Luiz Carlos de Sá-Rocha

Neural correlates of IgE-mediated food allergy.

Although many authors have considered the possibility of a direct interaction between food allergy and behavioral changes, the evidence supporting this hypothesis is elusive. Here, we show that after oral ovalbumin (OVA) challenge, allergic mice present higher levels of anxiety, increased Fos expression in emotionality-related brain areas, and aversion to OVA-containing solution. Moreover, treatment with anti-IgE antibody or induction of oral tolerance abrogate both food aversion and the expression of c-fos in the central nervous system (CNS). Our findings establish a direct relationship between brain function and food allergy, thus creating a solid ground for understanding the etiology of psychological disorders in allergic patients.

Variations in behavior, innate immunity and host resistance to B16F10 melanoma growth in mice that present social stable hierarchical ranks

The present study analyzed the effect of social stable hierarchical dominance/submissive relationships in C57BL/6 mice on behavior, innate immunity, serum corticosterone levels and host resistance to B16F10 melanoma growth. Adult mice (90 days old) kept in pairs since weaning, were analyzed for dominant/submissive ranking in three consecutive days according to the presence or absence of fighting and/or anticipatory submissive responses. Only the pairs of mice where dominant/submissive relationships were clearly stated were employed. Results showed that submissive mice presented in relation to dominants: (1) decreased time spent in the central open-field area; (2) decreased number of entries into the open arms and decreased time spent in the exploration of the open arms of the plus maze; (3) increased time spent in exploration of the plus-maze closed arms; (4) decreased number of entries and in the time spent in the exploration of the third part of the plus-maze open arms; (5) increased number of B16F10 metastasis in the lungs; (6) decreased NK cell cytotoxicity measured in vitro in the peripheral blood and spleen; (7) decreased basal but not in S. aureus induced oxidative burst in both neutrophils and monocytes and (8) similar basal serum levels of corticosterone. The present behavioral findings show that submissive mice, within a stable social hierarchy, present anxiety like-responses a fact that would make than more prone to stressful stimuli. This condition would be responsible for the decreases presently observed on basal neutrophil oxidative burst, NK cell activity and resistance to B16F10 tumor growth. Together the obtained data show that mice that present stable hierarchical relationships display neuro-immune alterations comparable to those reported in mice under a situation of chronic social stress.

Neural Correlates of IgE‐Mediated Allergy

Abstract:  Although many authors have considered a direct interaction between allergic reactions and behavioral changes, supporting evidence has been elusive. In this series of studies we show that after oral or nasal ovalbumin (OVA) challenge, allergic mice present increased Fos expression in the paraventricular nucleus of the hypothalamus (PVN) and in the central nucleus of the amygdala (CeA). Mice with food allergy display higher levels of anxiety and increased serum corticosterone levels, and allergy‐activated neurons express corticotropin‐releasing factor (CRF) in the PVN and CeA. OVA‐allergic mice develop aversion to an antigen‐containing solution, and also avoid a dark compartment previously associated with nebulized OVA. Results on brain Fos expression and behavioral data seem compatible with adaptive responses. Removal of IgE by either antibody depletion or the development of oral tolerance precluded all responses analyzed here. C‐sensitive fiber destruction by neonatal capsaicin inhibited the activation in the PVN, but not in the CeA, and decreased the magnitude of food aversion. Cromolyn, a mast cell stabilizer, completely blocked Fos expression in the PVN and CeA, and precluded the development of aversion to the dark compartment associated with nebulized OVA. Employing mice that do not develop an important inflammatory infiltrate following nasal OVA challenge, we found that inflammatory cells are not required at the site of challenge in order to trigger neural or behavioral correlates of murine experimental asthma. Altogether, we have built a solid foundation for understanding neuroimmune interactions during allergic responses that may contribute to the comprehension of psychological disorders associated with allergy.

Differential effects of lipopolysaccharide in the social behavior of dominant and submissive mice

Acutely infected animals show a set of non-specific behavioral changes known as sickness behavior. Recent studies have shown that occurrence of sickness behavior is regulated according to a motivational perspective. Thus, the display of sickness behavior may compete with display of other behaviors. In this work, we sought to determine the effects of lipopolysaccharide (LPS) administration (15 microg/mouse i.p.) in the social behavior of dominant and submissive mice. Results showed that social hierarchy influences the expression of sickness behavior. While dominant mice treated with LPS showed an expected reduction in total frequency of behaviors displayed, such decrease did not happen following the same treatment to submissive mice. Similar results occurred regarding social and aggressive behavior. The use of a motivational perspective provides the assumption that, due to their high social ranking, dominant mice were able to prioritize recuperative behavior. Submissive mice, on the other hand, even though treated with LPS, seemed to essentially focus on social defensive behaviors since they remained in the presence of the dominant individuals. Effects of sickness on the hierarchical organization of mice remain to be further investigated.

Cohabitation with a Sick Cage Mate: Consequences on Behavior and on Ehrlich Tumor Growth

The present study analyzed the effects of cohabitation for 11 days with a sick cage mate on behavior and Ehrlich tumor growth in mice. Pairs of female mice were divided into one control and one experimental group. One mouse of each control pair was kept undisturbed and called ‘healthy companion’ (HC). One animal of each experimental pair of mice was inoculated (i.p.) with 5 × 106 Ehrlich tumor cells, and the other, the object of this study, was called ‘sick companion’ (SC). The SC mice presented: (1) increased activity in an open field, (2) increased number of entries and of movements within the plus-maze open arms, (3) similar levels of plus-maze closed-arm exploration, (4) a decrease in the exploratory activity in a hole board, (5) a decrease in the number of white but not red blood cells, and (6) similar corticosterone serum levels. Eleven days after cohabitation with a conspecific, HC and SC mice were injected with 5 ×106 Ehrlich tumor cells. Results showed that SC animals presented decreased resistance to the ascitic form of the Ehrlich tumor. The observed data provide experimental evidence that psychosocial stress induced by cohabitation with a sick cage mate changed at the same time some behavioral and physiological parameters, and decreased resistance to Ehrlich tumor. These data are discussed in the light of a possible neuroimmune system interaction.

Neural pathways involved in food allergy signaling in the mouse brain: role of capsaicin-sensitive afferents.

There is increasing evidence supporting the notion that brain-gut communication is crucial for the manifestation of functional gastrointestinal (GI) disorders. Employing denervation by neonatal capsaicin treatment, we investigated here the role of unmyelinated C-fibers in food allergy signaling in the brain. We found that 90 min after oral ovalbumin (OVA) challenge, allergic mice present increased c-fos expression in emotionality-related brain areas such as the paraventricular nucleus of the hypothalamus (PVN) and the central nucleus of the amygdala (CeA). Food allergy also induced enhanced Fos immunoreactivity in the nucleus of tractus solitarii (NTS) of OVA-immunized animals. We also show that while the degree of Fos staining in the NTS of allergic mice was only diminished by neonatal capsaicin, it was completely blocked in the PVN. However, capsaicin did not modify food allergy-induced c-fos expression in the CeA. In conclusion, this study provides evidence showing that unmyelinated C-fibers are part of the neural pathways involved in food allergy-induced activation of specific brain areas, particularly the PVN and to a lesser extent the NTS.

Behavior: A Relevant Tool for Brain-immune System Interaction Studies

Neuroimmunomodulation describes the field focused on understanding the mechanisms by which the central nervous system interacts with the immune system, potentially leading to changes in animal behavior. Nonetheless, not many articles dealing with neuroimmunomodulation employ behavior as an analytical endpoint. Even fewer papers deal with social status as a possible modifier of neuroimmune phenomena. In the described sets of experiments, we tackle both, using a paradigm of social dominance and subordination. We first review data on the effects of different ranks within a stable hierarchical relationship. Submissive mice in this condition display more anxiety‐like behaviors, have decreased innate immunity, and show a decreased resistance to implantation and development of melanoma metastases in their lungs. This suggests that even in a stable, social, hierarchical rank, submissive animals may be subjected to higher levels of stress, with putative biological relevance to host susceptibility to disease. Second, we review data on how dominant and submissive mice respond differentially to lipopolysaccharide (LPS), employing a motivational perspective to sickness behavior. Dominant animals display decreased number and frequency in several aspects of behavior, particularly agonistic social interaction, that is, directed toward the submissive cage mate. This was not observed in submissive mice that maintained the required behavior expected by its dominant mate. Expression of sickness behavior relies on motivational reorganization of priorities, which are different along different social ranks, leading to diverse outcomes. We suggest that in vitro assessment of neuroimmune phenomena can only be understood based on the behavioral context in which they occur.

Immune-Induced Flavor Aversion in Mice: Modification by Neonatal Capsaicin Treatment

Objective: This study was designed to evaluate the role of c-sensitive fibers in the establishment of immune-induced flavor aversion in mice. Methods: Mice were treated neonatally with capsaicin in order to destroy c-sensitive fibers; after such treatment, adult animals, immunized or not with ovalbumin, were submitted to a two-bottle preference test, with a choice between water and a sweetened egg white solution. Results: Neonatal capsaicin treatment was unsuccessful in preventing the development of immune-induced aversion to the sweetened solution containing the antigen. Nonetheless, amongst immunized mice, those which had been previously treated with capsaicin showed a significant increment in the preference for the sweetened egg white solution. Furthermore, our data showed that neonatal capsaicin treatment did not interfere with either IgG1 or IgE production. Conclusion: The present results suggest that c-sensitive fibers have a role in the transmission of the signals generated by this immune response to the central nervous system, thus contributing to the development of a flavor aversion in mice.

Behavioral effects of LPS in adult, middle-aged and aged mice

Acute infections lead to alterations in behavior, collectively known as sickness behavior, which includes reduction in locomotion, food ingestion, sexual and social behavior, environmental exploration, and sleep profile. Although generally seen as undesired, sickness behavior represents a conserved strategy for animals to overcome disease. Aging process is associated with a variety of changes in immunity, which are referred to as immunosenescence, and include higher mortality by infectious diseases. Few works studied sickness behavior display in old animals. Thus, we sought to investigate the display of sickness related behaviors on aged mice. Adult (3-6 months old), middle-aged (12-15 m) and aged mice (18-22 m) were treated with i.p. LPS (200 microg/kg) and their behaviors were assessed in the open field and in the elevated plus-maze. Exploratory activity was similar in aged mice treated or not with LPS in both apparati. In the open field, locomotion remained at baseline levels; in the elevated plus-maze, there was a time-dependent decrease in motor activity.

Differential effects of bromopride and domperidone on cholinesterase activity in rat tissues

Bromopride (BRO) and domperidone (DOMP) are dopamine D2 blocking agents used in gastroenterology clinics because of their anti emetic effect as well as their central and peripheral actions of increasing gastrointestinal motor activity. The rationale for these experiments was to compare BRO- and DOMP-effects on plasma, brain, and intestinal cholinesterase activity in vitro. BRO and DOMP effects on cholinesterase activity in plasma, striatum, duodenum and ileum of adult male rats were measured for drug concentrations ranging from 0.006 to 3.134 microM for BRO and from 0.006 to 125 microM for DOMP. The results demonstrate that both BRO and DOMP can inhibit cholinesterase activity in all tissues studied, with DOMP being more potent than BRO in plasma and intestinal tissues. These data suggest the existence of a cholinergic mechanism of action for these dopamine blocking agents.