Eneritz Gómez-Lázaro

Individual differences in chronically defeated male mice: Behavioral, endocrine, immune, and neurotrophic changes as markers of vulnerability to the effects of stress

This study aimed to analyze different behavioral profiles in response to chronic social defeat using the sensorial contact model. We hypothesized that a passive profile, unlike an active one, would be associated with behavioral and physiological characteristics related to depression. Six-week-old OF1 male mice were subjected to defeat for 21 consecutive days. A combination of cluster and discriminant analyses of the behavior exhibited during confrontation on Day 21 established two behavioral profiles: active (n = 22) and passive (n = 34). Passive mice, with a high level of immobility and low non-social exploration, had higher plasma corticosterone concentrations than active mice after 21 days of defeat. Three days after the last defeat, passive mice had lower corticosterone levels than manipulated-control mice (n = 11). Higher levels of interleukin-6 and tumor necrosis factor-α (TNF-α) in the spleen and lower hippocampal brain-derived neurotrophic factor levels were observed in passive mice in comparison with those in active mice and the manipulated controls. The only differences observed in active mice in relation to the manipulated control were higher plasma corticosterone (Day 21) and TNF-α levels. The results show that different behavioral profiles in response to chronic defeat are associated with different physiological profiles, and that the passive profile presents physiological characteristics previously associated with depression.

Coping with Chronic Social Stress in Mice: Hypothalamic-Pituitary-Adrenal/ Sympathetic-Adrenal-Medullary Axis Activity, Behavioral Changes and Effects of Antalarmin Treatment: Implications for the Study of Stress-Related Psychopathologies

The aim of this study was to analyze the individual differences that lead to the development of psychopathological changes in response to chronic social stress. We also assessed the ability of an antagonist of the corticotrophin-releasing hormone (CRH) receptors to reverse the effects of stress. Male adult mice were exposed to repeated defeat experiences for 21 days using a sensorial contact model. After 18 days of defeat, two groups of subjects were established (active and passive), according to their behaviors during social confrontation. Antalarmin treatment was given for 4 and 6 days. The results corroborated previous data indicating that subjects who adopted a passive coping strategy had higher corticosterone levels after 21 days of defeat and decreased resting levels 3 days later. Moreover, they showed higher resting expression levels of hypothalamic CRH than their active counterparts. On day 24, the experimental animals were subjected to another social defeat to determine whether the stress response remained. The increase in corticosterone and hypothalamic CRH levels was similar for all of the stressed subjects, but the passive subjects also had a greater CRH response in the amygdala. Passive subjects had decreased levels of adrenal dopamine β-hydroxylase, tyrosine hydroxylase and plasma adrenaline compared to the active subjects, and lower plasma noradrenaline levels than manipulated controls. The passive profile of physiological changes in both the hypothalamic-pituitary-adrenal and sympathetic-adrenal-medullary (SAM) axes has been associated with changes related to mood disorders, such as posttraumatic stress disorder and depression. The active coping profile is characterized by similar corticosterone resting levels to controls and increased SAM activity. Both profiles showed alterations in the novel palatable and forced swimming tests, with the passive profile being the most vulnerable to the effects of stress in this last test. Pharmacological treatment with antalarmin failed to reverse the effects of stress.

Effects of a putative antidepressant with a rapid onset of action in defeated mice with different coping strategies

There is evidence suggesting that stressful social events may result in depressive-like disorders, but the development of these disorders depend on the way in which people cope with stress. Although antidepressants are useful their drawback is a delay in the therapeutic effects, moreover not all the patients show an adequate response to this treatment. The aim of this study was to analyse the effect of RS 67333, which is a 5-HT(4) receptor partial agonist and a putative antidepressant which exhibits a rapid onset of action and to determine whether this drug reverses the behavioural and physiological effects that are generated by chronic defeat in subjects who manifest a more vulnerable profile in their response to stress. Male mice were exposed to defeat for 21 consecutive days using a sensorial contact model. After 18 days of defeat, 2 groups of subjects were established, active and passive, in accordance with the behaviour that was manifested during social confrontation, and drug treatment was initiated for 5 days. Finally, the animals were subjected to a forced swimming test (FST). The results revealed higher corticosterone levels in passive mice after the last defeat. Additionally, 3 days after the last defeat, they showed lower corticosterone levels and higher splenic IL-6 and TNF-α levels and hypothalamic GR mRNA levels when compared to their active and manipulated control counterparts. Passive mice had higher 5-HT(1A) receptor mRNA levels than the manipulated controls and a lower MR/GR ratio than active mice. Similar to stress, the drug increased hypothalamic GR mRNA levels, but it did not affect other measured physiological variables or social behaviour, which suggested that the mechanism of this drug is not the most adequate for reversing stress-induced effects in this model. Nevertheless, the treatment increased swimming and decreased immobility in the FST, suggesting an antidepressant potential for this drug.

Melanoma tumors alter proinflammatory cytokine production and monoamine brain function, and induce depressive-like behavior in male mice.

Depression is a commonly observed disorder among cancer patients; however, the mechanisms underlying the relationship between these disorders are not well known. We used an animal model to study the effects of tumor development on depressive-like behavior manifestation, proinflammatory cytokine expression, and central monoaminergic activity. Male OF1 mice were inoculated with B16F10 melanoma tumor cells and subjected to a 21-day behavioral evaluation comprising the novel palatable food (NPF) test and tail suspension test (TST). The mRNA expression levels of proinflammatory cytokines, interleukin (IL)-1β and IL-6, and tumor necrosis factor-alpha (TNF-α), were measured in the hypothalamus and hippocampus and the levels of IL-6 and TNF-α were measured in the blood plasma. We similarly determined the monoamine turnover in various brain areas. The tumors resulted in increasing the immobility in TST and the expression level of IL-6 in the hippocampus. These increases corresponded with a decrease in dopaminergic activity in the striatum and a decrease in serotonin turnover in the prefrontal cortex. Similarly, a high level of tumor development produced increases in the brain expression levels of IL-6 and TNF-α and plasma levels of IL-6. Our findings suggest that these alterations in inflammatory cytokines and monoaminergic system function might be responsible for the manifestation of depressive-like behaviors in tumor-bearing mice.

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.

Abstract # 1726 Effects of tumor development and social stress on inflammation: Behavioral and physiological changes

The aim was to study the effect of tumor development and social stress on depressive behavior, and analyzed immune and neurochemical alterations as possible mediators of this relationship. Male C57BL/6J mice were inoculated with B16F10 melanoma tumor cells. After inoculation, a subgroup was subjected to a social stress. After twenty-one days of tumor development, the behavior was assessed using the open field test (OFT), the forced swim test (FST) and the sucrose preference test (SPT). The following physiological measurements were carried out: (a) indoleamine 2,3 dioxygenase (IDO), proinflammatory interleukins IL-1B, IL-6, tumor necrosis factor-alpha (TNF-alpha) and anti-inflammatory interleukins IL-10 and IL-4 mRNA expression; b) the levels of serotonin (5HT), tyrosine (Tyr), phenylalanine (Phe), kynurenine (Kyn) and tryptophan (Tryp) and c) plasma corticosterone levels. The surface area of the tumor was also measured. Inoculated subjects showed greater immobility in both the OFT and the FST, as well as a low SPT. Tumor-bearing mice exhibited greater mRNA expression of IL1B, IL6, TNF-alpha and IDO, as well as a higher Phe/Tyr ratio. Social stress only produced changes in corticosterone levels. Tumor development generates changes in behavior that are characteristic of a depressive state. These changes can be attributed to an alteration in the central monoaminergic activation, produced by a higher expression of proinflammatory cytokines.

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.

Abstract # 1727 Immune activity in accordance with pyschological characteristics in breast cancer survivors

It has been estimated that 30–40% of women with breast cancer suffer from symptoms of psychological distress, and that these symptoms may persist for years, even after the end of treatment. The presence of psychological distress does not just affect quality of life; it may also affect survival. Moreover, the psychological and physiological mechanisms underlying its development are still unknown. Of the psychological factors that may be involved, the coping strategy adopted in response to stress may play a key role. At a physiological level, immune dysregulation, particularly inflammation, may constitute one of the mechanisms underlying the development of this psychopathology. This study has two aims. Firstly, it seeks to study plasma levels of proinflammatory cytokines lL-6 and TNF-alpha in breast cancer survivors who have completed their course of chemotherapy and radiotherapy over one year ago. Secondly, it aims to assess coping strategies in response to stress and the presence of symptoms indicative of psychological distress. The results indicate that women with passive coping strategies score higher on anxiety and depression scales and have higher proinflammatory cytokines levels. Identifying the factors associated with psychological distress could help prevent symptoms and could aid in the design of specific interventions to improve these patients’ quality of life.