace element concentration and carbonyl protein levels in blue shark muscle may be related to variations in diet within different cohorts.     

Ameliorating effect and potential mechanism of Rehmannia glutinosa oligosaccharides on the impaired glucose metabolism in chronic stress rats fed with high-fat diet

The aim of this study was to determine whether the Rehmannia glutinosa oligosaccharides (ROS) ameliorate the impaired glucose metabolism and the potential mechanism in chronic stress rats fed with high-fat diet. The rats were fed by a high-fat diet and simultaneously stimulated by chronic stress over 5 weeks. Body weight, fasting plasma glucose, intraperitoneal glucose tolerance test (IPGTT), plasma lipids, gluconeogenesis test (GGT), glycogen content, and corticosterone, insulin and leptin levels were measured. The results showed that ROS administration (100, 200 mg/kg, i.g.) for 5 weeks exerted the effects of increasing the organ weights of thymus and spleen, lowering the fasting plasma glucose level, improving impaired glucose tolerance, increasing the contents of liver and muscle glycogen, decreasing the gluconeogenesis ability, plasma-free fatty acid's level, as well as plasma triglyceride and total cholesterol levels in chronic stress and high-fat fed rats, especially in the group of 200 mg/kg; while the plasma corticosterone level was decreased, and plasma leptin level was increased. These results suggest that ROS exert an ameliorating effect of impaired glucose metabolism in chronic stress rats fed with high-fat diet, and the potential mechanism may be mediated through rebuilding the glucose homeostasis in the neuroendocrine immuno-modulation (NIM) network through multilinks and multitargets.     

Pre-experience of social exclusion suppresses cortisol response to psychosocial stress in women but not in men

Lack of social support and social exclusion is associated with adverse effects for mental and physical health. Additionally, women appear to be more vulnerable to social triggers of health disturbances. The hypothalamus–pituitary–adrenocortical-axis (HPA axis) might play a key role in this context as it has been shown both to relate to psychosocial conditions and health outcomes and to respond differentially depending on gender. In a previous experiment we found no effects of exclusion alone (operationalized via Cyberball) on cortisol secretion. Here we examine the effects of a social exclusion pre-experience on psychological and cortisol responses to a public speaking stressor. Subjects (33 m, 34 f) were randomly assigned to social exclusion (SE) or one of two control conditions (exclusion attributed to technical default (TD) and social inclusion (SI)). Afterwards salivary cortisol and psychological responses to a public speaking paradigm were assessed. Exclusion pre-treatment does not affect psychological responses to public speaking stress though with respect to cortisol significant. Cyberball by gender and Cyberball by gender by time interactions are found. SE-women show a blunted cortisol stress response to public speaking while cortisol responses of SE-men fall between SI-men and TD-men. Pre-experience of social exclusion leads to a blunted cortisol response to stress in women but not in men. This factor might contribute to the higher vulnerability to social triggers of health disturbances observed in women.     

Glucocorticoids, prenatal stress and the programming of disease

An adverse foetal environment is associated with increased risk of cardiovascular, metabolic, neuroendocrine and psychological disorders in adulthood. Exposure to stress and its glucocorticoid hormone mediators may underpin this association. In humans and in animal models, prenatal stress, excess exogenous glucocorticoids or inhibition of 11β-hydroxysteroid dehydrogenase type 2 (HSD2; the placental barrier to maternal glucocorticoids) reduces birth weight and causes hyperglycemia, hypertension, increased HPA axis reactivity, and increased anxiety-related behaviour. Molecular mechanisms that underlie the ‘developmental programming’ effects of excess glucocorticoids/prenatal stress include epigenetic changes in target gene promoters. In the case of the intracellular glucocorticoid receptor (GR), this alters tissue-specific GR expression levels, which has persistent and profound effects on glucocorticoid signalling in certain tissues (e.g. brain, liver, and adipose). Crucially, changes in gene expression persist long after the initial challenge, predisposing the individual to disease in later life. Intriguingly, the effects of a challenged pregnancy appear to be transmitted possibly to one or two subsequent generations, suggesting that these epigenetic effects persist.     

Sex differences in the effects of Tyr-MIF-1 on morphine- and stress-induced analgesia

There is evidence suggesting that the endogenous tetrapeptide, Tyr-MIF-1 (Tyr-Prol-Leu-Gly-amide), has antagonistic or modulatory effects on opioid-mediated analgesia. There is also substantial evidence for sex differences in opioid effects, whereby male rodents display greater levels of opioid-mediated analgesia than females. In the present study, determinations were made of the effects of Tyr-MIF-1 on morphine- and restraint stress-induced opioid analgesia in adult male and female deer mice, Peromyscus maniculatus. Intraperitoneal treatment with Tyr-MIF-1 (0.10–10 mg/kg) reduced morphine- and stress-induced analgesia in both male and female mice, with Tyr-MIF-1 having markedly greater antagonistic effects in male than female mice. These results indicate that there are sex differences in the modulatory (antiopiate) effects of Tyr-MIF-1 on opioid-mediated analgesia.     

Social cognition under stress: Differential effects of stress-induced cortisol elevations in healthy young men and women

Humans as social beings often have to perform complex social cognitive tasks while under stress (e.g., during a social conflict). Previous research has established that the brain regions responsible for social cognitive tasks are target regions for stress hormones. However, little experimental research has been done testing the acute effects of stress on social cognition. Here, we investigated whether stress exposure and the ensuing glucocorticoid (i.e., cortisol) elevations affect social cognition. Thirty-two men and 32 women were exposed to either a psychosocial stress or a non-stressful control test before assessing their social cognition using the Reading the Mind in the Eyes Test (RMET) and the Movie for the Assessment of Social Cognition (MASC). Results showed differential effects of stress-induced cortisol responses among men and women for the MASC, but not the RMET. Among men, high cortisol responders displayed elevated MASC scores compared with low cortisol responders. Moreover, for stressed men a positive association between the magnitude of the cortisol responses to the stressor and MASC scores emerged. Among women, enhanced MASC scores were found for low cortisol responders relative to high cortisol responders and non-stressed controls. A strong negative association between cortisol reactivity and MASC scores was found among women. These results imply sex specific effects of glucocorticoids on social cognition and partially support the idea of sex differences in biobehavioral stress responses, with men engaging in fight-or-flight responses while women may react to stress with tending and befriending behavior.     

慢性温和应激抑郁模型大鼠5-羟色胺、色氨酸和应激激素的变化

目的：通过观察慢性温和应激对大鼠行为及5-羟色胺、色氨酸、应激激素的影响,进一步阐明应激致抑郁发生的机制。方法：利用慢性不可预计温和应激（CUMS）结合行为学指标建立大鼠抑郁动物模型;高效液相检测血浆和脑5-HT、儿荼酚胺;放免方法检测血浆皮质醇换算成皮质酮含量;氨基酸分析仪检测血清色氨酸的含量。结果：①CUMS诱导8周大鼠糖水偏爱性与对照组相比明显减低（P〈0．05）;体重和旷场实验评分下降（P〈0．05）。②CUMS诱导8周大鼠大脑和血浆5-HT含量显著下降（P〈0．05）;而血清色氨酸含量与对照组相比则明显升高（P〈0．05）。③CUMS诱导8周大鼠血浆去甲肾上腺素和肾上腺素含量与对照组相比明显升高（P〈0．05）：血浆皮质酮含量与对照组相比统计学上无显著性差异（P〉0．05）。结论：利用CUMS建立的抑郁模型大鼠存在着神经内分泌紊乱,CUMS大鼠抑郁样行为的发生可能与血浆去甲肾上腺素和肾上腺素升高对色氨酸代谢的影响有关。     

Long-term ovariectomy enhances anxiety and depressive-like behaviors in mice submitted to chronic unpredictable stress

Ovarian hormones exert anti-depressive and anxiolytic actions. In this study we have analyzed the effects of ovariectomy on the development of anxiety and depression-like behaviors and on cell proliferation in the hippocampus of mice submitted to chronic unpredictable stress. Animals submitted to stress 4 months after ovariectomy showed a significant increase in immobility behavior in the forced swimming test compared to animals submitted to stress 2 weeks after ovariectomy. In addition, long-term ovariectomy resulted in a significant decrease on the time spent in the open arms in the elevated plus-maze test compared to control animals. Stress did not significantly affect cell proliferation in the hilus of the dentate gyrus. However, ovariectomy resulted in a significant decrease in cell proliferation. These results indicate that long-term deprivation of ovarian hormones enhances the effect of chronic unpredictable stress on depressive- and anxiety-like behaviors in mice. Therefore, a prolonged deprivation of ovarian hormones may represent a risk factor for the development of depressive and anxiety symptoms after the exposure to stressful experiences.     

An association of early puberty with disordered eating and anxiety in a population of undergraduate women and men

Eating and anxiety disorders are more prevalent in females, increase during adolescence, and are associated with early pubertal development. This study examined whether timing of puberty onset is associated with disordered eating and anxiety in a large sample of postpubertal male and female undergraduate students. Self-report questionnaires assessed timing of puberty, disordered eating, anxiety, alcohol use, personality, and sensation seeking. Females scored significantly higher on measures of disordered eating (binge eating, dietary restraint, eating concerns, and weight and shape concerns) and anxiety (state and trait anxiety) than did males. In addition, early maturing women and men scored significantly higher on measures of disordered eating and anxiety than on time or late maturing women and men. Measures of alcohol use, sensation seeking, and personality characteristics differed in males and females but did not vary with pubertal timing. Findings suggest that early puberty is associated with disordered eating and anxiety, and this association may be due to an organizational effect of pubertal hormones. Despite important differences in body fat composition, both males and females experiencing early puberty had an increased incidence of disordered eating. The fact that early puberty was associated with increased eating and anxiety symptoms in both sexes suggests that puberty may influence these symptoms through both biological and psychosocial mechanisms.     

Variability of salivary markers of oxidative stress and antioxidant status in young healthy individuals

Objectives: Salivary advanced glycation end-products (AGEs), advanced oxidation protein products (AOPP), total antioxidant capacity (TAC), and ferric reducing ability of saliva (FRAS) are increased in various diseases. Little data exist for these markers in the healthy population. The aim of this study was to assess the inter-individual and intra-individual variability of AGEs, AOPP, TAC, and FRAS in the saliva of young healthy individuals.

Methods: Unstimulated saliva samples were collected from 16 females and 18 males daily over a period of 30 days. Markers were measured using spectrophotometric and spectrofluorometric microplate-based methods.

Results: All salivary markers measured were significantly higher in men than in women (P?<?0.05 for AGEs; P?<?0.001 for AOPP, TAC, and FRAS). The inter-individual variability was approximately 60% for AGEs and AOPP and 30–40% for TAC and FRAS in both genders. The inter-individual variability of FRAS was higher in men vs. women (P?<?0.01). Intra-individual variability ranged from 20% for TAC, to 30% for AGES and FRAS and 45% for AOPP.

Discussion: Intra-individual variability of salivary AGEs, AOPP, TAC, and FRAS indicates that their use is currently limited to large cohort studies. Identifying the underlying factors related to the high inter-individual and intra-individual variability is needed. Sex differences should be considered in future studies.