Sleep appears to play a critical role in regulating daytime functioning in children. However, few child-focused studies have used objective measures of sleep and examined its role in emotional functioning, memory, and attention. This dissertation consisted of 2 studies. Study 1 examined children’s typical sleep and how it correlates with daytime functioning in 32 typically developing children (14 boys, 18 girls), 8 to 12 years of age (M=9.8 y, SD=1.4). Participants wore actigraphs (recording devices that provide information about sleep and activity) for 1 week and then completed tasks to measure emotional functioning, memory, and attention. On average, children slept less than 9 h per night, which is approximately 1 h less than the recommended duration for this age. Older children had shorter sleep durations, higher sleep efficiency, and later sleep onset times. Correlational analyses revealed that within this group of typically developing children, small variations in sleep were associated with statistically significant effects on daytime functioning. Specifically, shorter sleep duration was associated with increased negative affective response, and lower sleep efficiency was associated with poorer performance on a divided attention task. Study 2 involved experimental manipulation of sleep duration in the same sample of children. Following a week of typical sleep, each child was randomly assigned to go to bed 1 h earlier for 4 nights (Extended condition) or 1 h hour later for 4 nights (Restricted condition) relative to their typical bedtime. Each child then completed the opposite condition. Following each condition, emotional functioning, memory, and attention were assessed using objective and subjective measures. The sleep manipulation was effective: the children slept significantly longer in the Extended (M=9.3 h, SD=0.6) versus Restricted (M=8.1 h, SD=0.7) condition, and children were significantly sleepier in the Restricted condition according to parent, child, and research assistant report. Positive affective response, emotion regulation, memory, and aspects of attention were worse in the Restricted, compared to Extended condition. These studies provide evidence that modest variations in sleep can have substantial effects on daytime functioning in children. Clinical implications are discussed, including the importance of identifying sleep problems and promoting healthy sleep habits in children.

No description available.

A via das Quinureninas (Via Quin) representa a principal via catabólica do metabolismo do triptofano (Trp) e é essencial para diversos processos fisiológicos. No fígado, o Trp é catalisado por triptofano 2,3-dioxigenase (TDO) quinurenina (Quin). A mesma reação também pode ser catalisada pela enzima indolamina 2,3-dioxigenase (IDO), produzida por células imunológicas. Em alguns processos patológicos, há um aumento do consumo de Trp pela Via Quin, que gera compostos que estão relacionados ao processo de imunotolerância. No presente estudo, foram selecionados dois modelos que mimetizam situações associadas às alterações da resposta imunológica: a restrição de sono e a obesidade. A partir do conhecimento das alterações na resposta imune nessas condições, geramos a hipótese de que parte do mecanismo se dê a partir da indução do catabolismo de Trp pela via Quin. Desse modo, foram investigadas as concentrações séricas e hepáticas de Trp nesses modelos experimentais, modelos esses que foram utilizados em outros projetos do nosso grupo de pesquisa. Não houve diferença significativa na concentração de Quin sérica e hepática entre os camundongos C57BL/6J restritos de sono (3 hs/15 dias), privação de sono paradoxal (72 hs) e período rebote (24 hs). A razão Quin/Trp também não diferiu entre os grupos RS e controle. Igualmente não houve diferenças estatísticas na concentração de Quin plasmática nos modelos privação de sono paradoxal e período rebote realizados em ratos Wistar. O mesmo foi observado em camundongos Swiss e camundongos C57BL/6J submetidos a protocolos experimentais de obesidade: ração hiperlipídica (21 dias) e de síndrome metabólica (20 semanas de ração hiperlipídica). Tais resultados sugerem que as alterações na resposta imunológica nesses quadros não estão associadas ao catabolismo de Trp. / The Kynurenine pathway (Kyn pathway) is the major catabolic pathway of tryptophan metabolism (Trp) and it is essential for many physiological processes. In the liver, Trp is catalyzed by tryptophan 2,3-dioxygenase (TDO), producing kynurenine (Kyn). The same reaction can also be catalyzed by the enzyme indoleamine 2,3-dioxygenase (IDO), produced by immune cells. In some pathological conditions, there is a high Trp consumption by Kyn pathway, that generate compounds related to immune tolerance. In this study, we chose two models strongly associated with changes in the immune response: sleep restriction and obesity. From the knowledge that there are immune response alterations in those conditions, we generated the hypotesis that in part, those alterations are correlated with induction the Trp catabolism by Kyn pathway. Thus, serum and liver concentrations of Trp and Kyn were investigated in these experimental models that have been used in other projects of our research group. There was no significant difference in concentration of Kyn in serum and liver among mice C57BL/6J induced to restricted sleep (3 hours / 15 days), paradoxical sleep deprivation (72 hours) and rebound period (24 hours). The Kyn/Trp ratio did not differ between control group and RS group. Also there were no statistical differences in plasma concentration of Kyn in paradoxical sleep deprivation and rebound period models performed in rats Wistar. The same profile was also observed in Swiss e C57BL/6J mice subjected to experimental obesity protocols: fat diet (21 days) and metabolic syndrome (20 weeks of fat diet). These results suggest that changes in the immune response in the conditions tested above are not associated with Trp catabolism.

Chronic low-grade endotoxemia is an important player in obesity and insulin resistance associated to a high-fat diet (HFD). On the other hand, although it is known that intense endotoxemia and infection reduce appetite and induce intense catabolism, leading to weight loss during the acute inflammatory phase, the late effects of an intense endotoxemia were previously unexplored. Here we report that, besides the concurrent effects, multiple and intense endotoxemia causes long lasting biochemical alterations in the adipose tissue that intensify the harmful effects of a HFD. Mice submitted to multiple and severe endotoxemia had increased the adipose tissue expression of TLR-4, CD14 and SAA3, remaining altered after one week in recovery. When associated to a HFD, mice previously submitted to acute endotoxemia showed a more severe weight gain and impaired insulin sensitivity. Adopting the HFD as an obesogenic stimulus, we evaluated the participation of the protein serum amyloid A (SAA) in obesity development. Using a SAA-targeted antisense oligonucleotide, we observed that the depletion of SAA prevented metabolic alterations, endotoxin elevation, weight gain and insulin resistance in a diet-induced obesity protocol. Inadequate sleep is another important factor to be considered in the obesity epidemic. We found that sleep restriction (SR) causes biochemical and morphological alterations in mice adipose tissue. The levels of serum resistin and the adipose tissue mRNA expression of resistin, TNF-α and IL-6 were increased after SR. When associated to a HFD, mice previously submitted to SR gained more weight with increased macrophage infiltration in the epididymal adipose tissue, and insulin resistance. SAA is also part of the initial biochemical alterations caused by SR. It was observed that the expression of SAA in liver and adipose tissue is upregulated, with return to baseline when sleep is restored. Furthermore, 48 hours of total sleep restriction in healthy human volunteers also caused a serum elevation in SAA concentrations. Considering that SAA induces cell proliferation, we suggest that situations with an increase in SAA production and the consecutive preadipocyte proliferation would prime the adipose tissue to further adipocyte differentiation and hypertrophy. Furthermore, we suggest that SAA alter LPS signaling, possibly inhibiting its clearance. The mechanism associating inflammation and obesity is complex and encompass a diversity of factors; the inflammatory protein SAA may be one of them. In conclusion, our data describes the relationship between SAA, acute inflammation, sleep restriction and obesity. / Endotoxemia crônica de baixo grau tem um importante papel na obesidade e resistência à insulina associada a uma ração hiperlipídica. Por outro lado, embora se saiba que a endotoxemia intensa e infecção reduzam o apetite e induzam a um intenso catabolismo, conduzindo a perda de peso durante a fase aguda da inflamação, os efeitos tardios da endotoxemia intensa nunca foram explorados. Aqui mostramos que, além dos efeitos correntes, a endotoxemia aguda provoca alterações bioquímicas prolongadas no tecido adiposo que intensificam os efeitos deletérios de uma ração hiperlipídica. Camundongos submetidos à endotoxemia aguda apresentaram aumento na expressão de TLR-4, CD14 e SAA3 no tecido adiposo, permanecendo alteradas após uma semana em recuperação. Quando associado a uma ração hiperlipídica, os camundongos previamente submetidos à endotoxemia aguda mostraram um ganho de peso mais pronunciado e uma maior resistência à insulina. Adotando a ração hiperlipídica como um estímulo obesogênico, foi avaliada a participação da proteína amilóide sérica A (SAA) no desenvolvimento da obesidade. Usando um oligonucleotídeo antisense anti-SAA, observamos que a depleção da SAA previne as alterações metabólicas, elevação de endotoxina, ganho de peso e resistência à insulina associadas a ração rica em gordura. O sono inadequado é outro fator importante a ser considerado na epidemia de obesidade. Descobrimos que a restrição do sono (SR) provoca alterações bioquímicas e morfológicas no tecido adiposo de camundongos. A concentração de resistina no soro e a expressão de mRNA no tecido adiposo de resistina, TNF-α e IL- 6 foram aumentadas após SR. Quando associado a uma ração hiperlipídica, os camundongos submetidos previamente à SR ganharam mais massa com aumento da infiltração de macrófagos no tecido adiposo epididimal, e resistência à insulina. SAA também faz parte das alterações bioquímicas iniciais provocadas pelo SR. Observou-se que a expressão de SAA no fígado e tecido adiposo é regulada positivamente, com retorno ao basal quando o sono é restaurado. Além disso, 48 horas de restrição de sono total em voluntários humanos saudáveis também causou uma elevação nas concentrações séricas de SAA. Considerando que SAA induz proliferação, sugerimos que situações onde ocorra aumento na produção de SAA e a consecutiva proliferação celular, o tecido adiposo se tornaria predisposto a futura diferenciação e hipertrofia. Além disso, sugerimos que SAA altera a sinalização de LPS, possivelmente inibindo sua depuração. O mecanismo de associação entre a inflamação e a obesidade é complexo e inclui uma diversidade de fatores; a proteína inflamatória SAA pode ser um deles. Em conclusão, nossos dados descrevem a relação entre SAA, inflamação aguda, restrição do sono e obesidade.

Chronic low-grade endotoxemia is an important player in obesity and insulin resistance associated to a high-fat diet (HFD). On the other hand, although it is known that intense endotoxemia and infection reduce appetite and induce intense catabolism, leading to weight loss during the acute inflammatory phase, the late effects of an intense endotoxemia were previously unexplored. Here we report that, besides the concurrent effects, multiple and intense endotoxemia causes long lasting biochemical alterations in the adipose tissue that intensify the harmful effects of a HFD. Mice submitted to multiple and severe endotoxemia had increased the adipose tissue expression of TLR-4, CD14 and SAA3, remaining altered after one week in recovery. When associated to a HFD, mice previously submitted to acute endotoxemia showed a more severe weight gain and impaired insulin sensitivity. Adopting the HFD as an obesogenic stimulus, we evaluated the participation of the protein serum amyloid A (SAA) in obesity development. Using a SAA-targeted antisense oligonucleotide, we observed that the depletion of SAA prevented metabolic alterations, endotoxin elevation, weight gain and insulin resistance in a diet-induced obesity protocol. Inadequate sleep is another important factor to be considered in the obesity epidemic. We found that sleep restriction (SR) causes biochemical and morphological alterations in mice adipose tissue. The levels of serum resistin and the adipose tissue mRNA expression of resistin, TNF-α and IL-6 were increased after SR. When associated to a HFD, mice previously submitted to SR gained more weight with increased macrophage infiltration in the epididymal adipose tissue, and insulin resistance. SAA is also part of the initial biochemical alterations caused by SR. It was observed that the expression of SAA in liver and adipose tissue is upregulated, with return to baseline when sleep is restored. Furthermore, 48 hours of total sleep restriction in healthy human volunteers also caused a serum elevation in SAA concentrations. Considering that SAA induces cell proliferation, we suggest that situations with an increase in SAA production and the consecutive preadipocyte proliferation would prime the adipose tissue to further adipocyte differentiation and hypertrophy. Furthermore, we suggest that SAA alter LPS signaling, possibly inhibiting its clearance. The mechanism associating inflammation and obesity is complex and encompass a diversity of factors; the inflammatory protein SAA may be one of them. In conclusion, our data describes the relationship between SAA, acute inflammation, sleep restriction and obesity. / Endotoxemia crônica de baixo grau tem um importante papel na obesidade e resistência à insulina associada a uma ração hiperlipídica. Por outro lado, embora se saiba que a endotoxemia intensa e infecção reduzam o apetite e induzam a um intenso catabolismo, conduzindo a perda de peso durante a fase aguda da inflamação, os efeitos tardios da endotoxemia intensa nunca foram explorados. Aqui mostramos que, além dos efeitos correntes, a endotoxemia aguda provoca alterações bioquímicas prolongadas no tecido adiposo que intensificam os efeitos deletérios de uma ração hiperlipídica. Camundongos submetidos à endotoxemia aguda apresentaram aumento na expressão de TLR-4, CD14 e SAA3 no tecido adiposo, permanecendo alteradas após uma semana em recuperação. Quando associado a uma ração hiperlipídica, os camundongos previamente submetidos à endotoxemia aguda mostraram um ganho de peso mais pronunciado e uma maior resistência à insulina. Adotando a ração hiperlipídica como um estímulo obesogênico, foi avaliada a participação da proteína amilóide sérica A (SAA) no desenvolvimento da obesidade. Usando um oligonucleotídeo antisense anti-SAA, observamos que a depleção da SAA previne as alterações metabólicas, elevação de endotoxina, ganho de peso e resistência à insulina associadas a ração rica em gordura. O sono inadequado é outro fator importante a ser considerado na epidemia de obesidade. Descobrimos que a restrição do sono (SR) provoca alterações bioquímicas e morfológicas no tecido adiposo de camundongos. A concentração de resistina no soro e a expressão de mRNA no tecido adiposo de resistina, TNF-α e IL- 6 foram aumentadas após SR. Quando associado a uma ração hiperlipídica, os camundongos submetidos previamente à SR ganharam mais massa com aumento da infiltração de macrófagos no tecido adiposo epididimal, e resistência à insulina. SAA também faz parte das alterações bioquímicas iniciais provocadas pelo SR. Observou-se que a expressão de SAA no fígado e tecido adiposo é regulada positivamente, com retorno ao basal quando o sono é restaurado. Além disso, 48 horas de restrição de sono total em voluntários humanos saudáveis também causou uma elevação nas concentrações séricas de SAA. Considerando que SAA induz proliferação, sugerimos que situações onde ocorra aumento na produção de SAA e a consecutiva proliferação celular, o tecido adiposo se tornaria predisposto a futura diferenciação e hipertrofia. Além disso, sugerimos que SAA altera a sinalização de LPS, possivelmente inibindo sua depuração. O mecanismo de associação entre a inflamação e a obesidade é complexo e inclui uma diversidade de fatores; a proteína inflamatória SAA pode ser um deles. Em conclusão, nossos dados descrevem a relação entre SAA, inflamação aguda, restrição do sono e obesidade.

A via das Quinureninas (Via Quin) representa a principal via catabólica do metabolismo do triptofano (Trp) e é essencial para diversos processos fisiológicos. No fígado, o Trp é catalisado por triptofano 2,3-dioxigenase (TDO) quinurenina (Quin). A mesma reação também pode ser catalisada pela enzima indolamina 2,3-dioxigenase (IDO), produzida por células imunológicas. Em alguns processos patológicos, há um aumento do consumo de Trp pela Via Quin, que gera compostos que estão relacionados ao processo de imunotolerância. No presente estudo, foram selecionados dois modelos que mimetizam situações associadas às alterações da resposta imunológica: a restrição de sono e a obesidade. A partir do conhecimento das alterações na resposta imune nessas condições, geramos a hipótese de que parte do mecanismo se dê a partir da indução do catabolismo de Trp pela via Quin. Desse modo, foram investigadas as concentrações séricas e hepáticas de Trp nesses modelos experimentais, modelos esses que foram utilizados em outros projetos do nosso grupo de pesquisa. Não houve diferença significativa na concentração de Quin sérica e hepática entre os camundongos C57BL/6J restritos de sono (3 hs/15 dias), privação de sono paradoxal (72 hs) e período rebote (24 hs). A razão Quin/Trp também não diferiu entre os grupos RS e controle. Igualmente não houve diferenças estatísticas na concentração de Quin plasmática nos modelos privação de sono paradoxal e período rebote realizados em ratos Wistar. O mesmo foi observado em camundongos Swiss e camundongos C57BL/6J submetidos a protocolos experimentais de obesidade: ração hiperlipídica (21 dias) e de síndrome metabólica (20 semanas de ração hiperlipídica). Tais resultados sugerem que as alterações na resposta imunológica nesses quadros não estão associadas ao catabolismo de Trp. / The Kynurenine pathway (Kyn pathway) is the major catabolic pathway of tryptophan metabolism (Trp) and it is essential for many physiological processes. In the liver, Trp is catalyzed by tryptophan 2,3-dioxygenase (TDO), producing kynurenine (Kyn). The same reaction can also be catalyzed by the enzyme indoleamine 2,3-dioxygenase (IDO), produced by immune cells. In some pathological conditions, there is a high Trp consumption by Kyn pathway, that generate compounds related to immune tolerance. In this study, we chose two models strongly associated with changes in the immune response: sleep restriction and obesity. From the knowledge that there are immune response alterations in those conditions, we generated the hypotesis that in part, those alterations are correlated with induction the Trp catabolism by Kyn pathway. Thus, serum and liver concentrations of Trp and Kyn were investigated in these experimental models that have been used in other projects of our research group. There was no significant difference in concentration of Kyn in serum and liver among mice C57BL/6J induced to restricted sleep (3 hours / 15 days), paradoxical sleep deprivation (72 hours) and rebound period (24 hours). The Kyn/Trp ratio did not differ between control group and RS group. Also there were no statistical differences in plasma concentration of Kyn in paradoxical sleep deprivation and rebound period models performed in rats Wistar. The same profile was also observed in Swiss e C57BL/6J mice subjected to experimental obesity protocols: fat diet (21 days) and metabolic syndrome (20 weeks of fat diet). These results suggest that changes in the immune response in the conditions tested above are not associated with Trp catabolism.

The main objective of this thesis was to examine the independent effects of sleep duration and timing on appetite, food reward and energy balance. Study 1 investigated the associations between satiety quotient (SQ) with habitual, self-reported sleep duration, quality and timing. No significant associations were noted between SQ and sleep parameters. Short-duration sleepers had a lower mean SQ vs. those with ≥7h sleep/night (P=0.04). Study 2 evaluated associations between changes in sleep duration, efficiency and timing with changes in next day food reward. Greater sleep duration and earlier wake-times were associated with greater food reward (P=0.001). However, these associations were no longer significant after controlling for elapsed time between awakening and completion of the food reward task. Study 3 examined the effects of 50% sleep restriction (SR) anchored during the first (delayed bedtime) or second (advanced wake-time) half of the night on appetite, SQ, food reward, energy intake (EI) and energy expenditure (EE). Greater appetite ratings and explicit high-fat food reward were noted following SR with an advanced wake-time vs. control and SR with a delayed bedtime (P=0.03-0.01). No difference in SQ was noted between sessions. Energy and carbohydrate intakes were greater on day 2 and over 36h in the delayed bedtime vs. control session (P=0.03). Activity EE and moderate-intensity physical activity (PA) time were greater following delayed bedtime vs. control and advanced wake-time on day 1, whereas vigorous-intensity PA time was greater following advanced wake-time vs. delayed bedtime on day 1 (P=0.01-0.04). Greater sleep quality and slow-wave sleep duration between SR sessions were associated with lower EI and increased vigorous-intensity PA time, respectively (P=0.01-0.04). Collectively, these findings suggest that appetite, SQ and food reward are influenced by sleep parameters, but these changes may not alter EI. These findings also suggest that individuals with greater sleep quality in response to SR had greater vigorous-intensity activity time and lower EI.

No description available.

The primary aim of the present study was to evaluate whether intra-individual variability in inhibition-related neural activation in response to sleep restriction is associated with eating behavior in adolescents aged 12-18 years. In addition, the potential moderating effects of sex and body mass index on the association between sleep and variability in neural activation were examined. This study employed a within-subjects crossover design that randomized subjects to both a 5 hours per night (sleep restricted) and 9 hours per night (well-rested) sleep condition for 5 nights, with experimental conditions separated by four weeks. On the 6th day of each study phase participants completed a 24-hour diet recall and a food-related inhibitory go/no-go task while undergoing functional magnetic resonance imaging. Repeated measures multilevel models examined individual differences attributable to sleep duration and a series of separate multivariate analysis of variance models examined the effect that vulnerability to sleep restriction has on eating behavior as well as the moderating impact of sex and weight status. Findings suggest that adolescents who exhibited greater efficiency in inhibitory and reward-related neural activation when sleep restricted demonstrated less pronounced decrements in neural activation when sleep restricted relative to when they were well-rested. These findings suggest that the effect of sleep restriction on inhibitory control may differ between individuals such that there are individuals who appear able to sustain inhibitory control comparable to when they are well-rested while other individuals show marked declines in executive functioning-related neural activation when sleep restricted. Results from separate exploratory models including regions of interest associated with reward valuation and across the whole brain were consistent with these findings. We also found that the effect of vulnerability to sleep restriction on inhibitory efficiency in the right inferior parietal lobule (R - IPL) and right middle frontal gyrus (R - MFG) differed by sex and was predictive of differences in overall eating behavior and sugar intake, respectively, when sleep restricted compared to well-rested. In addition, vulnerability in the inhibitory network was predictive of differences in individual eating behavior (i.e., total calories, added sugar, sugar, and total fat) for males and females across conditions. This finding demonstrates there is significant variability in the impact that sleep restriction has on inhibitory efficiency in adolescence relative to when they are well-rested, and vulnerability to inhibitory efficiency appears to effect male and female adolescent's dietary behaviors differently when they obtain insufficient sleep. Vulnerability to inhibitory efficiency when sleep restricted compared to well-rested may cause males and females to consume more energy dense foods when they obtain insufficient sleep and also differs for males and females irrespective of their sleep duration. Given the pervasiveness of chronic sleep restriction in adolescence, males who are unable to counter the effect that insufficient sleep has on palatable foods may be at greatest risk of obesity.

The present study aimed to evaluate associations between sleep duration and food-related inhibitory control and food reward in adolescents aged 12-18. Potential moderating effects of physical activity and weight status on the association between sleep, inhibitory control, and food reward were also examined. To evaluate these associations, the study employed a two-phase crossover design in which participants spent either 5 hours per night (restricted sleep) or 9 hours per night (habitual sleep) in bed for 5 nights. Participants completed a food-related inhibitory control task and a questionnaire assessing for food reward on the 6th day of each study phase. Repeated measures analyses of variance examined the effect of sleep restriction on food-related inhibitory control and food reward, and explored the moderating impact of weight status and physical activity. Adolescents performed more poorly on a food-related inhibitory control task and have heightened food reward following sleep restriction. Though no differences were noted across weight status in performance of a food inhibitory control task, adolescents with overweight/obesity demonstrated heightened food reward. An interaction between sleep duration and weight status predicted food reward, indicated that normal-weight adolescents are more susceptible to heightened food reward following sleep restriction compared to overweight/obese adolescents. Conversely, overweight/obese adolescents showed consistently high food reward with no effect of sleep duration, suggesting that they consistently view food as rewarding. These study findings may suggest that shortened sleep duration increased food reward for normal weight individuals, potentially putting them at risk for development of overweight/obesity.