Restrição prolongada de sono REM no período juvenil produz aumento de comportamento do tipo ansioso em ratos Wistar machos adolescentes e adultos : envolvimento das monoaminas cerebrais
Arquivos
Data
2017-05-31
Autores
Rocha-Lopes, Janaina da Silva 
Orientadores
Suchecki, Deborah
Tipo
Tese de doutorado
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ISSN da Revista
Título de Volume
Resumo
Introdução: Estudos epidemiológicos mostram que adolescentes têm dormido menos do que o necessário e, concomitantemente, observa-se aumento das queixas de sintomas ansiosos e/ou depressivos. Entretanto, não é possível estabelecer relação de causalidade nesse tipo de estudo. Visto que privação ou restrição de sono é estressante e parece representar um fator de risco para o desencadeamento de transtornos emocionais, por induzirem alterações na transmissão monoaminérgica no sistema límbico, o presente estudo teve como objetivo avaliar as consequências comportamentais e neurobiológicas, de curto- e longo-prazos, da restrição crônica de sono REM (RSREM) imposta durante o período juvenil. Métodos: Após o desmame, 81 de 161 ratos foram submetidos à RSREM por um período de 21 dias por 18 h diárias e 6 h de descanso nas gaiolas-moradia. Durante esse período, foi realizada avaliação do ganho de peso e de crescimento de todos os animais, inclusive dos controles (CTL, n = 80), a cada 3 dias. Ao final da RSREM, os animais foram subdivididos em três delineamentos experimentais diferentes. Os experimentos 1a e 1b tiveram início no dia pós-natal (DPN) 45 e envolveram testes comportamentais para avaliação dos comportamentos do tipo depressivo (1a: Teste de contraste negativo [TCNS]; 1b: Teste de contraste positivo de sacarose [TCPS]) e ansioso (1a: Labirinto em cruz elevado [LCE]; 1b: Campo aberto [CA]), comportamento social (1b: Investigação social) e memória (1b: Reconhecimento de objeto). Alíquotas de sangue foram coletadas 5 min antes (basal), 30 e 60 min depois do LCE para análise das concentrações de corticosterona (CORT); na última coleta, os animais foram eutanasiados e adrenais e encéfalos, dissecados para avaliação do peso das adrenais e das concentrações de monoaminas em áreas específicas. Para a avaliação das consequências tardias da RSREM, no experimento 2, os ratos permaneceram nas gaiolasmoradia após o final do protocolo até o DPN 90. Neste dia, os ratos foram submetidos à restrição de movimentos (RM) por 1 h, originando os subgrupos: CTL sem RM; CTL com RM; RSREM sem RM e RSREM com RM. No dia seguinte, 80 animais (n = 20/grupo) foram expostos ao LCE e os demais 40 (N = 10 animais/subgrupo) foram utilizados para medidas basais de CORT e monoaminas. Os animais expostos ao LCE foram eutanasiados 30 ou 60 min após o teste para coleta de sangue e encéfalo. Resultados: A RSREM prejudicou o ganho de peso e o crescimento dos animais durante e após o final do protocolo. Na adolescência, o grupo RSREM apresentou comportamento do tipo ansioso no LCE além de concentrações basais elevadas de CORT; aumento de noradrenalina na amígdala e no hipocampo ventral; aumento de serotonina concomitante à redução de seu turnover e da expressão do receptor 5-HT1A no hipocampo dorsal e aumento das concentrações de BDNF nesta região, porém sem alteração do comportamento do tipo depressivo no TCNS ou na expressão de receptores β1 (Experimento 1a). No experimento 1b, os animais exploraram menos o centro do campo aberto, sem mudança nos comportamentos tipo-depressivo, social e de memória. Nos animais adultos, tanto RSREM quanto RM foram ansiogênicos, porém sem efeito sinérgico entre si. A RSREM não modificou a resposta de CORT ao LCE, porém RM produziu aumento da resposta hormonal. O grupo RSREM+RM apresentou aumento das concentrações de noradrenalina na amígdala e córtex frontal, e aumento de dopamina no hipocampo dorsal. Conclusões: Esses resultados indicaram que a RSREM durante a adolescência prejudicou o desenvolvimento dos animais, propiciou um perfil do tipo ansioso e causou alterações na neurotransmissão monoaminérgica em estruturas do sistema límbico.
Introduction: Epidemiological studies have shown that adolescents are sleeping less than necessary; concurrently, there has been a rise in complaints of anxiety and depressive symptoms. However, epidemiological data do not allow the establishment of causality relationships between these events. Taking into consideration that sleep restriction or deprivation are considered risk factors for the development of emotional disorders, due to their stressful nature and impact on monoaminergic neurotransmission in the limbic system, the present study aimed to investigate the short- and long-term behavioural and neurobiological consequences of juvenile chronic REM sleep deprivation (REMSD). Methods: After weaning, 81 of 161 rats were sleep deprived for 21 days for 18 h/day and allowed to rest for 6 h on their home-cages. All animals, including controls (CTL, n = 80), were assessed for body weight gain and body growth every 3 days. After the REMSD protocol, animals were subdivided into three experimental designs. Experiments 1a and 1b started at postnatal day (PND) 45 and included assessment of depressive- (1a: sucrose negative contrast test [SNCT]; 1b: sucrose positive contrast test [SPCT]) and anxiety-like behaviours (1a: elevated plus maze [EPM]; 1b: open field [OF]), sociability (1b: social investigation) and memory (1b: object recognition). In Experiment 1a, blood samples were collected 5 min before (basal), and 30 and 60 min after the EPM for determination of plasma corticosterone (CORT) concentrations; at the 60 min timepoint, animals were decapitated and adrenals were weighted and brains, dissected for determination of monoamine concentrations in discrete areas. In experiment 2, we assessed the long-term consequences of juvenile REMSD. After the end of REMSD, rats were maintained in their home-cages until PND 90, when they were submitted to 1 h of movement restriction stress (MR), making up for the following subgroups: CTL without MR; CTL with MR; REMSD without MR and REMSD with MR. On the following day, 80 animals (n = 20/subgroup) were tested in the EPM, whereas another 40 were non-tested and used for basal measurements of CORT and monoamines. Animals exposed to the EPM were decapitated 30 or 60 min after the test for blood sampling and brain harvesting. Results: REMSD impaired weight gain and animal growth during and after the end of the protocol. During adolescence, animals subjected to REMSD displayed anxious-like behaviour in the EPM, as well as higher basal CORT concentrations; increased noradrenaline in the amygdala and ventral hippocampus; increased serotonin together with decreased turnover and 5-HT1A receptor expression in the dorsal hippocampus, whilst BDNF was elevated in this area; no depressive-like behaviour in the SNCT nor β1 changes in receptor expression were observed (experiment 1a). In experiment 1b, young animals explored less the centre of the OF whilst depressive-like, social and memory behaviours were unaffected. In adulthood, both REMSD and MR induced anxiety-like alterations, albeit not in a synergistic fashion. REMSR did not impact on the CORT response to EPM, but MR-exposed rats exhibited higher levels than their NMR counterparts. REMSR+MR group displayed higher levels of noradrenaline in the amígdala and frontal cortex and of dopamine in the dorsal hippocampus. Conclusions: These results indicated that REMSD during adolescence impaired the animals’ physical development, led to anxious-like profile and caused significant alterations in the monoaminergic neurotransmission in structures of the limbic system.
Introduction: Epidemiological studies have shown that adolescents are sleeping less than necessary; concurrently, there has been a rise in complaints of anxiety and depressive symptoms. However, epidemiological data do not allow the establishment of causality relationships between these events. Taking into consideration that sleep restriction or deprivation are considered risk factors for the development of emotional disorders, due to their stressful nature and impact on monoaminergic neurotransmission in the limbic system, the present study aimed to investigate the short- and long-term behavioural and neurobiological consequences of juvenile chronic REM sleep deprivation (REMSD). Methods: After weaning, 81 of 161 rats were sleep deprived for 21 days for 18 h/day and allowed to rest for 6 h on their home-cages. All animals, including controls (CTL, n = 80), were assessed for body weight gain and body growth every 3 days. After the REMSD protocol, animals were subdivided into three experimental designs. Experiments 1a and 1b started at postnatal day (PND) 45 and included assessment of depressive- (1a: sucrose negative contrast test [SNCT]; 1b: sucrose positive contrast test [SPCT]) and anxiety-like behaviours (1a: elevated plus maze [EPM]; 1b: open field [OF]), sociability (1b: social investigation) and memory (1b: object recognition). In Experiment 1a, blood samples were collected 5 min before (basal), and 30 and 60 min after the EPM for determination of plasma corticosterone (CORT) concentrations; at the 60 min timepoint, animals were decapitated and adrenals were weighted and brains, dissected for determination of monoamine concentrations in discrete areas. In experiment 2, we assessed the long-term consequences of juvenile REMSD. After the end of REMSD, rats were maintained in their home-cages until PND 90, when they were submitted to 1 h of movement restriction stress (MR), making up for the following subgroups: CTL without MR; CTL with MR; REMSD without MR and REMSD with MR. On the following day, 80 animals (n = 20/subgroup) were tested in the EPM, whereas another 40 were non-tested and used for basal measurements of CORT and monoamines. Animals exposed to the EPM were decapitated 30 or 60 min after the test for blood sampling and brain harvesting. Results: REMSD impaired weight gain and animal growth during and after the end of the protocol. During adolescence, animals subjected to REMSD displayed anxious-like behaviour in the EPM, as well as higher basal CORT concentrations; increased noradrenaline in the amygdala and ventral hippocampus; increased serotonin together with decreased turnover and 5-HT1A receptor expression in the dorsal hippocampus, whilst BDNF was elevated in this area; no depressive-like behaviour in the SNCT nor β1 changes in receptor expression were observed (experiment 1a). In experiment 1b, young animals explored less the centre of the OF whilst depressive-like, social and memory behaviours were unaffected. In adulthood, both REMSD and MR induced anxiety-like alterations, albeit not in a synergistic fashion. REMSR did not impact on the CORT response to EPM, but MR-exposed rats exhibited higher levels than their NMR counterparts. REMSR+MR group displayed higher levels of noradrenaline in the amígdala and frontal cortex and of dopamine in the dorsal hippocampus. Conclusions: These results indicated that REMSD during adolescence impaired the animals’ physical development, led to anxious-like profile and caused significant alterations in the monoaminergic neurotransmission in structures of the limbic system.
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Citação
LOPES, Janaína da Silva Rocha. Restrição prolongada de sono REM no período juvenil produz aumento de comportamento do tipo ansioso em ratos Wistar machos adolescentes e adultos: envolvimento das monoaminas cerebrais. São Paulo, 2017. [185] p. Tese (Doutorado em Psicobiologia) - Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, 2017.