Made available in DSpace on 2014-06-11T19:25:26Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-11Bitstream added on 2014-06-13T18:26:28Z : No. of bitstreams: 1 nascimento_tb_me_botib.pdf: 563358 bytes, checksum: f368726d0ce2a3b729d717d9b8eed2e9 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O estresse é entendido como um processo complexo e multidimensional, cuja resposta adaptativa é vista como um processo dinâmico no qual mecanismos fisiológicos do indivíduo mudam continuamente para ajustarem-se ao ambiente. Esse fator pode contribuir para alterações na função cardíaca, associada, ou não, ao trânsito de Ca2+ e a alteração vascular devido ao aumento da atividade da via l-arginina/óxido nítrico. A obesidade é uma doença complexa, caracterizada pelo acúmulo excessivo de tecido adiposo, levando a disfunções cardíacas e vasculares, que podem estar envolvidas com alteração no fluxo de Ca2+ e comprometimento da resposta vasodilatadora. O estresse é considerado um fator ambiental, portanto, responsável por alterações no balanço energético e peso corpóreo, uma vez que o peso corpóreo é a interação entre fatores genéticos e ambientais. Devido à escassez de estudos que avaliam o estresse crônico e dieta hipercalórica nas alterações cardiovasculares, e considerando a hipótese de que esta associação é capaz de atenuar o desenvolvimento da obesidade e intensificar as alterações cardiovasculares, o objetivo do presente trabalho foi confirmar essa hipótese em animais submetidos à dieta hipercalórica e ao estresse crônico. Ratos machos Wistar, divididos em quatro grupos: DN: dieta normocalórica; DN/Es: dieta normocalórica e submetidos ao estresse crônico; DH: dieta hipercalórica; DH/Es: dieta hipercalórica e submetidos ao estresse crônico, foram avaliados quanto aos perfis nutricionais, metabólicos e a remodelação cardiovascular. Os dados demonstraram que o estresse crônico impediu o desenvolvimento da obesidade, e em oposição à hipótese, o estresse crônico melhorou a função cardíaca e vascular, independente do tipo de dieta utilizada / The stress is a complex and multidimensional process, the adaptive response is a dynamic process, in which individual physiologic mechanisms change to adjust to the environment, that causes alteration in the cardiac function, involved, or not, with Ca2+ flux and vascular alterations due to the increase of the l-arginine/nitric oxide pathway activity. The obesity is a complex disease, characterized by the excess of adipose tissue that causes cardiac and vascular dysfunction, involved with Ca2+ flux alterations and injury the vasodilating response. The stress is considered an environmental factor, therefore, it is responsible for the energetic balance alterations and weight gain, once the body weight is an interaction between genetic and environmental factors. There are few studies about chronic stress associated with the hypercaloric diet that evaluate the cardiovascular alterations, and considering the idea that this association can decrease the obesity development and increase the cardiovascular alterations, the aim of this research was evaluate the cardiovascular alterations and the obesity development in animals submitted to the hypercaloric diet and chronic stress. Male Wistar rats were separated into four groups: DN: standard diet; DN/Es: standard diet and chronic stress; DH: hypercaloric diet; DH/Es: hypercaloric diet and chronic stress were evaluated in relation to the nutritional and metabolic profile and cardiovascular remodellating. The data show that the chronic stress inhibited the obesity development, and different of the initial idea, the chronic stress improved the cardiac and vascular function, in both diets

abstract: Post-Traumatic Stress Disorder (PTSD) is characterized by intrusive memories from a traumatic event. Current therapies rarely lead to complete remission. PTSD can be modeled in rodents using chronic stress (creating vulnerable phenotype) combined with fear conditioning (modeling a traumatic experience), resulting in attenuated extinction learning and impaired recall of extinction. Studies typically investigate cognition soon after chronic stress ends; however, as days and weeks pass (“rest” period) some cognitive functions may improve compared to soon after stress. Whether a rest period between chronic stress and fear conditioning/extinction would lead to improvements is unclear. In Chapter 2, male rats were chronically stressed by restraint (6hr/d/21d), a reliable method to produce cognitive changes, or assigned to a non-stressed control group (CON). After chronic stress ended, fear conditioning occurred within a day (STR-IMM), or after three (STR-R3) or six weeks (STR-R6). During the first three extinction trials, differences emerged in fear to the non-shock context: STR-R3/R6 showed significantly less fear to the context than did STR-IMM or CON. Differences were unlikely attributable to generalization or to second-order conditioning. Therefore, a rest period following chronic stress may lead to improved fear extinction and discrimination between the conditioned stimulus and environment. In Chapter 3, the infralimbic cortex (IL) was investigated due to the IL’s importance in fear extinction. Rats were infused with chemogenetics to target IL glutamatergic neurons and then assigned to CON, STR-IMM or STR-R3. During the rest period of STR-R3 and the restraint for STR-IMM, the IL was inhibited using CNO (1mg/kg BW, i.p., daily), which ended before behavioral testing. STR-R3 with IL inhibition failed to demonstrate a tone-shock association as spontaneous recovery was not observed. CON with IL inhibition behaved somewhat like STR-IMM; freezing to the extinction context was enhanced. Consequently, inhibiting IL function during the rest period following chronic stress was particularly disruptive for learning in STR-R3, impaired freezing to a safe context for CON, and had no effect in STR-IMM. These studies show that time since the end of chronic stress (recently ended or with a delay) can interact with IL functioning to modify fear learning and response. / Dissertation/Thesis / Doctoral Dissertation Psychology 2020

No description available.

Background: Psychological and physical stress can either enhance or suppress immune functions depending on a variety of factors such as duration and severity of stressful situation. Chronic stress exerts a significantly suppressive effect on immune functions. However, the mechanisms responsible for this phenomenon remain to be elucidated. Autophagy plays an essential role in modulating cellular homeostasis and immune responses. However, it is not known yet whether autophagy contributes to chronic stress-induced immunosuppression. T cell immunoglobulin and mucin domain 3 (Tim-3) has shown immune-suppressive effects and obviously positive regulation on cell apoptosis. Tim-3 combines with Tim-3 ligand galectin-9 to modulate apoptosis. However, its impact on autophagy and chronic stress-induced immunosuppression is not yet identified. Results: We found remarkably higher autophagy level in the spleens of mice that were subjected to chronic restraint stress compared with the control group. We also found that inhibition of autophagy by the autophagy inhibitor 3-methyladenine (3-MA) significantly attenuated chronic stress-induced alterations of pro-inflammatory and anti-inflammatory cytokine levels. We further elucidated that 3-MA dramatically inhibited the reduction of lymphocyte numbers. Moreover, chronic stress dramatically enhanced the expression of Tim-3 and galectin-9. Inhibition of Tim-3 by small interfering RNA against Tim-3 significantly decreased the level of autophagy and immune suppression in isolated primary splenocytes from stressed mice. In addition, α-lactose, a blocker for the interaction of Tim-3 and galectin-9, also decreased the autophagy level and immune suppression. Conclusion: Chronic stress induces autophagy, resulting with suppression of immune system. Tim-3 and galectin-9 play a crucial regulatory role in chronic stress-induced autophagy. These studies suggest that Tim-3 mediated autophagy may offer a novel therapeutic strategy against the deleterious effects of chronic stress on the immune system.

Objectives: Mental and physical stress can suppress the immune system in both humans and animals. The mechanism by which stress affects immune responses, however, remains poorly defined. Toll-like receptors (TLRs) play a key role in modulating immune responses and cell survival. The mechanisms by which TLRs modulate chronic stress are largely unexplored. Methods: Six- to 8-week-old male mice were subjected to chronic 12-hour daily physical restraint stress. Apoptotic cells were determined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay. We examined cytokine levels by enzyme-linked immunosorbent Assay (ELISA). The expression of CYP11A1 was determined by quantitative real-time RT-PCR. Results: TLR9-deficient mice were resistant to chronic stress-induced lymphocyte apoptosis. In addition, in TLR9 knockout (KO) mice, chronic stress-induced upregulation of corticosterone levels was significantly decreased. Notably, lymphocytes from both TLR9 KO and wild-type mice were similarly sensitive to corticosteroid-induced cell apoptosis. Moreover, TLR9 deficiency blocked the chronic stress-induced imbalance in T helper (Th) 1 and Th2 cytokine levels. Conclusion: Taken together, our findings reveal that TLR9 plays an essential role in chronic stress-induced immune suppression.

Objectives: Mental and physical stress can suppress the immune system in both humans and animals. The mechanism by which stress affects immune responses, however, remains poorly defined. Toll-like receptors (TLRs) play a key role in modulating immune responses and cell survival. The mechanisms by which TLRs modulate chronic stress are largely unexplored. Methods: Six- to 8-week-old male mice were subjected to chronic 12-hour daily physical restraint stress. Apoptotic cells were determined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay. We examined cytokine levels by enzyme-linked immunosorbent Assay (ELISA). The expression of CYP11A1 was determined by quantitative real-time RT-PCR. Results: TLR9-deficient mice were resistant to chronic stress-induced lymphocyte apoptosis. In addition, in TLR9 knockout (KO) mice, chronic stress-induced upregulation of corticosterone levels was significantly decreased. Notably, lymphocytes from both TLR9 KO and wild-type mice were similarly sensitive to corticosteroid-induced cell apoptosis. Moreover, TLR9 deficiency blocked the chronic stress-induced imbalance in T helper (Th) 1 and Th2 cytokine levels. Conclusion: Taken together, our findings reveal that TLR9 plays an essential role in chronic stress-induced immune suppression.

Stress can either enhance or suppress immune functions depending on a variety of factors such as duration of stressful condition. Chronic stress has been demonstrated to exert a significant suppressive effect on immune function. However, the mechanisms responsible for this phenomenon remain to be elucidated. Here, male C57BL/6 mice were placed in a 50-ml conical centrifuge tube with multiple punctures to establish a chronic restraint stress model. Serum IL-10 levels, IL-10 production by the splenocytes, and activation of STAT3 in the mouse spleen were assessed. We demonstrate that IL-10/STAT3 axis was remarkably activated following chronic stress. Moreover, TLR4 and p38 MAPK play a pivotal role in the activation of IL-10/STAT3 signaling cascade. Interestingly, blocking antibody against IL-10 receptor and inhibition of STAT3 by STAT3 inhibitor S3I-201 attenuates stress-induced lymphocyte apoptosis. Inhibition of IL-10/STAT3 dramatically inhibits stress-induced reduction in IL-12 production. Furthermore, disequilibrium of Th1/Th2 cytokine balance caused by chronic stress was also rescued by blocking IL-10/STAT3 axis. These results yield insight into a new mechanism by which chronic stress regulates immune functions. IL-10/STAT3 pathway provides a novel relevant target for the manipulation of chronic stress-induced immune suppression.

No description available.

This experiment explored whether a long-term aerobic exercise program may induce significant structural and functional changes in the hippocampus, an area of the brain that is important for spatial navigation and memory formation. Based on existing rodent studies, we hypothesize that exercise will cause a shift to allocentric processing, away from a less robust egocentric learning strategy. It is possible that exercise-induced relief of chronic stress, which contributes to improved hippocampal function, will increase reliance on allocentric spatial navigation. Neurogenesis, which occurs in the dentate gyrus region of the hippocampus, is another indicator of hippocampal function that may influence this shift to allocentric learning. The current study examines whether six weeks of aerobic exercise enhances allocentric processing in healthy young adults. Forty-nine young adults (35 female; age range 18-29 years) were randomly assigned to one of three groups: 1) High intensity interval training group, 2) Moderate intensity training group, or 3) Non-exercising control group. Hippocampus-dependent memory was assessed before and after the intervention on a Virtual Reality Water Maze task, and a high interference memory task, the Mnemonic Similarity Task (MST) which may be dependent on hippocampal neurogenesis. Levels of chronic stress and depression were measured using the Beck Depression Inventory II. It was expected that exercise would improve spatial memory performance on the water maze task, and that performance would improve in proportion to enhanced fitness levels. This improvement in spatial memory performance was expected to correlate with the two indicators of hippocampal function that were assessed in the current study—chronic stress and performance on the high interference memory task. Six weeks of regular aerobic exercise resulted in a 21.5% improvement in spatial memory performance on the water maze task, indicating improved hippocampus-mediated spatial memory function. Improvements displayed by high intensity exercisers were greater than those observed in the moderate intensity exercisers, suggesting that higher intensity exercise may be more effective in enhancing hippocampal function. Importantly, low responders to exercise exhibited a 30% improvement in water maze performance, suggesting that even minor fitness improvements can lead to significant cognitive gains. Chronic stress and depression, and performance on the MST were not significantly associated with changes in spatial memory performance; however trends observed may offer some explanation to the aforementioned changes in spatial memory. Findings from the current study have important implications for treatment options in populations that are currently, or at risk of suffering from impaired hippocampal function. / Thesis / Master of Science (MSc)

No description available.