RESUMO
Hypocretin, also known as orexin, maintains the vigilance state and regulates various physiological processes, such as arousal, sleep, food intake, energy expenditure, and reward. Previously, we found that when wild-type mice and hypocretin/ataxin-3 littermates (which are depleted of hypothalamic hypocretin-expressing neurons postnatally) were administered lipopolysaccharide (LPS), the two genotypes exhibited significant differences in their sleep/wake cycle, including differences in the degree of increase in sleep periods and in recovery from sickness behaviour. In the present study, we examined changes in the hypothalamic vigilance system and in the hypothalamic expression of inflammatory factors in response to LPS in hypocretin/ataxin-3 mice. Peripheral immune challenge with LPS affected the hypothalamic immune response and vigilance states. This response was altered by the loss of hypocretin. Hypocretin expression was inhibited after LPS injection in both hypocretin/ataxin-3 mice and their wild-type littermates, but expression was completely abolished only in hypocretin/ataxin-3 mice. Increases in the number of histidine decarboxylase (HDC)-positive cells and in Hdc mRNA expression were found in hypocretin/ataxin-3 mice, and this increase was suppressed by LPS. Hypocretin loss did not impact the change in expression of hypothalamic inflammatory factors in response to LPS, except for interferon gamma and colony stimulating factor 3. The number of c-Fos-positive/HDC-positive cells in hypocretin/ataxin-3 mice administered LPS injections was elevated, even during the rest period, in all areas, suggesting that there is an increase in the activity of histaminergic neurons in hypocretin/ataxin-3 mice following LPS injection. Taken together, our results suggest a novel role for hypocretin in the hypothalamic response to peripheral immune challenge. Our findings contribute to the understanding of the pathophysiology of narcolepsy.
Assuntos
Hipotálamo/imunologia , Hipotálamo/metabolismo , Inflamação , Lipopolissacarídeos/farmacologia , Orexinas/metabolismo , Sono/imunologia , Vigília , Animais , Ataxina-3/metabolismo , Expressão Gênica , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/metabolismo , Lipopolissacarídeos/administração & dosagem , Masculino , Camundongos , Camundongos TransgênicosRESUMO
Sleep supports the formation of immunological memory as evidenced by a stronger immune response to vaccination if subjects sleep during the subsequent night than if they stay awake. One mechanism underlying this adjuvant-like action of sleep might be an enhanced homing of circulating naïve T cells to lymph nodes. Indeed, compared to nocturnal wakefulness, sleep acutely lowers T cell counts in peripheral blood during the early night, with the efflux of these cells to lymphoid tissues possibly mediated by sleep-associated release of the mineralocorticoid aldosterone. We show here that blocking mineralocorticoid receptors by spironolactone (200mg, orally at 23:00 h and again at 4:00 h) in 11 healthy men enhances naïve T-helper cell counts in blood during early nocturnal sleep. Effects in the same direction on naïve cytotoxic T cells and central memory T-helper cells were less consistent. Spironolactone did not influence T cell subsets not migrating to lymph nodes (i.e., CD62L(-) effector memory and effector T cells), or expression of CD62L and CXCR4. The typical circadian decrease in T cell numbers in the morning hours was not affected by the blockade of mineralocorticoid receptors, in line with the view that this decrease is mainly due to activation of glucocorticoid receptors during the circadian morning rise in cortisol. We assume that sleep-associated activation of mineralocorticoid receptors at a time of low cortisol levels contributes to an enhanced redistribution of circulating naïve T-helper cells to lymph nodes, as a mechanism that eventually promotes immunological memory formation.
Assuntos
Receptores de Mineralocorticoides/efeitos dos fármacos , Sono/imunologia , Linfócitos T Auxiliares-Indutores/fisiologia , Adolescente , Adulto , Aldosterona/fisiologia , Pressão Sanguínea/fisiologia , Movimento Celular/efeitos dos fármacos , Método Duplo-Cego , Hormônios/sangue , Humanos , Hidrocortisona/sangue , Selectina L/metabolismo , Contagem de Linfócitos , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Polissonografia , Receptores CXCR4/metabolismo , Fases do Sono , Espironolactona/farmacologia , Adulto JovemRESUMO
Chronobiological problems are always present as aetiological or pathoplastic conditions almost in all psychiatric disorders and considered as the greatest contributors to the mood and sleep disorders associated problems. The present review summarise the recent advances in the chronobiology research from the point of the clinician with particular emphasis on the psychobiology and pharmacotherapy of the depression. Human behaviour builds up from different length of circadian, ultradian and seasonal rhytms, strictly controlled by a hierarchical organisation of sub-cellullar, cellular, neuro-humoral and neuro-immunological clock systems. These internal clock systems are orchestrated at molecular level by certain clock genes and on the other hand--at neuro-humoral level--by the effect of the sleep hormone, melatonine, produced by the neurons of the suprachiasmatic nucleus (SCN). Beside the biological factors, social interactions are also considered as important regulators of the biological clock systems. The pacemaker centers of the SCN receive efferents from the serotoninergic raphe nuclei in order to regulate stress responses and neuroimmunological functions. The direction and the level of the chronobiological desynchronisation could be totally divergent in the case of the different affective disorders. Different chronobiological interventions are required therefore in the case of the advanced and delayed sleep disorders. Sleeping disorders are considered as the most recognised signs of the chronobiological desynchronisation in depression, but these symptoms are only the tip of the iceberg, since other chronobiological symptoms could be present due to the hidden physiological abnormalities. The serum melatonine profile is considered to be characteristic to age, gender and certain neuropsychiatric disorders. The natural and synthetic agonist of the melatonine receptors could be used as chronobiotics. The recently marketed agomelatine with a highly selective receptor binding profile (MT1 and MT2 agonism and 5HT2C antagonism) targets the desynchronised circadian rhytm in affective disorders and it has mainly antidepressive effect. Among the non-pharmacological chronobiological interventions, the different forms of the sleep deprivation, light and social rhytm therapies could offer alternative treatment options for the clinician.
Assuntos
Relógios Biológicos , Cronoterapia , Ritmo Circadiano , Depressão/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Melatonina/sangue , Transtornos do Sono-Vigília/fisiopatologia , Acetamidas/farmacologia , Acetamidas/uso terapêutico , Afeto , Cronoterapia/métodos , Ritmo Circadiano/imunologia , Depressão/sangue , Depressão/etiologia , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/etiologia , Humanos , Hipnóticos e Sedativos/uso terapêutico , Melatonina/agonistas , Transtornos do Humor/fisiopatologia , Receptor MT1 de Melatonina/efeitos dos fármacos , Receptor MT2 de Melatonina/efeitos dos fármacos , Sono/imunologia , Privação do Sono , Transtornos do Sono-Vigília/sangue , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/terapia , Núcleo Supraquiasmático/fisiopatologiaRESUMO
An important component of psychoneuroimmunology research is to reveal the myriad ways that behaviors and health are inter-related, with a focus on the immunological mechanisms that underlie these interactions. Research in human psychoneuroimmunology has shown that immunoregulatory processes are an integral part of a complex network of adaptive responses. As such, this review provides a perspective from our laboratory over the last 20 years to define the inter-relationships between behavior and immunity; to identify the hypothalamic pituitary adrenal (HPA) and autonomic mechanisms that link the central nervous system and immune responses; to examine the clinical implications of immune alterations during depression or life stress on inflammatory and infectious disease risk; and to explore the reciprocal role of immune mediators on behavior in humans.
Assuntos
Psiconeuroimunologia/métodos , Psiconeuroimunologia/tendências , Estresse Psicológico/imunologia , Estresse Psicológico/fisiopatologia , Doenças Cardiovasculares/imunologia , Doença Crônica , Doenças Transmissíveis/imunologia , História do Século XX , História do Século XXI , Humanos , Psiconeuroimunologia/história , Sono/imunologiaRESUMO
Influenza virus infection up-regulates cytokines such as interleukin-1beta (IL-1beta) and activates the somatotropic axis and the hypothalamic-pituitary axis. Mice with deficits in growth hormone releasing hormone (GHRH) signaling (lit/lit mice) respond to influenza virus challenge with a progressive decrease in sleep and lower survival rates. Current experiments characterize plasma glucocorticoid responses and hypothalamic and lung mRNA expression of sleep-related genes in lit/lit mice and their heterozygous controls after influenza virus challenge. lit/lit mice had higher basal and post-infection plasma corticosterone levels compared to controls. In contrast, the heterozygous mice increased hypothalamic GHRH-receptor, CRH-type 2 receptor, IL-1beta, and tumor necrosis factor-alpha (TNF-alpha) mRNAs after virus treatment while the lit/lit mice failed to up-regulate these substances. In contrast, lung levels of IL-1beta and TNF-alpha mRNAs were greater in the lit/lit mice. These data are consistent with the hypothesis that the sleep response to influenza infection is mediated, in part, by an up-regulation of hypothalamic sleep-related transcripts and they also show that a primary deficit in GHRH signaling is associated with enhanced corticosterone secretion and attenuated hypothalamic cytokine response to infection.
Assuntos
Corticosterona/sangue , Citocinas/metabolismo , Hipotálamo/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Pulmão/imunologia , Infecções por Orthomyxoviridae/imunologia , Receptores de Neuropeptídeos/fisiologia , Receptores de Hormônios Reguladores de Hormônio Hipofisário/fisiologia , Análise de Variância , Animais , Ritmo Circadiano/imunologia , Corticosterona/imunologia , Citocinas/imunologia , Perfilação da Expressão Gênica , Hormônio Liberador de Hormônio do Crescimento/deficiência , Hipotálamo/metabolismo , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/sangue , Infecções por Orthomyxoviridae/complicações , Infecções por Orthomyxoviridae/virologia , RNA Mensageiro/análise , Sono/imunologia , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/fisiopatologia , Regulação para CimaRESUMO
INTRODUCTION: The idea of the healing effects of the sleep over the disease is quite extended. Besides, the sleep and the circadian rhythms cause deep changes on the immune function. Reciprocally, the sleep also suffers deep changes when the immune system is challenged during an external aggression. DEVELOPMENT: This review shows some of the data supporting both observations. From the relationships between the sleep and the immune system, it has been proposed that one function of sleep is just to support the immune defense. However, an important fraction of the relationships between sleep and immune function might be a response to the stress produced both during the sleep disorders and when the organism activates the immune defense. Moreover, the epidemiological evidence only shows negligible results when contrasting the amount of sleep and the life expectancy. CONCLUSION: It seems thus probable that the relationships between sleep and immune function are only a reflect of additional factors, such as stress, which cause deep changes in sleep and immunity.
Assuntos
Ritmo Circadiano/fisiologia , Sistema Imunitário/fisiologia , Sono/imunologia , Animais , Temperatura Corporal , Humanos , Expectativa de Vida , Psiconeuroimunologia , Estresse Psicológico/imunologiaAssuntos
Citocinas/fisiologia , Neurofisiologia/história , Psiconeuroimunologia/história , Sono/imunologia , Vigília/fisiologia , Animais , Citocinas/imunologia , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Neuroimunomodulação/imunologia , Neuroimunomodulação/fisiologiaRESUMO
Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder, characterized by repeated disruptions of breathing during sleep. The sleep fragmentation and accompanying hypoxemia lead to many negative consequences including cardiac arrhythmias, nocturnal hypertension, confusion, cognitive impairment, daytime sleepiness, as well as depressive symptoms. From the perspective of psychoneuroimmunology (PNI), OSA holds promise as a model for studying sleep and cytokines because of its many relevant characteristics, including neuroimmune interactions, mood changes, and behaviors that directly affect the course of the disorder. In this minireview we briefly summarize the existing literature on cytokines and sleep and then discuss work on cytokines and OSA. We believe that the study of OSA presents researchers with an excellent opportunity to tease apart the many complex and interwoven components of sleep that are relevant to PNI.