Depression is a commonly observed disorder among cancer patients; however, the mechanisms underly... more 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.
There is increasing evidence that stress and emotional reactions produce changes in various immun... more There is increasing evidence that stress and emotional reactions produce changes in various immune processes. These changes may be due to alterations of the stress responses endocrine and for autonomic mediating mechanisms. In order to study such effects, the impact of chronic mild stress (CMS) application, and of subsequent imipramine administration were studied on the spleen mononuclear cell proliferative response period. OFI strain male mice were subjected to 4 or 7 weeks of CMS. The effects of these treatments on serum corticosterone levels and hypothalamic and hippocampal norepinephrine (NE) contents were also assessed. Subjects submitted to CMS had a higher spleen mononuclear cell proliferative response after either treatment duration. Imipramine treatment diminished this response enhancement in CMS exposed animals, but did not alter the proliferative responses of control subjects. Serum corticosterone levels, as well as hypothalamic and hippocampal nonrepinephrine contents did not significantly vary between groups. Taken together, these results suggest that CMSs effects on immune reactivity are not related to serum glucocorticoids or NE changes in these locations associated with the hypothalamic-pituitary- adrenocortical (HPA) axis.
Male OF1 strain mice were allocated, after 2 weeks of individual housing, to cohabitating (6 or 1... more Male OF1 strain mice were allocated, after 2 weeks of individual housing, to cohabitating (6 or 16 days), fixed dyadic interaction pairs (6 or 16 daily encounters) or control groups (6 or 16 days). These different social stress situations were assessed for their effects on splenic contents of NE, IL-1 and IL-2 and serum levels of corticosterone. Spleen NE contents showed no significant variations, but serum corticosterone titers were generally higher in interacting pairs and subordinates. Splenic IL-2 did not respond in the same way to the treatments as IL-1. The differences in splenic interleukin contents could not be simply related to observed changes in serum corticosterone levels. Different mechanisms appear to regulate changes in glucocorticoids and the measured cytokines. These physiological phenomena do not simply reflect in the animal's social status (dominant or submissive). The intensity and duration of the agonistic behavior displayed as well as the interaction experience accumulated may account for the observed differences between the paradigms.
fatigue (n = 34) and a non-fatigued group (n = 38) were included. Cytokines/chemokines in plasma ... more fatigue (n = 34) and a non-fatigued group (n = 38) were included. Cytokines/chemokines in plasma and in whole blood cultures stimulated with either a T-cell mitogen or lipopolysaccharide were determined by multiplex analysis. Principal component analysis of T-cell mitogen-induced cytokine/chemokine production identified three components (Th1-type cytokines, Th2-type cytokines and chemokines) that explained 76% of the variance in the cytokine data. Further analysis demonstrated that the capacity to produce Th2 cytokines (IL-4, IL-5, IL-10) was decreased in patients reporting chronic fatigue after clinical remission of sarcoidosis as compared to the non-fatigued group. Furthermore, we observed higher levels of LPS-induced IL-8 production, as well as lower levels of plasma MCP-1 in fatigued as compared to non-fatigued patients with sarcoidosis-in-clinical-remission. Our findings indicate that specific cytokine profiles are associated with chronic fatigue after clinical remission of sarcoidosis. We propose that these cytokine profiles might play a role in the etiology of chronic fatigue after remission of sarcoidosis. Preliminary data of a follow-up study show that fatigue even increased further and that the level of Th2 cytokines can predict the severity of chronic fatigue at follow-up.
cytokine levels in patients and controls. Moreover, to improve the statistical power, Pearson's c... more cytokine levels in patients and controls. Moreover, to improve the statistical power, Pearson's correlation, was conducted investigating the relationship between pro-inflammatory cytokines and cognition in the entire sample. Results: As expected, patients scored significantly worse on all the cognitive tasks presented compared to controls (p < 0.05), together with a trend for higher levels of pro-inflammatory cytokine IL-8 (p = 0.069). Particularly, high levels of IL-8, and IL-6 were related to significantly (p < 0.05) worse cognitive performance on perception and visuospatial domain (r = 0.37, p = 0.03), executive function/working memory domain (r = À0.38, p = 0.02), and verbal memory (r = À0.42, p = 0.02) in the entire sample. Conclusions: Our data demonstrate that pro-inflammation in first-episode psychosis may be one possible mechanism behind cognitive dysfunction in psychosis.
Involvement of IL-1 and NMDA receptors in central sensitization induced by a modified wind-up pro... more Involvement of IL-1 and NMDA receptors in central sensitization induced by a modified wind-up protocol Repetitive low-frequency (0.3-5 Hz) nociceptive stimulation leads to a progressive increase in action potential output from dorsal horn neurons, a phenomenon known as temporal summation, or wind-up. Using a modified protocol, composed of 3 trains of nociceptive stimulation (each train consists of 20 pulses at 1 Hz, 4 mA, 2 ms; trains separated by 10 min intervals), we have confirmed that the 1st train produced a characteristic wind-up as previously reported. Moreover, applying two additional trains produced potentiated responses (amplified by $2.5-fold). We named this potentiation wind-up of wind-up, or ''WoW". This protocol results in enhanced pain sensitivity as reflected by thermal hyperalgesia and mechanical allodynia, observed for 24 h post stimulation. The present study seeks to evaluate the involvement of interleukin-1 (IL-1) or NMDA receptors in this potentiation phenomenon. Acute injection of interleukin-1 receptor antagonist (IL-1ra; 200 mg/kg) had no significant effect on the WoW phenomenon. Moreover, transgenic mice overexpressing hIL-1ra in the CNS (IL-1raTG) did not differ in their WoW response. However, treatment with an NMDA antagonist (MK-801, 1 mg/kg, ip) blocked WoW responses in the WT strain but not in the IL-1raTG strain. The present results demonstrate that the WoW phenomenon does not depend on endogenous IL-1 signaling, but is NMDA receptor-dependent. In addition, IL-1ra may interact with the effect of MK-801 on NMDA receptor (supported by an ISF Grant No. 512/08).
Through the proinflammatory cytokines secreted in response to inflammation or injury, the immune ... more Through the proinflammatory cytokines secreted in response to inflammation or injury, the immune system produces physiological and behavioral alterations. This study analyzes the effects on behavior, mononuclear proliferative response and central monoamine activity in response to the inoculation of tumor cells in mice submitted to social stress. Two groups of male OF1 mice were used, one of which was inoculated with B16 melanoma cells. Both groups were subdivided into two new groups, with one being submitted to social stress through sensory contact model with a selected aggressive subject, and the other being handled without social interaction. Subjects were exposed to social stress for a 24-h period, with three 5 min intervals of direct physical interaction, where the behavior was recorded and assessed. One hour after the stress and/or handling, they were put down and samples taken for physiological assessment. Significant behavioral changes were found in subjects with implanted tumors, mainly characterized by an increase in avoidance behavior and a decrease in immobility, defense-submission and non-social exploration behavior, coupled with an increase in the spleen mononuclear cell proliferative response. Similarly, an increase was observed in the density of dopamine(2) (D(2))-receptors in the striatum (SRT) and an increase in dopaminergic (DOPAC/DA) and serotonergic (5HIAA/5HT) turnover in the hypothalamus. The increase in the density of D(2)-receptors in the SRT coincides with the decrease in some behaviors with a predominant motor component. The results indicate significant changes in the defensive strategy used to cope with situations of intense social stress in mice bearing tumors.
It has been found that acute social stress in male OF1 mice produced a general immunosuppression ... more It has been found that acute social stress in male OF1 mice produced a general immunosuppression and increased B16F10 tumor development. This study examined the effects of blocking either the hypothalamic–pituitary–adrenocortical (HPA) axis or the sympathetic adrenomedullary (SAM) system on the impact of such stress on tumor development. Naive male OF1 mice were individually housed for 12 days before being
Individual variation in behavioral coping strategies to stress implies that animals may have a di... more Individual variation in behavioral coping strategies to stress implies that animals may have a distinct physiological adaptation to stress; these differences may underlie differences in vulnerability to stress-related diseases. This study was designed to test the hypothesis that different behavioral coping strategies (active vs. passive) are stable over time and that they would be associated with differences in hypothalamic-pituitary-adrenal (HPA) and sympathetic-adreno-medular (SAM) axes, and monoaminergic and immune activity. Male mice were subjected to social stress. Twelve days after the first social interaction, mice were subjected to a second identical social stress interaction. Behavior was videotaped and assessed during both sessions. One hour after the final social interaction, serum was collected for corticosterone and adrenaline concentrations and brains were collected for hypothalamic corticotrophin-releasing hormone (CRH) mRNA expression. Monoaminergic system activity was determined by mRNA expression of serotonin, dopamine and noradrenaline synthetic enzymes in the brain stem. Immune system activity was determined by mRNA expression of hypothalamic interleukin-1β (IL-1β) and splenic IL-1β and interleukin-2 (IL-2). Mice engaging in a passive strategy had higher serum corticosterone and lower serum adrenaline concentrations than the active group. The passive group showed lower hypothalamic mRNA expression of IL-1β and CRH and lower splenic mRNA expression of IL-2 and IL-1β relative to mice in the active group. An active strategy was associated with higher expression of the dopaminergic synthetic enzyme, while a passive strategy was associated with decreased expression of the serotonergic synthetic enzyme. These findings indicate that individual coping strategies are stable over time and are related to differences in the physiological stress response and immune activity.
... of possible stress factors is particularly important given that each subject is exposed to it... more ... of possible stress factors is particularly important given that each subject is exposed to it throughout their whole life, not to mention the fact that their species has been previously exposed to the effects of its influence for generations (Valencia-Alfonso, Feria-Velasco, Luquin, Diaz ...
peer estimation technique carried out in the classroom. Children's dominance behavior was measure... more peer estimation technique carried out in the classroom. Children's dominance behavior was measured by teachers using the Hawley Dominance Test.
Depression is a commonly observed disorder among cancer patients; however, the mechanisms underly... more 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.
There is increasing evidence that stress and emotional reactions produce changes in various immun... more There is increasing evidence that stress and emotional reactions produce changes in various immune processes. These changes may be due to alterations of the stress responses endocrine and for autonomic mediating mechanisms. In order to study such effects, the impact of chronic mild stress (CMS) application, and of subsequent imipramine administration were studied on the spleen mononuclear cell proliferative response period. OFI strain male mice were subjected to 4 or 7 weeks of CMS. The effects of these treatments on serum corticosterone levels and hypothalamic and hippocampal norepinephrine (NE) contents were also assessed. Subjects submitted to CMS had a higher spleen mononuclear cell proliferative response after either treatment duration. Imipramine treatment diminished this response enhancement in CMS exposed animals, but did not alter the proliferative responses of control subjects. Serum corticosterone levels, as well as hypothalamic and hippocampal nonrepinephrine contents did not significantly vary between groups. Taken together, these results suggest that CMSs effects on immune reactivity are not related to serum glucocorticoids or NE changes in these locations associated with the hypothalamic-pituitary- adrenocortical (HPA) axis.
Male OF1 strain mice were allocated, after 2 weeks of individual housing, to cohabitating (6 or 1... more Male OF1 strain mice were allocated, after 2 weeks of individual housing, to cohabitating (6 or 16 days), fixed dyadic interaction pairs (6 or 16 daily encounters) or control groups (6 or 16 days). These different social stress situations were assessed for their effects on splenic contents of NE, IL-1 and IL-2 and serum levels of corticosterone. Spleen NE contents showed no significant variations, but serum corticosterone titers were generally higher in interacting pairs and subordinates. Splenic IL-2 did not respond in the same way to the treatments as IL-1. The differences in splenic interleukin contents could not be simply related to observed changes in serum corticosterone levels. Different mechanisms appear to regulate changes in glucocorticoids and the measured cytokines. These physiological phenomena do not simply reflect in the animal&#39;s social status (dominant or submissive). The intensity and duration of the agonistic behavior displayed as well as the interaction experience accumulated may account for the observed differences between the paradigms.
fatigue (n = 34) and a non-fatigued group (n = 38) were included. Cytokines/chemokines in plasma ... more fatigue (n = 34) and a non-fatigued group (n = 38) were included. Cytokines/chemokines in plasma and in whole blood cultures stimulated with either a T-cell mitogen or lipopolysaccharide were determined by multiplex analysis. Principal component analysis of T-cell mitogen-induced cytokine/chemokine production identified three components (Th1-type cytokines, Th2-type cytokines and chemokines) that explained 76% of the variance in the cytokine data. Further analysis demonstrated that the capacity to produce Th2 cytokines (IL-4, IL-5, IL-10) was decreased in patients reporting chronic fatigue after clinical remission of sarcoidosis as compared to the non-fatigued group. Furthermore, we observed higher levels of LPS-induced IL-8 production, as well as lower levels of plasma MCP-1 in fatigued as compared to non-fatigued patients with sarcoidosis-in-clinical-remission. Our findings indicate that specific cytokine profiles are associated with chronic fatigue after clinical remission of sarcoidosis. We propose that these cytokine profiles might play a role in the etiology of chronic fatigue after remission of sarcoidosis. Preliminary data of a follow-up study show that fatigue even increased further and that the level of Th2 cytokines can predict the severity of chronic fatigue at follow-up.
cytokine levels in patients and controls. Moreover, to improve the statistical power, Pearson's c... more cytokine levels in patients and controls. Moreover, to improve the statistical power, Pearson's correlation, was conducted investigating the relationship between pro-inflammatory cytokines and cognition in the entire sample. Results: As expected, patients scored significantly worse on all the cognitive tasks presented compared to controls (p < 0.05), together with a trend for higher levels of pro-inflammatory cytokine IL-8 (p = 0.069). Particularly, high levels of IL-8, and IL-6 were related to significantly (p < 0.05) worse cognitive performance on perception and visuospatial domain (r = 0.37, p = 0.03), executive function/working memory domain (r = À0.38, p = 0.02), and verbal memory (r = À0.42, p = 0.02) in the entire sample. Conclusions: Our data demonstrate that pro-inflammation in first-episode psychosis may be one possible mechanism behind cognitive dysfunction in psychosis.
Involvement of IL-1 and NMDA receptors in central sensitization induced by a modified wind-up pro... more Involvement of IL-1 and NMDA receptors in central sensitization induced by a modified wind-up protocol Repetitive low-frequency (0.3-5 Hz) nociceptive stimulation leads to a progressive increase in action potential output from dorsal horn neurons, a phenomenon known as temporal summation, or wind-up. Using a modified protocol, composed of 3 trains of nociceptive stimulation (each train consists of 20 pulses at 1 Hz, 4 mA, 2 ms; trains separated by 10 min intervals), we have confirmed that the 1st train produced a characteristic wind-up as previously reported. Moreover, applying two additional trains produced potentiated responses (amplified by $2.5-fold). We named this potentiation wind-up of wind-up, or ''WoW". This protocol results in enhanced pain sensitivity as reflected by thermal hyperalgesia and mechanical allodynia, observed for 24 h post stimulation. The present study seeks to evaluate the involvement of interleukin-1 (IL-1) or NMDA receptors in this potentiation phenomenon. Acute injection of interleukin-1 receptor antagonist (IL-1ra; 200 mg/kg) had no significant effect on the WoW phenomenon. Moreover, transgenic mice overexpressing hIL-1ra in the CNS (IL-1raTG) did not differ in their WoW response. However, treatment with an NMDA antagonist (MK-801, 1 mg/kg, ip) blocked WoW responses in the WT strain but not in the IL-1raTG strain. The present results demonstrate that the WoW phenomenon does not depend on endogenous IL-1 signaling, but is NMDA receptor-dependent. In addition, IL-1ra may interact with the effect of MK-801 on NMDA receptor (supported by an ISF Grant No. 512/08).
Through the proinflammatory cytokines secreted in response to inflammation or injury, the immune ... more Through the proinflammatory cytokines secreted in response to inflammation or injury, the immune system produces physiological and behavioral alterations. This study analyzes the effects on behavior, mononuclear proliferative response and central monoamine activity in response to the inoculation of tumor cells in mice submitted to social stress. Two groups of male OF1 mice were used, one of which was inoculated with B16 melanoma cells. Both groups were subdivided into two new groups, with one being submitted to social stress through sensory contact model with a selected aggressive subject, and the other being handled without social interaction. Subjects were exposed to social stress for a 24-h period, with three 5 min intervals of direct physical interaction, where the behavior was recorded and assessed. One hour after the stress and/or handling, they were put down and samples taken for physiological assessment. Significant behavioral changes were found in subjects with implanted tumors, mainly characterized by an increase in avoidance behavior and a decrease in immobility, defense-submission and non-social exploration behavior, coupled with an increase in the spleen mononuclear cell proliferative response. Similarly, an increase was observed in the density of dopamine(2) (D(2))-receptors in the striatum (SRT) and an increase in dopaminergic (DOPAC/DA) and serotonergic (5HIAA/5HT) turnover in the hypothalamus. The increase in the density of D(2)-receptors in the SRT coincides with the decrease in some behaviors with a predominant motor component. The results indicate significant changes in the defensive strategy used to cope with situations of intense social stress in mice bearing tumors.
It has been found that acute social stress in male OF1 mice produced a general immunosuppression ... more It has been found that acute social stress in male OF1 mice produced a general immunosuppression and increased B16F10 tumor development. This study examined the effects of blocking either the hypothalamic–pituitary–adrenocortical (HPA) axis or the sympathetic adrenomedullary (SAM) system on the impact of such stress on tumor development. Naive male OF1 mice were individually housed for 12 days before being
Individual variation in behavioral coping strategies to stress implies that animals may have a di... more Individual variation in behavioral coping strategies to stress implies that animals may have a distinct physiological adaptation to stress; these differences may underlie differences in vulnerability to stress-related diseases. This study was designed to test the hypothesis that different behavioral coping strategies (active vs. passive) are stable over time and that they would be associated with differences in hypothalamic-pituitary-adrenal (HPA) and sympathetic-adreno-medular (SAM) axes, and monoaminergic and immune activity. Male mice were subjected to social stress. Twelve days after the first social interaction, mice were subjected to a second identical social stress interaction. Behavior was videotaped and assessed during both sessions. One hour after the final social interaction, serum was collected for corticosterone and adrenaline concentrations and brains were collected for hypothalamic corticotrophin-releasing hormone (CRH) mRNA expression. Monoaminergic system activity was determined by mRNA expression of serotonin, dopamine and noradrenaline synthetic enzymes in the brain stem. Immune system activity was determined by mRNA expression of hypothalamic interleukin-1β (IL-1β) and splenic IL-1β and interleukin-2 (IL-2). Mice engaging in a passive strategy had higher serum corticosterone and lower serum adrenaline concentrations than the active group. The passive group showed lower hypothalamic mRNA expression of IL-1β and CRH and lower splenic mRNA expression of IL-2 and IL-1β relative to mice in the active group. An active strategy was associated with higher expression of the dopaminergic synthetic enzyme, while a passive strategy was associated with decreased expression of the serotonergic synthetic enzyme. These findings indicate that individual coping strategies are stable over time and are related to differences in the physiological stress response and immune activity.
... of possible stress factors is particularly important given that each subject is exposed to it... more ... of possible stress factors is particularly important given that each subject is exposed to it throughout their whole life, not to mention the fact that their species has been previously exposed to the effects of its influence for generations (Valencia-Alfonso, Feria-Velasco, Luquin, Diaz ...
peer estimation technique carried out in the classroom. Children's dominance behavior was measure... more peer estimation technique carried out in the classroom. Children's dominance behavior was measured by teachers using the Hawley Dominance Test.
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