Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers.

Temporal Analysis of Lipopolysaccharide-Induced Sickness Behavior in Virgin and Lactating Female Rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

TNFR1 is essential for CD40, but not for lipopolysaccharide-induced sickness behavior and clock gene dysregulation

Autoimmune and infectious diseases are associated with behavioral changes referred to as sickness behavior syndrome (SBS). In autoimmunity, the generation of anti-self T lymphocytes and autoantibodies critically involves binding of CD40 ligand on T-cells to its receptor CD40 on B-cells, dendritic cells and macrophages. Activation of CD40 leads to production of proinflammatory cytokines and, as shown here, induces SBS. Here we report that these behavioral changes depend on the expression of tumor necrosis factor alpha receptor 1 (TNFR1), but not on interleukin-1 receptor 1 or interleukin-6. Moreover, the intensity of SBS correlates with suppression of E-box controlled clock genes, including Dbp, and upregulation of Bmal1. However, the absence of TNFR1 does not interfere with the development of SBS and dysregulation of clock genes in mice treated with lipopolysaccharide. Thus, our results suggest that TNFR1 mediates SBS and dysregulation of clock genes in autoimmune diseases.

Perinatal Periodontal Disease Reduces Social Behavior in Male Offspring

Objective: Our objective was to verify whether prenatal maternal periodontitis is a risk factor for the development of central nervous system disorders in rats. Methods: Periodontitis was induced by placing a ligature around the upper and lower first molars in 9 female Wistar rats (experimental group); 9 rats were left unligated (control group). The maternal general activity in an open field was observed on gestational day (GD) 0, GD 4, and GD 14, and the maternal performance was assessed on the second day after birth. The pups' play behavior was assessed on postnatal day 30. The relative level of reelin was measured in the frontal cortex by real-time PCR analysis. Results: The results showed that, compared with the control group, (1) the general activity in female rats with periodontitis was decreased, (2) the maternal performance of these rats was not modified by periodontitis, (3) the play behavior of pups from dams with periodontitis was decreased, and (4) there were no differences in the frontal cortex reelin levels of pups from dams with periodontitis. Conclusions: We conclude that pre- and postnatal periodontitis induces maternal sickness behavior and reduces the pups' play behavior without interference with frontal cortex reelin expression. Copyright (C) 2012 S. Karger AG, Basel

Perfil sociodemográfico y clínico de los pacientes con lepra atendidos en el Hospital San Salvador de Chiquinquirá, Boyacá, durante el periodo 1951-1999

El objetivo del estudio describir el perfil sociodemográfico y clínico de los casos de enfermedad de Hansen, atendidos en el consultorio dermatológico del Hospital San Salvador, entre 1951 y 1999, para la formulación de recomendaciones en la búsqueda de la eliminación de la lepra como problema de salud pública en el país. Por lo tanto, la investigación corresponde a un estudio descriptivo longitudinal, en el cual se revisaron en total de 302 historias clínicas, que recogían 43 años del programa. Se encontró que el perfil de los enfermos correspondía a hombres jóvenes con edad promedio de 39 años, casados, procedentes en su mayoría de Boyacá, del área rural y dedicados a la agricultura. El promedio de tiempo entre síntomas y diagnóstico fue de 5,4 años. El 98,2 % de los pacientes presentaron síntomas primarios de lepra, en su mayoría neurológicos y dermatológicos. Predominaron las formas multibacilares en los mayores de quince años con un diagnóstico por baciloscopia y en los paucibacilares por clínica. La monoterapia fue el esquema más utilizado, tomado de forma regular. Los hombres presentaron mayor discapacidad en  manos, tanto al inicio como al final del tratamiento, en relación con las mujeres (x2: 14,23 p: 0,0000). El promedio de tiempo entre el diagnóstico y el inicio de tratamiento fue nueve días, mientras el promedio de tiempo total de tratamiento, 12,7 años. En un 40% de los casos no se conoció el desenlace, el 26,8% se reportaron como curados y el 19,5 % falleció. Un campesino joven con lepra lepromatosa tratado con monoterapia en tiempos prolongados y mayor discapacidad en manos es el perfil de los pacientes que concuerda con el comportamiento de la enfermedad en el mundo.

Lipopolysaccharide reduces sodium intake and sodium excretion in dehydrated rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Inhibition of sodium appetite by lipopolysaccharide: involvement of alpha(2)-adrenoceptors

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

The neuroimmune changes induced by cohabitation with an Ehrlich tumor-bearing cage mate rely on olfactory information

Cohabitation for 14 days with Ehrlich tumor-bearing mice was shown to increase locomotor activity, to decrease hypothalamic noradrenaline (NA) levels, to increase NA turnover and to decrease innate immune responses and decrease the animals' resistance to tumor growth. Cage mates of a B16F10 melanoma-bearer mice were also reported to show neuroimmune changes. Chemosignals released by Ehrlich tumor-bearing mice have been reported to be relevant for the neutrophil activity changes induced by cohabitation. The present experiment was designed to further analyze the effects of odor cues on neuroimmune changes induced by cohabitation with a sick cage mate. Specifically, the relevance of chemosignals released by an Ehrlich tumor-bearing mouse was assessed on the following: behavior (open-field and plus maze); hypothalamic NA levels and turnover; adrenaline (A) and NA plasmatic levels; and host resistance induced by tumor growth. To comply with such objectives, devices specifically constructed to analyze the influence of chemosignals released from tumor-bearing mice were employed. The results show that deprivation of odor cues released by Ehrlich tumor-bearing mice reversed the behavioral, neurochemical and immune changes induced by cohabitation. Mice use scents for intraspecies communication in many social contexts. Tumors produce volatile organic compounds released into the atmosphere through breath, sweat, and urine. Our results strongly suggest that volatile compounds released by Ehrlich tumor-injected mice are perceived by their conspecifics, inducing the neuroimmune changes reported for cohabitation with a sick companion. (C) 2011 Elsevier Inc. All rights reserved.

Lipopolysaccharide administration in the dominant mouse destabilizes social hierarchy

Sickness behavior is a set of behavioral changes that are part of an adaptive strategy to overcome infection. Mice that interact with conspecifics displaying sickness behavior also show relevant behavioral changes. In this work we sought to determine the role of sickness behavior display by a dominant mouse as a promoter of hierarchy instability. We treated the dominant mouse within a dyad with lipopolysaccharide (LPS) (400 mu g/kg, i.p.) for three consecutive days and assessed social dominance behavior. Since elder animals display increased inflammatory responses and the behaviors toward conspecifics are influenced by kinship we also assessed whether kinship and age, might influence sickness related hierarchy instability. Our results show that administration of LPS in the dominant mouse promotes social instability within a dyad, and indicates that this instability could be influenced by kinship and age. (C) 2012 Elsevier B.V. All rights reserved.

A crucial role for IL-6 in the CNS of rats during fever induced by the injection of live E. coli

Interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, and IL-6 have been established as important mediators of fever induced by lipopolysaccharide (LPS) from Gram-negative bacteria. Whether these pro-inflammatory cytokines are also important in mediating fever induced by live bacteria remains less certain. We therefore investigated the following: (1) the synthesis of TNF-alpha, IL-1 beta, and IL-6 during E. coli-induced fever and (2) the effect of blocking the action of cytokines within the brain on E. coli-induced fever. Body or tail skin temperature (bT or Tsk, respectively) was measured by biotelemetry or telethermometry, every 30 min, during 6 or 24 h. Depending on the number of colony-forming units (CFU) injected i.p., administration of E. coli induced a long-lasting increase in bT of male Wistar rats. The duration of fever did not correlate with the number of CFU found in peritoneal cavity or blood. Because 2.5 x 10(8) CFU induced a sustained fever without inducing a state of sepsis/severe infection, this dose was used in subsequent experiments. The E. coli-induced increase in bT was preceded by a decrease in Tsk, reflecting a thermoregulatory response. TNF-alpha, IL-1 beta, and IL-6 were detected at 3 h in serum of animals injected i.p. with E. coli. In the peritoneal exudates, TNF-alpha, IL-1 beta, and IL-6 were detected at 0.5 and 3 h after E. coli administration. Moreover, both IL-1 beta and IL-6, but not TNF-alpha, were found in the cerebrospinal fluid (CSF) and hypothalamus of animals injected with E. coli. Although pre-treatment (i.c.v., 2 mu l, 15 min before) with anti-IL-6 antibody (anti-IL-6, 5 mu g) reduced E. coli-induced fever, pre-treatment with either IL-1 receptor antagonist (IL-1ra, 200 mu g) or soluble TNF receptor I (sTNFRI, 500 ng) had no effect on the fever response. In conclusion, replicating E. coli promotes an integrated thermoregulatory response in which the central action of IL-6, but not IL-1 and TNF, appears to be important.

Antidepressants prevent hierarchy destabilization induced by lipopolysaccharide administration in mice: a neurobiological approach to depression

In spite of the high prevalence and negative impact of depression, little is known about its pathophysiology. Basic research on depression needs new animal models in order to increase knowledge of the disease and search for new therapies. The work presented here aims to provide a neurobiologically validated model for investigating the relationships among sickness behavior, antidepressants treatment, and social dominance behavior. For this purpose, dominant individuals from dyads of male Swiss mice were treated with the bacterial endotoxin lipopolysaccharide (LPS) to induce social hierarchy destabilization. Two groups were treated with the antidepressants imipramine and fluoxetine prior to LPS administration. In these groups, antidepressant treatment prevented the occurrence of social destabilization. These results indicate that this model could be useful in providing new insights into the understanding of the brain systems involved in depression.

Association between longitudinal changes in depressive symptoms and plasma fibrinogen levels in school teachers

Depression and anxiety previously predicted coronary artery disease (CAD) risk. Inflammation contributes to CAD and shows an association with depression. We followed 57 teachers (mean 49+/-8 years) over 21 months and investigated whether changes in depressive and anxiety symptoms relate to those in the CAD risk and inflammation marker fibrinogen and vice versa. Increase in depressive symptoms and in fibrinogen levels were significantly correlated. While controlling for baseline depression rendered the association between changes in depression and fibrinogen nonsignificant, taking into account baseline fibrinogen levels maintained the predictive value of fibrinogen change for depression change. Anxiety and fibrinogen changes were not significantly correlated. This dynamic relationship between depression and the inflammatory biomarker fibrinogen might advance our knowledge about psychobiological mechanisms underlying both CAD and sickness behavior.

The Role of Work Group in Individual Sickness Absence Behavior

The purpose of our two-year follow-up study was to examine the effect of the social components of the work group, such as group absence norms and cohesion, on sickness absence behavior among individuals with varying attitudes toward work attendance. The social components were measured using a questionnaire survey, and data on sickness absence behavior were collected from the employers' records. The study population consisted of 19,306 Finnish municipal employees working in 1,847 groups (78% women). Multilevel Poisson regression modeling was applied. The direct effects of work group characteristics on sickness absence were mostly insignificant. In contrast, both of the social components of a work group had an indirect impact: The more tolerant the group absence norms (at both individual- and cross-level) and the lower the group cohesion (at the individual level), the more the absence behavior of an individual was influenced by his or her attitude toward work attendance. We conclude that work group moderates the extent to which individuals with a liberal attitude toward work attendance actually engage in sickness absence behavior.

Fish oil diet associated with acute reperfusion related hemorrhage, and with reduced stroke-related sickness behaviors and motor impairment

Ischemic stroke is associated with motor impairment and increased incidence of affective disorders such as anxiety/clinical depression. In non-stroke populations, successful management of such disorders and symptoms has been reported following diet supplementation with long chain omega-3-polyunsaturated-fatty-acids (PUFAs). However, the potential protective effects of PUFA supplementation on affective behaviors after experimentally induced stroke and sham surgery have not been examined previously. This study investigated the behavioral effects of PUFA supplementation over a 6-week period following either middle cerebral artery occlusion or sham surgery in the hooded-Wistar rat. The PUFA diet supplied during the acclimation period prior to surgery was found to be associated with an increased risk of acute hemorrhage following the reperfusion component of the surgery. In surviving animals, PUFA supplementation did not influence infarct size as determined 6 weeks after surgery, but did decrease omega-6-fatty-acid levels, moderate sickness behaviors, acute motor impairment, and longer-term locomotor hyperactivity and depression/anxiety-like behavior.