Effects of sleep restriction during pregnancy on lipids and glucose homeostasis of female offspring submitted to ovariectomy.

Sleep shortening during pregnancy may alter the mother's environment, affecting the offspring. Thus, the present study evaluated the metabolic profile of female offspring from sleep-restricted rats during the last week of pregnancy. Pregnant Wistar rats were distributed into two groups: control (C) and sleep restriction (SR). The SR was performed 20 h/day, from 14th to 20th day of pregnancy. At 2 months, half of the offspring were subjected to ovariectomy (OVX); the others, to sham surgery. Studied groups were Csham, Covx, SRsham and SRovx. Cholesterol (HDL, LDL and C-total), triglycerides (TG) and glucose and insulin tolerance tests (GTT-ITT) were evaluated at 8 months. RSsham presented higher values of TG, while SRovx presented higher TG, LDL and C-total. Basal glucose concentration was increased in SRsham and SRovx. These data suggest that SR during pregnancy may be a risk factor for the development of diseases in adult female offspring.

Sleep restriction during pregnancy: hypertension and renal abnormalities in young offspring rats.

STUDY OBJECTIVES: Because the maternal environment can affect several physiological functions of the newborn, the aim of the present study was to examine the impact of sleep restriction during pregnancy on renal morphology and function in young offspring. DESIGN: Female 3-month-old Wistar rats were divided in 2 experimental groups: C (control) and SR (sleep restriction between the 14th and 20th day of pregnancy). Pregnancy was confirmed by vaginal smear. SR females were subjected to sleep restriction by the multiple platform technique for 20 h daily. After birth, only male litters (6 for each mother) were selected and designated OC (offspring from C) and OSR (offspring from SR). At 2 months of age, blood pressure (BP) was measured by tail plethysmography; at 3 months the renal plasma flow (RPF), glomerular filtration rate (GFR), glomerular area, and number of glomeruli per mm3 were evaluated. MEASUREMENTS AND RESULTS: Offspring from SR had higher systolic blood pressure than OC. In this group (OSR), we also observed significant increase in RPF and GFR, enlarged glomeruli diameter, and reduced number of glomeruli per mm3 of renal tissue. CONCLUSIONS: Our data suggest that sleep restriction during pregnancy is able to modify renal development, resulting in morphologic and functional alterations in young offspring.

Increased disease activity is associated with altered sleep architecture in an experimental model of systemic lupus erythematosus.

STUDY OBJECTIVES: The aim of this study was to evaluate sleep patterns during the course of the disease in (NZB/NZW)F1 mice, an experimental model of systemic lupus erythematosus (SLE). DESIGN: Female mice were implanted with electrodes for chronic recording of sleep-wake cycles during the entire experimental phase (9, 19, and 29 weeks of age). The disease course was also assessed. At each time-point, blood samples were collected from the orbital plexus to evaluate serum antinuclear antibodies (ANA), which are important serologic parameters of disease evolution. Pain perception was also evaluated. MEASUREMENTS AND RESULTS: During the dark phase, (NZB/NZW)F, mice aged 19 weeks spent more time in sleep, and, as a consequence, the total waking time was lower when compared with earlier periods. An augmented number of sleep-stage transitions and microarousals were observed at the 29th week of life in both light and dark phases. At this same time-point, the mice showed lower pain thresholds than they had at 9 weeks of life. The disease status was confirmed; the entire group of mice at 29 weeks of life showed positive ANA with high titer levels. CONCLUSIONS: The sleep-recording data showed that, during the progress and severe phases of the disease (19 and 29 wks of age, respectively), sleep architecture is altered. According to these results, increased sleep fragmentation, disease activity, and pain sensitivity are features observed in these mice, similar to symptoms of SLE.

Brief and long maternal separations decrease corticosterone secretion in a lupus-prone strain: dissociation from disease-related parameters.

Neonatal manipulations are known to alter the activity of the immune system and the hypothalamus-pituitary-adrenal (HPA) axis. This study was performed in order to examine whether brief and long maternal separations (BMS and LMS, respectively) interfere with the onset and development of murine lupus in NZB/NZWF1 females, and to determine whether the pattern of corticosterone (CORT) secretion throughout life is associated to the expression of the disease. Maternal separation was performed daily during postnatal days 1-14, lasting 15 min in the BMS group and 3h in the LMS group. Blood was sampled from the retro-orbital plexus on the 9th week, and every other week, from 10th to 34th weeks of life, for detection of anti-nuclear antibodies (ANA) and anti-double-strand DNA (anti-dsDNA) antibodies, and for determination of CORT serum levels. Urine samples were collected on the 21st, 27th, 33rd and 37th weeks of life. There were no group differences in regard to disease-related parameters, but LMS females presented a tendency for late onset of anti-dsDNA antibodies. BMS and LMS mice exhibited reduced CORT levels compared to non-manipulated (NM) animals. There was a strong negative correlation between total mean CORT concentration and onset of ANA, and a strong positive correlation between total mean CORT concentration and life span only in the NM group. Neonatal manipulations appeared to eliminate these correlations; hence, both BMS and LMS modified basal CORT secretion and the association between glucocorticoids and immune activity in the NZB/NZWF1 mouse strain.

Effect of sleep deprivation on the corticosterone secretion in an experimental model of autoimmune disease.

OBJECTIVE: Sleep disturbances have been observed in a number of chronic inflammatory conditions, such as systemic lupus erythematosus. Previous results from our laboratory showed that when NZB/NZWF1 mice, an experimental model of lupus, are submitted to sleep deprivation (SD), they exhibit an earlier onset of the disease. Sleep disturbances have far-reaching effects on the endocrine and immune system, changes that may be linked to disease manifestation. Immunoendocrine communication via the hypothalamic-pituitary-adrenal axis has been proposed as an important modulatory factor for the development of autoimmune disease. We hypothesized here that corticosterone (CORT) could be involved in earlier onset of the disease in sleep-deprived NZB/NZWF1 mice. METHODS: The profile of CORT secretion was measured immediately after the end of SD (platform method) and during the development of the disease. Also, we analyzed the effects of SD on CORT secretion of Swiss albino mice, which do not present immune alterations. RESULTS: The results showed that NZB/NZWF1 mice exhibited a CORT response to SD similar to Swiss albino mice. However, CORT levels remained elevated throughout the whole period of evaluation. There was an increase in circulating levels of CORT in the NZB/NZWF1 mice as the disease progressed, but this effect was more evident in the sleep-deprived mice. CONCLUSION: According to these results, we suggest that elevated CORT levels are involved in the earlier onset of the disease.

[Immune outcomes of sleep disorders: the hypothalamic-pituitary-adrenal axis as a modulatory factor]. / Repercussões imunológicas dos distúrbios do sono: o eixo hipotálamo-pituitária-adrenal como fator modulador.

OBJECTIVE: To review the literature on the interaction between sleep and the immune system. METHOD: A search on Web of Science and Pubmed database including the keywords sleep, sleep deprivation, stress, hypothalamic-pituitary-adrenal axis, immune system, and autoimmune diseases. RESULTS: On Web of Science, 588 publications were retrieved; 61 references, more significant and closer to our objective, were used, including original articles and review papers. CONCLUSION: Sleep deprivation and immune system exert a bidirectional influence on each other. Since sleep deprivation is considered a stressor, inasmuch as it induces elevation of cortisol or corticosterone levels in humans and rodents, respectively, and given the well-known immunosuppressive effect of glucocorticoids, we propose that increased activation of the hypothalamic-pituitary-adrenal axis is a major mediator of the immune alterations observed in patients with insomnia or in sleep deprived subjects.

Repercussões imunológicas dos distúrbios do sono: o eixo hipotálamo-pituitária-adrenal como fator modulador / Immune outcomes of sleep disorders: the hypothalamic-pituitary-adrenal axis as a modulatory factor

OBJETIVO: Revisar a literatura a respeito da interação entre sono e sistema imunológico. MÉTODO: Busca no Web of Science e no PubMed com os descritores: sono, privação de sono, estresse, eixo hipotálamo-pituitária-adrenal, sistema imunológico e doenças auto-imunes. RESULTADOS: Foram encontrados 588 artigos no Web of Science. As 61 referências mais significativas e mais relacionadas aos objetivos do estudo foram utilizadas. Foram incluídos artigos originais e de revisão. CONCLUSÃO: A privação de sono e o sistema imunológico exercem e sofrem influências mútuas. A privação de sono é considerada um estressor, uma vez que induz a elevação do cortisol em seres humanos - ou da corticosterona em roedores. Os glicocorticóides, por sua vez, exercem um efeito imunossupressor. Por essas razões, foi proposto que o aumento da ativação do eixo hipotálamo-pituitária-adrenal seja um importante mediador das alterações imunológicas observadas em pacientes com insônia ou privados de sono.

OBJECTIVE: To review the literature on the interaction between sleep and the immune system. METHOD: A search on Web of Science and Pubmed database including the keywords sleep, sleep deprivation, stress, hypothalamic-pituitary-adrenal axis, immune system, and autoimmune diseases. RESULTS: On Web of Science, 588 publications were retrieved; 61 references, more significant and closer to our objective, were used, including original articles and review papers. CONCLUSION: Sleep deprivation and immune system exert a bidirectional influence on each other. Since sleep deprivation is considered a stressor, inasmuch as it induces elevation of cortisol or corticosterone levels in humans and rodents, respectively, and given the well-known immunosuppressive effect of glucocorticoids, we propose that increased activation of the hypothalamic-pituitary-adrenal axis is a major mediator of the immune alterations observed in patients with insomnia or in sleep deprived subjects.

Effects of sleep deprivation on the development of autoimmune disease in an experimental model of systemic lupus erythematosus.

Sleep is hypothesized to play a restorative role on immune system. In addition, disturbed sleep is thought to impair host defense mechanisms. Chronic sleep deprivation is a common occurrence in modern society and has been observed in a number of chronic inflammatory conditions, such as systemic lupus erythematosus (SLE). New Zealand Black/New Zealand White (NZB/NZW) F1 mice develop an autoimmune disease that strongly resembles SLE in humans, exhibiting high titers of antinuclear antibodies associated with the development of rapidly progressive and lethal glomerulonephritis. On the basis of this evidence, the present study examined the onset and progress of lupus in as-yet healthy female mice submitted to sleep deprivation. Sleep deprivation was accomplished by two 96-h periods in the multiple-platform method when mice were 10 wk old, and they were observed until 28 wk of age. Blood samples were collected from the orbital plexus fortnightly to evaluate serum antinuclear antibodies and anti-double-stranded DNA. Proteinuria and longevity as well as body weight were also assessed. The results indicated that mice submitted to sleep deprivation exhibited an earlier onset of the disease, as reflected by the increased number of antinuclear antibodies. However, no statistical difference was found in the other parameters analyzed. According to these results, sleep deprivation could be considered as a risk factor for the onset but not for the evolution of the disease.

Privação de sono em modelo experimental de doença auto-imune / Sleep deprivation in the experimental model of autoimmune disease

Uma das funções atribuídas ao sono é a de restauração e regulação da qualidade do sistema imunológico. Por sua vez, distúrbios de sono estão associados a prejuízo do sistema imunológico, e condições onde há privação crônica de sono, tornam-se fatores de risco ao desenvolvimento de determinadas doenças. Os camundongos NZBjNZWF1 caracterizam-se por desenvolver espontaneamente quadro auto-imune muito semelhante ao lupus eritematoso sistêmico em humanos. Assim como em seres humanos, a incidência do lupus é maior em fêmeas e observa-se a influência de fatores hormonais e psico-sociais (como o estresse) na manifestação da doença nestes camundongos. Além disso, observa-se, em geral, que pacientes lúpicas referem sono de qualidade ruim, não reparador. Diante destas evidências, o presente trabalho tem como objetivo avaliar o efeito da PS no desencadeamento e na evolução do lupus nestes camundongos. No Experimento 1, os animais foram privados de sono por 2 períodos de 96h pela técnica da plataforma múltipla. Os animais controles permaneceram em suas gaiolas-moradia no mesmo ambiente onde foi realizada a privação de sono. Os animais foram privados de sono quando estavam na 10a semana de vida (período considerado clinicamente sadio) e foram acompanhados até a 2sa semana. Em ambos os grupos (controle e experimental), amostras de sangue foram coletadas pelo plexo retro-orbital a cada quinze dias para avaliar a presença de fatores anti-nuclerares (FAN) e de anticorpos a-DNA, importantes parâmetros sorológicos para estagiamento da doença. Além disso, outros parâmetros foram avaliados, tais como: peso corpóreo, proteinúria e longevidade. No Experimento 2, os animais foram privados de sono pelo mesmo procedimento, e imediatamente após a PS, o sangue dos animais foi coletado para dosagem de prolactina e o cérebro foi removido para o estudo da marcação de receptores dopaminérgicos 01, O2 e transportador de dopamina (OAT). No Experimento 3, seguindo o mesmo protocolo de privação de sono, avaliou-se o perfil de secreção de corticosterona (CORT) imediatamente após a PS (12a), na 13a, 19a , 2Sa e 31 a semana de vida. Os resultados mostraram que os animais submetidos a PS exibiram início precoce da doença em comparação com o grupo controle, revelado pela positividade e altos títulos de fatores anti-nucleares (FAN) medidos na primeira semana após a PS. No entanto, não houve diferença estatística nos outros parâmetros avaliados. No segundo experimento, observou-se que os animais privados de sono apresentaram redução na concentração de PRL circulante e também aumento na marcação do OAT no caudado-putamen. Não houve alteração na marcação dos receptores 01 e O2 entre os grupos estudados. E finalmente, no último experimento, observamos que imediatamente após a PS os animais apresentaram altos níveis de CORT e que se manteve durante todo o período avaliado. Além disso, observamos que na 13a semana de vida, ambos os grupos apresentaram um pico de secreção quando comparados à semana anterior. Desta forma, conclui-se que a PS é um estímulo capaz de acelerar o início do lupus, no entanto, sem alterar a gravidade da doença. Esses resultados sugerem que o sono é importante na manutenção da integridade do sistema imunológico, assim como no controle da função endócrina e do sistema nervoso. Portanto, o sono se revela um instrumento valioso para estudar a interação entre os sistemas imunológico, endócrino e nervoso central.

Effects of early handling on basal and stress-induced sleep parameters in rats.

Exposure of humans and animals to stressful events early in life leads to significant and often permanent behavioural, neuroendocrine and central alterations. Early handling consists of removing the litter from the nest for 15 min/day, from post-natal days 2 to 14 and results in lowered ACTH and corticosterone stress response and reduced anxiety-like and fear behaviours. Stress-induced sleep alterations usually consists of increased sleep time, known as sleep rebound. In the present study, basal and stress-induced sleep pattern of control non-manipulated (CTL) and early handled (EH) adult male rats was investigated. Sleep was evaluated by 21-h polysomnographic recordings (from 10:00 to 07:00 h of the next day) before and after a 1-h session of restraint stress. The results showed that in the first 3 h following stress, both CTL and EH animals exhibited an impairment of sleep, with a reduction of sleep efficiency, duration of slow wave sleep and of paradoxical sleep. On the contrary, time awake and awakening bouts were augmented in this period. Sleep rebound was observed mainly in the dark period of the light-dark cycle. Stress-induced sleep changes were similar between CTL and EH animals for most sleep parameters. However, EH animals exhibited more bouts of paradoxical sleep on the night following stress exposure and longer bouts of paradoxical sleep in the light period that followed restraint stress. These data indicate that stress-induced alterations of sleep in early handled animals are similar to that observed in control animals, except for some parameters related to paradoxical sleep.