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Violence and aggression represent severe social problems, with profound impacts on public health. Despite the development of experimental models to study aggressive behavior is highly appreciated, the underlying mechanisms remain poorly understood. Given the key contribution of mitochondria to central nervous system bioenergetics, we hypothesized that mitochondrial function in brain would be altered by social stress. Using a model of spontaneous aggression, we investigated here the effects of social stress on brain mitochondrial function in prefrontal cortex of Swiss mice. Animals were categorized as highly aggressive, subordinate and non-aggressive (harmonic) after stress induced by regrouping and compared them with non-regrouped animals. Despite social stress did not affect brain cortex oxygen consumption rates and NADH:cytochrome c oxidoreductase activity, cytochrome c oxidase expression and activity were significantly lower in highly aggressive animals compared to non-regrouped ones. These changes were not observed in ATP synthase and adenine nucleotide translocator content suggesting a selective effect of social stress on cytochrome c oxidase. Therefore, aggressive behavior generated upon social stress associates to selective reduction in cytochrome c oxidase activity, with potential detrimental effects on brain bioenergetics and function.

Alterations in the extracellular matrix have been observed in the cardiomyopathy of Chagas disease caused by Trypanosoma cruz i infection. However, the mechanism of extracellular matrix regulation in T. cruzi -infected cultured cardiomyocytes (CMs) is unclear. Using confocal laser microscopy, we demonstrated that treatment of these cultures with transforming growth factor beta (TGF- β ) and tumor necrosis factor alpha (TNF- α ) leads to an enhancement of the fibronectin matrix only in uninfected CMs, while infected myocytes displayed low fibronectin expression. Digital image analysis also revealed low superposition of the fibronectin signal with parasite nests in cytokine treated and untreated cultures. Cytochalasin D treatment resulted in microfilament disarray that induced a disturbance in the fibronectin network of CMs, suggesting that cytoskeleton disruption caused by T. cruzi infection disorganizes the fibronectin matrix. Western blot analysis revealed a 2-fold increase in the fibronectin expression in CM cultures after cytokine treatment, whereas T. cruzi infection significantly reduced fibronectin levels in all conditions. In contrast, no change in the laminin expression was detected after cytokine treatment. Laminin distribution was altered in T. cruzi -infected CMs, with intense laminin labeling only at the cell periphery even after cytokine treatment. Our observations indicate that TGF- β and TNF- α stimulates fibronectin expression only in uninfected cells of the T. cruzi -infected cultures, whereas the cells harboring the parasites display low or no fibronectin fibrils.

Fas/Fas ligand (Fas-L) engagement, a potent inducer of apoptosis, is also important for cellular activation, regulation of effector and chemotactic activity, and secretion of chemokines and cytokines. We evaluated the relevance of Fas/Fas-L in the regulation of myocarditis induced by Trypanosoma cruzi infection and observed that in Fas-L(-/-) mice (gld/gld), cardiac infiltration was significantly reduced, accordingly showing less cardiomyocyte destruction. Fluorescence-activated cell sorting analysis of cardiac inflammatory cells showed higher numbers of CD8(+) T cells in BALB/c compared with gld/gld mice but similar levels of lymphocyte function-associated antigen-1, intercellular adhesion molecule, CD2, and CD69 expression; MAC-1(+) myeloid cells and mast cells were increased in BALB/c mice, whereas gld/gld mice exhibited an enrichment of CD4(+/low) T cells. Intracellular labeling of cytokines revealed no clear cardiac skewing of Th1 or Th2 responses, but we found a higher number of interleukin-10(+) cells in gld/gld mice and a deficient expression of vascular cell adhesion molecule-1 on cardiac endothelial cells in gld/gld mice. Finally, we found a population of CD3(+) but CD4/CD8 double negative cardiac T cells in both groups of infected mice, but down-regulation of some adhesion molecules and surface receptors was only observed in gld/gld mice, indicating a targeted T-cell population mostly affected by the lack of Fas-L engagement. These results point to a role for myocarditis regulation by Fas/Fas-L beyond its possible direct relevance in cellular death.

In the acute phase of Trypanosoma cruzi infection, there is dramatic atrophy of the thymus. However, the pathways involved in this change have not yet been identified. This event is mainly characterized by a massive loss of cortical CD4+/CD8+ double-positive cells, but also by other structural and functional alterations in the organ. A number of molecules, including extracellular ATP, have been suggested to play a role in the selective processes that take place in the thymus. ATP and analogues trigger many different cellular responses in thymocytes and other cell types, such as the opening of plasma membrane cation channels and a pore that may induce cell death. Herein, we investigated the possible involvement of extracellular ATP in thymus atrophy induced by infection with T. cruzi. We observed that ATP induces an increase in plasma membrane permeabilization and cellular death in CD4+/CD8+ double-positive thymocytes collected from infected mice during the atrophy phase. No differences were observed prior to the atrophy phase or during the chronic phase. Our results indicate that P2Z/P2X7 receptors may play a central role in thymus atrophy during T. cruzi infection.