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.     

Possible involvement of corticosterone and serotonin in antidepressant and antianxiety effects of chromium picolinate in chronic unpredictable mild stress induced depression and anxiety in rats

In the present study, we investigated the effects of chromium picolinate (CrP) on behavioural and biochemical parameters in chronic unpredictable mild stress (CUMS) induced depression and anxiety in rats. The normal and stressed male Swiss albino rats were administered CrP (8 and 16 μg/mL in drinking water), they received stressors for seven days (each day one stressor) and this cycle was repeated three times for 21 days. On 22nd day, behaviour assessments followed by biochemical estimations were conducted. The results showed that treatment of CrP produced significant antidepressant effect, which has been evidenced by decrease in immobility time in modified forced swimming test (FST) in chronic unpredictable mild stress (CUMS) induced depression in rats. In elevated plus maze (EPM), CrP (16 μg/mL) showed significant reduction in time spent in open arm. CrP (8 μg/mL and 16 μg/mL) also showed significant decrease in number of entries in open arm that shows antianxiety effect of CrP in CUMS rats. It was also found that CrP (8 and 16 μg/mL) significantly increased 5-HT concentration in the discrete regions of brain (cortex and cerebellum). On the other hand, the plasma corticosterone level was significantly decreased with CrP (16 μg/mL). The results suggested that increase in the concentration of 5-HT and decrease in plasma corticosterone levels could be responsible for improvement in symptoms of depression and anxiety in CUMS induced depression and anxiety in rats.     

Effect of maximal-intensity exercise on systemic nitro-oxidative stress in men and women

Objectives: The aim of this study was to test the hypotheses: (1) there is a negative correlation between protein and lipid oxidative damage following maximal-intensity exercise, and oxygen uptake and work intensity (%VO_2max) at the respiratory compensation point (RCP) in women and men; (2) nitro-oxidative stress following maximal-intensity exercise results from the intensification of anaerobic processes and muscle fibre micro-damage.

Methods: Study participants comprised 20 women (21.34±1.57 years) and 20 men (21.97±1.41 years) who performed a treadmill incremental test (IT); VO_2max: 45.08?±?0.91 and 57.38?±?1.22?mL?kg^?1?min^?1 for women and men, respectively. The oxidized low-density lipoprotein (ox-LDL), 3-nitrotyrosine (3-NT) concentration and creatine kinase (CK) as well as lactate dehydrogenase (LDH) activity were measured in the blood serum, and total antioxidative capacity (TAC) and lactate concentration (Lac) were determined in blood plasma before and after IT.

Results: After the IT, increases in ox-LDL, 3-NT, CK, and LDH were seen in both groups (P?P?P?Conclusions: The gain of ox-LDL and 3-NT following maximal-intensity exercise is independent of VO_2max, oxygen consumption and exercise intensity at RCP. This increase of ox-LDL and 3-NT is indicative of similar lipid and protein damage in women and men. A significant increase in TAC in women following maximal-intensity exercise is the result of muscle fibre micro-injuries.     

Prenatal stress differentially affects habituation of corticosterone responses to repeated stress in adult male and female rats

Environmental factors operating early in life have long-lasting and important consequences for the mental and physical health of the adult organism. In particular, prenatal exposure to stress represents one category of adverse early environmental events that are associated with development of depression and schizophrenia in adulthood. In the present studies, we examined whether prenatal stress alters the habituation of hypothalamic-pituitary-adrenal (HPA) activity that occurs with repeated stress exposure in adulthood. We compared corticosterone responses to the first vs. the eighth restraint, with lower responses to the eighth vs. the first considered evidence of habituation. In males, prenatal stress prevented the habituation of corticosterone responses to repeated restraint that was observed in non-prenatally stressed rats. Limited evidence of habituation was seen in either group of females and prenatally stressed females did not exhibit the enhanced corticosterone response during recovery from the eighth restraint that was seen in non-prenatally stressed females. Together, these results suggest a sex-specific interaction between prenatal stress and adult chronic stress on HPA activity.     

The impact of mineralocorticoid receptor ISO/VAL genotype (rs5522) and stress on reward learning

Research suggests that stress disrupts reinforcement learning and induces anhedonia. The mineralocorticoid receptor (MR) determines the sensitivity of the stress response, and the missense iso/val polymorphism (Ile180Val, rs5522) of the MR gene (NR3C2) has been associated with enhanced physiological stress responses, elevated depressive symptoms and reduced cortisol‐induced MR gene expression. The goal of these studies was to evaluate whether rs5522 genotype and stress independently and interactively influence reward learning. In study 1, participants (n = 174) completed a probabilistic reward task under baseline (i.e. no‐stress) conditions. In study 2, participants (n = 53) completed the task during a stress (threat‐of‐shock) and no‐stress condition. Reward learning, i.e. the ability to modulate behavior as a function of reinforcement history, was the main variable of interest. In study 1, in which participants were evaluated under no‐stress conditions, reward learning was enhanced in val carriers. In study 2, participants developed a weaker response bias toward a more frequently rewarded stimulus under the stress relative to no‐stress condition. Critically, stress‐induced reward learning deficits were largest in val carriers. Although preliminary and in need of replication due to small sample size, findings indicate that psychiatrically healthy individuals carrying the MR val allele, gene, which has been recently linked to depression, showed a reduced ability to modulate behavior as a function of reward when facing an acute, uncontrollable stressor. Future studies are warranted to evaluate whether rs5522 genotype interacts with naturalistic stressors to increase the risk of depression and whether stress‐induced anhedonia might moderate such risk.     

Transgenerational inheritance of chronic adolescent stress: Effects of stress response and the amygdala transcriptome

Adolescent stress can impact health and well‐being not only during adulthood of the exposed individual but even in future generations. To investigate the molecular mechanisms underlying these long‐term effects, we exposed adolescent males to stress and measured anxiety behaviors and gene expression in the amygdala—a critical region in the control of emotional states—in their progeny for two generations, offspring and grandoffspring. Male C57BL/6 mice underwent chronic unpredictable stress (CUS) for 2 weeks during adolescence and were used to produce two generations of offspring. Male and female offspring and grandoffspring were tested in behavioral assays to measure affective behavior and stress reactivity. Remarkably, transgenerational inheritance of paternal stress exposure produced a protective phenotype in the male, but not the female lineage. RNA‐seq analysis of the amygdala from male offspring and grandoffspring identified differentially expressed genes (DEGs) in mice derived from fathers exposed to CUS. The DEGSs clustered into numerous pathways, and the “notch signaling” pathway was the most significantly altered in male grandoffspring. Therefore, we show that paternal stress exposure impacts future generations which manifest in behavioral changes and molecular adaptations.     

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.     

Cardiac medication use in patients with suspected ischaemia without obstructive coronary arteries: sex differences and psychological distress

BackgroundIschaemia without obstructive coronary arteries (INOCA) is more prevalent in women and associated with psychological distress. Pharmacological treatment goals are angina relief and cardiovascular risk management. The present study aims to examine sex differences in cardiac and non-cardiac medication use, as well as medication and sex differences related to consistent psychological distress in patients with suspected INOCA.DesignA TweeSteden mild stenosis observational cohort study in patients with suspected INOCA as detected by ischaemic reason for referral and non-obstructive arteries based on coronary angiography or computed tomography.MethodsMedication documented in the hospital records of 488 patients (53% women) was coded as angina relief medication, blood-pressure-lowering medication, antithrombotics, statins, and non-cardiac medication, using the Anatomical Therapeutic Chemical code. Depressive symptoms and anxiety were recoded as ‘consistent distress’ (above the cut-off score for depression and anxiety on validated questionnaires), ‘inconsistent distress’ (above the cut-off for depression or anxiety) or ‘no distress’ (below the cut-off).ResultsNo sex differences were observed in cardiac medication use. Women used anxiolytic benzodiazepines more often (12% vs 4%, p = 0.002) compared to men. Consistent distress was more prevalent in women (22% vs 15%, p = 0.004) and was related to the use of more angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and diuretics in women and to calcium antagonist use as well as lower adherence levels in men. Women who reported chest pain more often received angina relief medication and blood-pressure-lowering medication than men.ConclusionNo sex differences were observed in cardiac medication use in patients with suspected INOCA. Psychological distress may reflect hypertension and subsequent medication use in women, and experiencing chest pain and subsequent medication use in men.     

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.     

Cytokines and glucocorticoid receptors are associated with the antidepressant-like effect of alarin

Little is known about the physiological or pharmacological properties of alarin, a new neuropeptide belonging to the galanin family. We previously showed that alarin has an antidepressant-like effect and is associated with a decrease in the hyperactivity of hypothalamic–pituitary–adrenal (HPA) axis that is observed in patients with depression using unpredictable chronic mild stress (UCMS) mouse model of depression. However, the mechanisms underlying these effects have not been uncovered. Inflammatory cytokines are reportedly associated with depression. Animal studies and cytokine immune therapy in humans suggest that pro-inflammatory cytokines induce depressive symptomatology and potently activate the HPA axis, whereas anti-inflammatory cytokines may decrease activation. Thus, we first determined the levels of inflammatory cytokines in the blood and brain to evaluate whether the antidepressant-like effect of alarin in UCMS-treated mice is related to its regulation of these inflammatory cytokines. Pro-inflammatory cytokines disrupt the function and/or expression of glucocorticoid receptors (GRs), which mediate the negative feedback of glucocorticoids on the HPA axis to keep it from being overactivated. We next explored the expression level of GRs in the brains of mice subjected to UCMS and to the administration of alarin. We found that intracerebroventricular administration of alarin significantly ameliorated depression-like behaviors in the UCMS-treated mice. Alarin restored the UCMS-induced an increase in the levels of the pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor α and a decrease in the anti-inflammatory cytokine IL-10 level in the blood, prefrontal cortex, hippocampus and hypothalamus. Alarin also reversed the UCMS-induced down-regulation of GR expression in these brain regions. Thus, the antidepressant-like effects of alarin may be mediated by restoring altered pro-inflammatory and anti-inflammatory cytokine levels and GR expression to decrease HPA axis hyperactivity. Our findings provide additional knowledge to interpret the pathophysiology of depression.     

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.     

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.