Submitted by PPG Pediatria e Sa?de da Crian?a (pediatria-pg@pucrs.br) on 2018-09-11T11:48:41Z No. of bitstreams: 1 TESE-VERS?O_FINALLuisEduardo.pdf: 1410228 bytes, checksum: 2182e3ab4fb82033fdb96b0f40cbec8f (MD5) / Approved for entry into archive by Sheila Dias (sheila.dias@pucrs.br) on 2018-09-12T14:26:10Z (GMT) No. of bitstreams: 1 TESE-VERS?O_FINALLuisEduardo.pdf: 1410228 bytes, checksum: 2182e3ab4fb82033fdb96b0f40cbec8f (MD5) / Made available in DSpace on 2018-09-12T14:40:17Z (GMT). No. of bitstreams: 1 TESE-VERS?O_FINALLuisEduardo.pdf: 1410228 bytes, checksum: 2182e3ab4fb82033fdb96b0f40cbec8f (MD5) Previous issue date: 2018-04-24 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Early life stress exposure is a global issue and is associated with decreased quality of life and it is considered a risk factor for several diseases. There are several evidences in the literature suggesting that early life stress impact brain development, as well as cognition and motricity. The neurobiological mechanisms behind these effects are poorly understood. Aim: This study aims to investigate the impact of an experimental model of early life stress on cognitive abilities and walk adaptability during adolescence, looking at the gene expression of targets related to learning and memory in different brain regions. Methods: Briefly, we exposed male C56BL/6 mice to the limited bedding protocol postnatal day (PND)2 to PND9 and then tested animals in the radial 8-arm maze, Y-maze and Step-Down avoidance task and Ladder Rung Walking Test at the end of adolescence. RT-qPCR was used to investigate BDNF exon IV, Drd1 and Drd2 gene expression in the mPFC, Motor Cortex and Cerebellum 2h after the task. Results: Mice raised in Limited Bedding conditions presented fewer perseverative errors compared to our reference group. This effect was followed by an increased BDNF exon IV expression in the mPFC with no differences in Drd1 and Drd2. When looking at the ability of adapt walking of mice, we found two distinct subgroups of animals that presented a superior performance (SP) when compared to controls or an inferior performance (IP). We observed that Drd1 expression is increased in the mPFC of IP animals and in the cerebellum of SP with no differences regarding Drd2 expression on mPFC, motor cortex and cerebellum. We observed that both SP and IP groups increased BDNF expression in the mPFC together with a significant difference between SP and IP groups in BDNF expression on motor cortex. We found a strong negative correlation between BDNF exon IV expression in the motor cortex and walking adaptability. No differences between groups regarding TrkB mRNA expression in any brain region investigated were observed although there is a positive correlation between TrkB expression in the mPFC and a better ability to adapt walking. Conclusions: Our study showed that mice exposed to Limited Bedding showed fewer perseveration and increased BDNF exon IV expression in the mPFC during adolescence. Also, our data suggest that exposure to Limited Bedding early in life can lead to distinct phenotypes followed by differential expression in Drd1 and BDNF in brain regions involved in the regulation of walking adaptability. / Introdu??o: A exposi??o ao estresse no in?cio da vida est? associado a uma diminui??o na qualidade de vida e ? considerada como fator de risco para diversas patologias. Ainda que o impacto do estresse precoce no desenvolvimento cerebral e cognitivo, bem como no sistema motor, esteja bem documentado na literatura, pouco se sabe sobre os mecanismos neurobiol?gicos mediadores destes efeitos. Objetivos: Este trabalho tem como objetivo investigar o impacto de um modelo experimental de estresse precoce no funcionamento cognitivo e na adaptabilidade da marcha na adolesc?ncia, avaliando a express?o g?nica de alvos relacionados ? mem?ria e aprendizagem em diferentes regi?es do c?rebro. M?todos: Camundongos machos da linhagem C57BL/6 foram expostos ao modelo de Limited Bedding do P2 ao P9 e testados no Labirinto Radial de 8 bra?os, Labirinto Y, Esquiva Inibit?ria e Escada Horizontal no final da adolesc?ncia. RT-qPCR foi realizado para investigar a express?o g?nica do exon IV do BDNF, Drd1 e Drd2 nas regi?es do mPFC, C?rtex Motor e Cerebelo. Resultados: Camundongos expostos ao modelo de Limited Bedding na inf?ncia cometeram menos erros perseverativos quando comparados ao grupo controle. Este efeito foi seguido por um aumento na express?o do exon IV do BDNF no mPFC, embora nenhuma diferen?a entre Drd1 e Drd2 tenha sido observada. Ao observar a adaptabilidade da marcha, encontramos dois subgrupos distintos de animais que apresentaram desempenho superior (SP) quando comparados aos controles ou desempenho inferior (IP). Observamos uma express?o exarcebada de Drd1 no mPFC de animais com performance inferior e aumento na express?o de Drd1 no cerebelo de animais com performance superior, sem diferen?as em rela??o ? express?o de Drd2 no mPFC, c?rtex motor e cerebelo. Observamos que ambos os grupos aumentaram a express?o do BDNF no mPFC, juntamente com uma diferen?a significativa entre os grupos SP e IP na express?o do BDNF no c?rtex motor. Encontramos uma forte correla??o negativa entre a express?o do exon IV do BDNF no c?rtex motor e a adaptabilidade da marcha. N?o foram observadas diferen?as entre os grupos em rela??o ? express?o de TrkB nas regi?es do c?rebro investigadas, embora haja uma correla??o positiva entre a express?o de TrkB no mPFC e uma melhor capacidade de adapta??o da marcha. Conclus?o: Nosso estudo demonstrou que camundongos expostos ao Limited Bedding apresentaram menos comportamentos perseverativos e aumento da express?o do exon IV do BDNF na adolesc?ncia. Al?m disso, nossos dados sugerem que a exposi??o ao Limited Bedding pode levar a fen?tipos distintos na tarefa de adaptabilidade da marcha, seguido de uma express?o diferenciada de Drd1 e BDNF em regi?es cerebrais envolvidas na adaptabilidade da marcha.