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Previous issue date: 2016-07-18 / Funda??o de Amparo ? Pesquisa do Estado do Rio Grande do Sul - FAPERGS / Childhood maltreatment (CM) exposure, including physical, sexual and psychological abuse, as well as physical or emotional neglect, is associated to long-term effects on mental health. The individual?s earlier years of life are characterized by rapid neurobiological and psychological development; therefore, CM is considered an important risk factor for psychological impairment and increased vulnerability to mood disorders. It is well established that alterations in the stress response systems, such as the immune and neuroendocrine systems are involved in this process. Based on this, investigating the effects of CM exposure in healthy adolescents can help to identify patterns of vulnerability to mood disorders in adulthood. The main objectives are: 1) to investigate the effects of CM exposure in neuroimunoendocrine and oxidative parameters in healthy adolescents without mood disorder; 2) to analyze early life stress effects in an animal model of maternal separation (MS) in cognitive performance, immune and oxidative parameters. The first study recruited thirty healthy adolescents reporting CM and twenty-seven healthy adolescents with no history of CM as control group. Blood, plasma and hair samples were obtained from all participants. Lymphocytes were isolated and stimulated in vitro to evaluate lymphocyte subsets, Th1/Th2/Th17 cytokines, mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (Nfkb) signaling pathways as well as lymphocyte sensitivity to dexamethasone by flow cytometry. Brain-derived neurotrophic factor (BDNF) and hair cortisol were assessed with enzyme-linked immunosorbent assays (ELISA). Increased percentage of activated T cells (CD3+CD+CD25+ and CD3+CD69+) and senescent T cells (CD8+CD28- and CD4+CD28-), as well as a reduction of NK cells (CD3-CD56+), and NKT cells (CD3+CD56+) were observed in healthy adolescents exposed to CM. Also, it was observed an increase of intracellular signaling through increased phosphorylation of ERK1 / 2 and NF-?B and increased cytokine production, such as IL-2, IFN-y and IL-17 following CM, suggesting increased cellular activation. Increased hair cortisol levels along with increased lymphocyte resistance to glucocorticoids in vitro, as well as low BDNF concentrations were observed in CM, reflecting the chronic stress effects on neuroendocrine parameters. The second study showed cognitive impairment, loss of parvalbumin and increased pro-inflammatory cytokines (TNF-?) peripherally following MS. The intervention of the enriched environment was effective in reversing memory damage as well as inflammation caused by MS. In conclusion, our results suggest that CM alter neuroimunoendocrine and oxidative responses in both, animal and human models. Thus, the understanding of the underlying mechanisms by which CM modulates the central nervous system, endocrine, and immune system and how these systems interact to alter the physiological responses of children and healthy adolescents, may help to increase preventive actions against the development of chronic inflammatory diseases and mood disorders in adulthood. / A exposi??o aos maus-tratos na inf?ncia (MTI), incluindo diferentes formas de abuso e neglig?ncia, est? associada com repercuss?es em longo prazo na sa?de do indiv?duo. Os primeiros anos de vida de um indiv?duo caracterizam-se por r?pido desenvolvimento neurobiol?gico e psicol?gico, portanto os MTI s?o considerados importantes fatores de risco para danos psicol?gicos e aumento da vulnerabilidade para transtornos de humor. Acredita-se que, altera??es em mecanismos de resposta ao estresse, incluindo os sistemas neuroend?crino e imunol?gico/oxidativo, estejam envolvidas neste processo. Diante disto, investigar os efeitos da exposi??o aos MTI no adolescente saud?vel pode ajudar a identificar padr?es de vulnerabilidade para transtornos de humor na idade adulta. Os objetivos da tese apresentada s?o: 1) investigar os efeitos neuroimunoend?crinos e oxidativos da exposi??o aos MTI em adolescentes saud?veis sem transtorno de humor e 2) analisar os efeitos do estresse precoce em modelo animal atrav?s do protocolo de separa??o materna (SM) no desempenho cognitivo e par?metros imunol?gicos/oxidativos. Para avalia??o do primeiro objetivo, foram recrutados trinta adolescentes saud?veis com hist?rico de MTI e vinte e sete adolescentes saud?veis sem hist?ria de MTI como grupo controle. Amostras de sangue, plasma e cabelo foram obtidas de todos os participantes. Linf?citos foram isolados e estimulados in vitro para identificar subtipos linfocit?rios, citocinas Th1/Th2/Th17, vias de sinaliza??o intracelular MAPKs e NF-?B, bem como a sensibilidade dos linf?citos ao dexametasona, por citometria de fluxo. Ainda, os n?veis de BDNF plasm?tico e cortisol capilar foram avaliados pela t?cnica de ELISA. Os adolescentes com MTI apresentaram um aumento na porcentagem das c?lulas T ativadas (CD3+CD4+CD25+ e CD3+CD69+) e c?lulas T senescentes (CD8CD28- e CD4+CD28-), al?m de redu??o em c?lulas NK (CD3-CD56+) e c?lulas NKT (CD3+CD56+). Al?m disso, os linf?citos de adolescentes expostos aos MTI apresentaram maior resist?ncia ao glicocorticoide dexametasona in vitro. Tamb?m evidenciamos altera??es em rotas de sinaliza??o intracelular, observada por aumento na fosforila??o de ERK1/2 e NF-?B em c?lulas T CD8+, e aumento de citocinas como IL-2, IFN-y and IL-17 ap?s MTI, confirmando um perfil de ativa??o imune celular. Aumento dos n?veis de cortisol capilar juntamente com a redu??o das concentra??es de BDNF plasm?tico foi detectado nos adolescentes expostos aos MTI, refletindo os efeitos a longo prazo do estresse cr?nico em par?metros neuroend?crinos. Ainda, um desequil?brio entre os marcadores de dano oxidativo e defesas antioxidantes foi encontrado nos adolescentes com hist?rico de MTI. Em rela??o ao segundo objetivo, os resultados do estudo experimental demonstraram que a SM causou altera??es de mem?ria, perda de parvalbumina e aumento de citocinas pr?-inflamat?rias (TNF-?) no plasma deanimais adolescentes. Ap?s a interven??o do ambiente enriquecido foi poss?vel reverter os preju?zos de mem?ria e a inflama??o causados pela exposi??o a SM. Concluindo, nossos resultados indicam que a exposi??o ao estresse durante a inf?ncia altera a resposta neuroimunoend?crina e oxidativa em modelo animal e humano. Deste modo, compreender de que forma os MTI modulam o sistema nervoso, end?crino e imune e como estes sistemas interagem entre si para alterar precocemente as respostas fisiol?gicas da crian?a e do adolescente saud?vel pode auxiliar no aumento de a??es preventivas contra o desenvolvimento de doen?as inflamat?rias cr?nicas e transtornos de humor na idade adulta.
| Identifer | oai:union.ndltd.org:IBICT/oai:tede2.pucrs.br:tede/6971 |
| Date | 18 July 2016 |
| Creators | Prado, Carine Hartmann do |
| Contributors | Bauer, Mois?s Evandro, Grassi-Oliveira, Rodrigo |
| Publisher | Pontif?cia Universidade Cat?lica do Rio Grande do Sul, Programa de P?s-Gradua??o em Biologia Celular e Molecular, PUCRS, Brasil, Faculdade de Bioci?ncias |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da PUC_RS, instname:Pontifícia Universidade Católica do Rio Grande do Sul, instacron:PUC_RS |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 8198246930096637360, 600, 600, 600, 600, 36528317262667714, -1634559385931244697, -3614735573891122254 |
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