RESUMO
Circadian phase shifts in peripheral clocks induced by changes in feeding rhythm often result in insulin resistance. However, whether the hypothalamic control system for energy metabolism is involved in the feeding rhythm-related development of insulin resistance is unknown. Here, we show the physiological significance and mechanism of the involvement of the agouti-related protein (AgRP) in evening feeding-associated alterations in insulin sensitivity. Evening feeding during the active dark period increased hypothalamic AgRP expression and skeletal muscle insulin resistance in mice. Inhibiting AgRP expression by administering an antisense oligo or a glucocorticoid receptor antagonist mitigated these effects. AgRP-producing neuron-specific glucocorticoid receptor-knockout (AgRP-GR-KO) mice had normal skeletal muscle insulin sensitivity even under evening feeding schedules. Hepatic vagotomy enhanced AgRP expression in the hypothalamus even during ad-lib feeding in wild-type mice but not in AgRP-GR-KO mice. The findings of this study indicate that feeding in the late active period may affect hypothalamic AgRP expression via glucocorticoids and induce skeletal muscle insulin resistance.
Assuntos
Proteína Relacionada com Agouti/metabolismo , Metabolismo Energético , Comportamento Alimentar , Glucocorticoides/farmacologia , Hipotálamo/patologia , Resistência à Insulina , Músculo Esquelético/patologia , Proteína Relacionada com Agouti/genética , Animais , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Receptores de Glucocorticoides/metabolismoRESUMO
Orexin is known as an important neuropeptide in the regulation of energy metabolism. However, the role of orexin in exercise-induced leptin sensitivity in the hypothalamus has been unclear. In this study, we determined the effect of transient treadmill exercise on leptin sensitivity in the mediobasal hypothalamus (MBH) of mice and examined the role of orexin in post-exercise leptin sensitivity. Treadmill running for 45â¯min increased the orexin neuron activity in mice. Intraperitoneal injection of a submaximal dose of leptin after exercise stimulated the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in MBH of mice post-exercise compared with that in non-exercised mice, although intracerebroventricular (icv) injection of leptin did not enhance STAT3 phosphorylation, even after exercise. Icv injection of an orexin receptor antagonist, SB334867 reduced STAT3 phosphorylation, which was enhanced by icv injection of orexin but not by direct injection of orexin into MBH. Exercise increased the phosphorylation of extracellular signal-regulated kinases (ERKs) in the MBH of mice, while ERK phosphorylation was reduced by SB334867. Leptin injection after exercise increased the leptin level in MBH, whereas icv injection of SB334867 suppressed the increase in the leptin level in MBH of mice. These results indicate that the activation of orexin neurons by exercise may contribute to the enhancement of leptin sensitivity in MBH. This effect may be mediated by increased transportation of circulating leptin into MBH, with the involvement of ERK phosphorylation.
Assuntos
Hipotálamo/fisiologia , Leptina/farmacologia , Orexinas/metabolismo , Animais , Benzoxazóis/farmacologia , Teste de Esforço , Hipotálamo/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Naftiridinas/farmacologia , Neurônios/efeitos dos fármacos , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Orexinas/farmacologia , Fosforilação , Condicionamento Físico Animal , Receptores para Leptina/metabolismo , Fator de Transcrição STAT3/metabolismo , Ureia/análogos & derivados , Ureia/farmacologiaRESUMO
The fact that resting wakefulness does not satisfy the need for sleep suggests that sleep has a critical role for the brain, probably for its maintenance or repair. Neuronal oxidative stress, neuroinflammation, or energy insufficiency in the brain is now considered to be a trigger or cause for sleep induction. And the timing for sleep is controlled by circadian clock which also exists in the brain. Sleep is occurred in the brain, which is regulated by the brain itself. "Why do we sleep ?" Although everyone wants to know the answer for this issue, scientists should still question that "How do we sleep"?
Assuntos
Encéfalo/fisiologia , Sono/fisiologia , Relógios Circadianos , Ritmo Circadiano , Humanos , Fatores de Tempo , VigíliaRESUMO
Although several previous studies have suggested a relationship between sleep and the stress response, the mechanism underlying this relationship remains largely unknown. Here, we show that fibroblast growth factor 21 (FGF21), a lipid metabolism-related hormone, may play a role in this relationship. In this study, we examined differences in the stress response between FGF21 knockout (KO) mice and wild-type (WT) mice after social defeat stress (SDS). When the amount of non-rapid eye movement (NREM) sleep, rapid eye movement (REM) sleep and wakefulness were averaged over the dark period after SDS, only KO mice showed significant differences in NREM sleep and wakefulness. In the social interaction test, KO mice seemed to be more prone to social avoidance. Our real-time (RT) -PCR results revealed that the mRNA expression of the stress- and sleep-related gene gamma-aminobutyric acid A receptor subunit alpha 2 was significantly lower in WT mice than in KO mice. Moreover, KO mice showed lower plasma levels of ketone bodies, which also affect sleep/wake regulation, than WT mice. These results suggested that FGF21 might influence sleep/wake regulation by inducing production of an anti-stress agent and/or ketone bodies, which may result in resilience to social stress.
Assuntos
Sono , Vigília , Animais , Camundongos , Eletroencefalografia , Corpos Cetônicos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sono/fisiologia , Vigília/fisiologia , Estresse FisiológicoRESUMO
AIMS: This study aimed to evaluate the involvement of the orexin system in predictable chronic mild stress (PCMS) and the effects of suvorexant, a dual orexin receptor antagonist, on nociceptive behavior in PCMS. MATERIALS AND METHODS: Male C57BL/6 J mice were separated into various PCMS groups: a control group with sawdust on the floor of the rearing cage (C), a group with mesh wire on the floor (M), and a group with water just below the mesh wire (W). Activation of lateral hypothalamic orexin neurons was assessed using immunofluorescence. In another experiment, half of the mice in each group were administered an intraperitoneal injection of suvorexant (10 mg/kg), and the remaining mice were injected with the same amount of vehicle (normal saline). Thermal hyperalgesia was examined using tail immersion and hot plate tests, while mechanical hyperalgesia was investigated using the tail pinch test after 21 days of PCMS. KEY FINDINGS: Animals subjected to PCMS showed an increased percentage of activated orexin neurons in the lateral hypothalamic region after 21 days. Mice raised in the PCMS environment showed increased pain sensitivity in several pain tests; however, the symptoms were significantly reduced by suvorexant administration. SIGNIFICANCE: The findings revealed that PCMS activates hypothalamic orexin neuronal activity, and the use of suvorexant can help attenuate PCMS-induced thermal and mechanical hyperalgesia.
Assuntos
Hiperalgesia , Antagonistas dos Receptores de Orexina , Animais , Azepinas , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina , Orexinas/farmacologia , Dor , Preparações Farmacêuticas , TriazóisRESUMO
Mast cells (MCs) exist intracranially and have been reported to affect higher brain functions in rodents. However, the role of MCs in the regulation of emotionality and social behavior is unclear. In the present study, using male mice, we examined the relationship between MCs and social behavior and investigated the underlying mechanisms. Wild-type male mice intraventricularly injected with a degranulator of MCs exhibited a marked increase in a three-chamber sociability test. In addition, removal of MCs in Mast cell-specific Toxin Receptor-mediated Conditional cell Knock out (Mas-TRECK) male mice showed reduced social preference levels in a three-chamber sociability test without other behavioral changes, such as anxiety-like and depression-like behavior. Mas-TRECK male mice also had reduced serotonin content and serotonin receptor expression and increased oxytocin receptor expression in the brain. These results suggested that MCs may contribute to the regulation of social behavior in male mice. This effect may be partially mediated by serotonin derived from MCs in the brain.
Assuntos
Comportamento Animal/fisiologia , Encéfalo , Mastócitos/fisiologia , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Comportamento Social , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Masculino , Mastócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , p-Metoxi-N-metilfenetilamina/farmacologiaRESUMO
Even though it has been well documented that stress can lead to the development of sleep disorders and the intensification of pain, their relationships have not been fully understood. The present study was aimed at investigating the effects of predictable chronic mild stress (PCMS) on sleep-wake states and pain threshold, using the PCMS rearing conditions of mesh wire (MW) and water (W) for 21 days. Exposure to PCMS decreased the amount of non-rapid eye movement (NREM) sleep during the dark phase. Moreover, the chronicity of PCMS decreased slow-wave activity (SWA) during NREM sleep in the MW and W groups in both the light and dark phases. Mechanical and aversively hot thermal hyperalgesia were more intensified in the PCMS groups than the control. Higher plasma corticosterone levels were seen in mice subjected to PCMS, whereas TNF-α expression was found higher in the hypothalamus in the W and the trigeminal ganglion in the MW group. The W group had higher expression levels of IL-6 in the thalamus as well. The PCMS paradigm decreased SWA and may have intensified mechanical and thermal hyperalgesia. The current study also suggests that rearing under PCMS may cause impaired sleep quality and heightened pain sensation to painful mechanical and aversively hot thermal stimuli.
Assuntos
Dor Facial/fisiopatologia , Locomoção/fisiologia , Transtornos do Sono-Vigília/fisiopatologia , Animais , Corticosterona/sangue , Eletroencefalografia , Dor Facial/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dor/sangue , Dor/fisiopatologia , Limiar da Dor , Reação em Cadeia da Polimerase em Tempo Real , Privação do Sono/sangue , Privação do Sono/fisiopatologia , Transtornos do Sono-Vigília/sangue , Sono REM/fisiologia , Vigília/fisiologiaRESUMO
Peroxisome proliferator-activated receptor alpha (PPARα) is a transcription factor that belongs to the nuclear receptor family and plays an important role in regulating gene expression associated with lipid metabolism. PPARα promotes hepatic fatty acid oxidation and ketogenesis in response to fasting. Because energy metabolism is known to affect sleep regulation, manipulations that change PPARα are likely to affect sleep and other physiological phenotypes. In this study, we examined the role of PPARα in sleep/wake regulation using PPARα knockout (KO) mice. Sleep, body temperature (BT), locomotor activity, arterial pressure (AP) and heart rate (HR) were recorded in KO mice and wild-type (WT) controls under ad libitum-fed conditions and 24-hour food deprivation (FD). KO and WT mice were identical in basal sleep amount, BT, mean AP and HR, although KO mice showed enhanced sleepiness (enhanced EEG slow-wave activity). In response to FD, KO mice showed a large drop in wakefulness and locomotor activity at the end of the dark phase, whereas WT mice did not. Similarly, AP and HR, which were suppressed by FD, decreased more in KO than in WT mice. Compared to WT mice, KO mice showed a reduced concentration of plasma ketone bodies and decreased mRNA expression of the ketogenic enzyme gene Hmgcs2 in the liver and brain under FD conditions. These results suggest that PPARα and/or lipid metabolism is involved in the maintenance of wakefulness and locomotor activity during fasting in mice.
Assuntos
Jejum/fisiologia , PPAR alfa/deficiência , Sono/fisiologia , Animais , Glicemia/metabolismo , Ácidos Graxos não Esterificados/sangue , Coração/fisiopatologia , Corpos Cetônicos/sangue , Masculino , Camundongos , Camundongos Knockout , PPAR alfa/genética , Fotoperíodo , Triglicerídeos/sangue , Vigília/fisiologiaRESUMO
Caloric restriction (CR) is an effective method for prevention of age-associated diseases as well as overweight and obesity; however, there is controversy regarding the effects of dieting regimens on behavior. In this study, we investigated two different dieting regimens: repeated fasting and refeeding (RFR) and daily feeding of half the amount of food consumed by RFR mice (CR). CR and RFR mice had an approximate 20% reduction in food intake compared with control mice. Open field, light-dark transition, elevated plus maze, and forced swimming tests indicated that CR, but not RFR, reduced anxiety- and depressive-like behaviors, with a reduction peak on day 8. Using a mouse whole genome microarray, we analyzed gene expression in the prefrontal cortex, amygdala, and hypothalamus. In addition to the CR-responsive genes commonly modified by RFR and CR, each regimen differentially changed the expression of distinct genes in each region. The most profound change was observed in the amygdalas of CR mice: 884 genes were specifically upregulated. Ingenuity pathway analysis revealed that these 884 genes significantly modified nine canonical pathways in the amygdala. alpha-Adrenergic and dopamine receptor signalings were the two top-scoring pathways. Quantitative RT-PCR confirmed the upregulation of six genes in these pathways. Western blotting confirmed that CR specifically increased dopamine- and cAMP-regulated phosphoprotein (Darpp-32), a key regulator of dopamine receptor signaling, in the amygdala. Our results suggest that CR may change behavior through altered gene expression.
Assuntos
Comportamento Animal/fisiologia , Restrição Calórica , Perfilação da Expressão Gênica , Transdução de Sinais/fisiologia , Tonsila do Cerebelo/metabolismo , Animais , Western Blotting , Peso Corporal , Fosfoproteína 32 Regulada por cAMP e Dopamina/genética , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Ingestão de Alimentos , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , NataçãoRESUMO
STUDY OBJECTIVES: The goal of this study was to clarify whether ginseng fermented by lactic acid bacteria (fermented ginseng, FG), can improve the first-night effect (FNE) in humans. DESIGN: Behavioral tests and quantification of mRNA expression related to GABAergic neurotransmission in brain (glutamic acid decarboxylase 1, gamma-aminobutyrate aminotransferase [Abat], gamma-aminobutyric acid transporter 1 [GAT1], gamma-aminobutyric acid transporter 4, gamma-aminobutyric acid A receptor subunit alpha 1 and gamma-aminobutyric acid A receptor subunit alpha 2) were carried out in FG-treated mice. We also performed double-blind sleep recordings of human subjects given FG or placebo. SETTING: A university-based sleep laboratory. PATIENTS OR PARTICIPANTS: Sixteen healthy male volunteers (aged 20.69 +/- 0.44 years) were observed in the human study. INTERVENTIONS: At the end of administration, 2 consecutive all-night polysomnography recordings were performed. Subjects also completed psychological questionnaires, and urine and saliva samples were taken to analyze stress-sensitive markers. MEASUREMENTS AND RESULTS: The light-dark transition test demonstrated that FG had some anxiolytic effect in mice, but other anxiety measures were unaffected. The hippocampal mRNA expression showed a decrease of Abat and GAT1 suggesting an increase of GABA. Other regions (amygdala and cerebellum) showed no differences. Furthermore, there was some evidence (using simple pairwise comparisons but not supported in the full ANOVA model) that administration of FG tended to diminish decreases in total sleep time and sleep efficiency (seen as first night effects in the placebo group) without affecting sleep architecture. CONCLUSIONS: Our results suggest the administration of FG could improve the FNE in humans. The improvement may be related to an anxiolytic effect of FG which acts via GABAergic modification.
Assuntos
Ansiedade/tratamento farmacológico , Nível de Alerta/efeitos dos fármacos , Fermentação , Ginsenosídeos/uso terapêutico , Panax , Fitoterapia , Extratos Vegetais/uso terapêutico , Polissonografia/psicologia , Animais , Encéfalo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Medo/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Lactobacillus , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inventário de Personalidade , Pré-Medicação , RNA Mensageiro/genética , Tempo de Reação/efeitos dos fármacos , Adulto Jovem , Ácido gama-Aminobutírico/genética , Ácido gama-Aminobutírico/metabolismoRESUMO
Idiopathic restless legs syndrome (RLS) has a genetic basis wherein BTBD9 is associated with a higher risk of RLS. Hemodialysis patients also exhibit higher rates of RLS compared with the healthy population. However, little is known about the relationship of BTBD9 and end-stage renal disease to RLS pathophysiology. Here we evaluated sleep and leg muscle activity of Btbd9 mutant (MT) mice after administration of serum from patients with either idiopathic or RLS due to end-stage renal disease (renal RLS) and investigated the efficacy of treatment with the dopamine agonist rotigotine. At baseline, the amount of rapid eye movement (REM) sleep was decreased and leg muscle activity during non-REM (NREM) sleep was increased in MT mice compared to wild-type (WT) mice. Wake-promoting effects of rotigotine were attenuated by injection of serum from RLS patients in both WT and MT mice. Leg muscle activity during NREM sleep was increased only in MT mice injected with serum from RLS patients of ideiopatic and renal RLS. Subsequent treatment with rotigotine ameliorated this altered leg muscle activity. Together these results support previous reports showing a relationship between the Btbd9/dopamine system and RLS, and elucidate in part the pathophysiology of RLS.
Assuntos
Músculos/fisiologia , Fenômenos Fisiológicos Musculoesqueléticos , Proteínas do Tecido Nervoso/fisiologia , Síndrome das Pernas Inquietas/sangue , Soro/química , Sono REM/fisiologia , Tetra-Hidronaftalenos/farmacologia , Tiofenos/farmacologia , Animais , Estudos de Casos e Controles , Modelos Animais de Doenças , Agonistas de Dopamina/farmacologia , Humanos , Falência Renal Crônica/terapia , Masculino , Camundongos , Camundongos Knockout , Músculos/efeitos dos fármacos , Diálise Renal/efeitos adversos , Síndrome das Pernas Inquietas/etiologia , Síndrome das Pernas Inquietas/patologia , Sono REM/efeitos dos fármacosRESUMO
We aimed to identify the neurotransmitters and brain regions involved in exercise efficiency in mice during continuous complicated exercises. Male C57BL/6J mice practiced treadmill running with intermittent obstacles on a treadmill for 8 days. Oxygen uptake (VO2) during treadmill running was measured as exercise efficiency. After obstacle exercise training, the VO2 measured during treadmill running with obstacles decreased significantly. Obstacle exercise-induced c-Fos expressions and dopamine turnover (DOPAC/dopamine) in the septum after obstacle exercise training were significantly higher than that before training. The dopamine turnover was correlated with exercise efficiency on the 3rd day after exercise training. Furthermore, the training effect on exercise efficiency was significantly decreased by injection of dopamine receptor antagonists into the septum and was associated with decreased c-Fos expressions in the septum and hippocampus of the mice. These results suggest that dopaminergic function in the septum is involved in exercise efficiency during continuous complicated exercises.
Assuntos
Dopamina/farmacologia , Consumo de Oxigênio/fisiologia , Condicionamento Físico Animal/fisiologia , Septo do Cérebro/efeitos dos fármacos , Animais , Benzazepinas/farmacologia , Biomarcadores , Antagonistas de Dopamina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Genes fos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Dopamina D1/antagonistas & inibidores , Corrida , Serotonina/metabolismo , Sulpirida/farmacologiaRESUMO
AIMS: Psychosocial stress is a form of mental stress associated with human relationships that underlies the pathogenesis of mental disorders such as depression. Previous studies have suggested that intake of energy-dense foods, also known as "palatable foods," can relieve psychosocial stress. However, it remains unclear whether the volume of palatable food affects abnormal behavior induced by psychosocial stress. In the present study, we aimed to determine whether levels of high-fat food intake significantly influence psychosocial stress using the social-defeat stress (SDS) paradigm. MAIN METHODS: Mice subjected to SDS ate either a high-fat or normal chow diet for 10â¯days. Behavioral tests were conducted following the completion of the SDS paradigm. The hypothalamus, liver, and blood were examined post-mortem. KEY FINDINGS: Mice with sufficient intake of high-fat chow immediately following exposure to SDS did not exhibit social avoidance behavior, suggesting that a high-fat diet may improve social behavior. However, inadequate intake of high-fat food, which did not alter cholesterol metabolism or hypothalamic-pituitary-adrenal axis activity, was not associated with such benefits, instead increased anxiety-like behavior. SIGNIFICANCE: The results of the present study demonstrate that eating a high-fat diet may attenuate stress, but that this benefit disappears with insufficient intake of high-fat foods. The benefits of a high-fat diet under SDS may be related to cholesterol metabolism in the liver.
Assuntos
Aprendizagem da Esquiva , Dieta Hiperlipídica , Comportamento Social , Estresse Psicológico/psicologia , Animais , Encéfalo/metabolismo , Colesterol/sangue , Corticosterona/sangue , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , Estresse Psicológico/dietoterapiaRESUMO
Peroxisome proliferator-activated receptor alpha (PPARα) is a member of the nuclear receptor superfamily and regulates fatty acid oxidation. Although PPARα is expressed not only in the peripheral tissues but also in the brain, its role in higher brain function is unclear. In this study, we investigated the role of PPARα in the control of behavior, including memory/learning and mood change, using PPARα knockout (KO) mice. A significant difference between wild-type (WT) and KO mice was seen in the passive avoidance test, demonstrating that KO mice showed enhanced fear leaning. In the amygdala of KO mice, the levels of dopamine and its metabolites were increased, and the mRNA expression of dopamine degrading enzyme was decreased. When dopamine D1 receptor antagonist was administered, the enhanced fear learning observed in KO mice was attenuated. These results suggest that PPARα is involved in the regulation of emotional memory via the dopamine pathway in the amygdala.
Assuntos
Medo/fisiologia , Aprendizagem/fisiologia , PPAR alfa/deficiência , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/metabolismo , Benzazepinas/farmacologia , Depressão/metabolismo , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Medo/psicologia , Masculino , Camundongos da Linhagem 129 , Camundongos Knockout , PPAR alfa/genética , RNA Mensageiro/metabolismo , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismoRESUMO
Arterial pressure (AP), heart rate (HR), and cardiovascular diseases, including ischemic heart attack and cerebrovascular accident, show diurnal variation. Evidence that circadian-related genes contribute to cardiovascular control has been accumulated. In this study, we measured the AP and HR of Clock mutant mice on the Jcl/ICR background to determine the role of the Clock gene in cardiovascular function. Mice with mutated Clock genes had a dampened diurnal rhythm of AP and HR, compared with wild-type control mice, and this difference disappeared after adrenalectomy. The diurnal acrophase in both mean arterial pressure and HR was delayed significantly in Clock mutant mice, compared with wild-type mice, and this difference remained after adrenalectomy. Clock mutant mice had a lower concentration of plasma aldosterone, compared with wild-type mice. Our data suggest that the adrenal gland is involved in the diurnal amplitude, but not the acrophase, of AP and HR, and that the function of the Clock gene may be related to the nondipping type of AP elevation.
Assuntos
Adrenalectomia/métodos , Pressão Sanguínea/fisiologia , Ritmo Circadiano/fisiologia , Frequência Cardíaca/fisiologia , Transativadores/fisiologia , Animais , Proteínas CLOCK , Feminino , Genótipo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Mutantes , Mutação , Transativadores/genéticaRESUMO
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor family. PPARs play a critical role in lipid and glucose metabolism. We examined whether chronic treatment with bezafibrate, a PPAR agonist, would alter sleep and body temperature (BT). Mice fed with a control diet were monitored for BT, electroencephalogram (EEG), and electromyogram for 48 h under light-dark conditions. After obtaining the baseline recording, the mice were provided with bezafibrate-supplemented food for 2 wk, after which the same recordings were performed. Two-week feeding of bezafibrate decreased BT, especially during the latter half of the dark period. BT rhythm and sleep/wake rhythm were phase advanced about 2-3 h by bezafibrate treatment. Bezafibrate treatment also increased the EEG delta-power in nonrapid eye movement sleep compared with the control diet attenuating its daily amplitude. Furthermore, bezafibrate-treated mice showed no rebound of EEG delta-power in nonrapid eye movement sleep after 6 h sleep deprivation, whereas values in control mice largely increased relative to baseline. DNA microarray, and real-time RT-PCR analysis showed that bezafibrate treatment increased levels of Neuropeptide Y mRNA in the hypothalamus at both Zeitgeber time (ZT) 10 and ZT22, and decreased proopiomelanocortin-alpha mRNA in the hypothalamus at ZT10. These findings demonstrate that PPARs participate in the control of both BT and sleep regulation, which accompanied changes in gene expression in the hypothalamus. Activation of PPARs may enhance deep sleep and improve resistance to sleep loss.
Assuntos
Bezafibrato/farmacologia , Temperatura Corporal/efeitos dos fármacos , Ritmo Delta/efeitos dos fármacos , Hipolipemiantes/farmacologia , Fases do Sono/efeitos dos fármacos , Animais , Regulação da Temperatura Corporal/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiologia , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neuropeptídeo Y/genética , Neuropeptídeo Y/farmacologia , Análise de Sequência com Séries de Oligonucleotídeos , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Pró-Opiomelanocortina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vigília/efeitos dos fármacosRESUMO
Music is known to be able to elicit emotional changes, including anxiolytic effects. The gonadal steroid hormones estradiol and progesterone have also been reported to play important roles in the modulation of anxiety. In the present study, we examined whether the effect of music on anxiety is related to ovarian steroid in female mice. Behavioral paradigms measuring anxiety were tested in gonadally intact (SHAM) and ovariectomized (OVX) female mice chronically treated with either placebo (OVX/Placebo), 17beta-estradiol (OVX/E), or progesterone (OVX/P). In the elevated plus maze, light-dark transition, and marble burying tests, SHAM and OVX/P mice exposed to music showed less anxiety than those exposed to white noise or silence while OVX/placebo mice did not show these effects at all. OVX/E mice showed the anxiolytic effect of music only in the marble burying test. Furthermore, pretreatment with progesterone's metabolite inhibitor completely prevented the anxiolytic effect of music in behavioral tests, while pretreatment with a progesterone receptor blocker did not prevent the anxiolytic effect of music. These results suggest that exposure to music reduces anxiety levels, and ovarian steroids, mainly progesterone, may be involved in the anxiolytic effect of music observed in female mice.
Assuntos
Ansiedade/psicologia , Estradiol/fisiologia , Atividade Motora/fisiologia , Música/psicologia , Progesterona/fisiologia , Estimulação Acústica/métodos , Análise de Variância , Animais , Ansiedade/sangue , Ansiedade/terapia , Estradiol/sangue , Comportamento Exploratório/fisiologia , Feminino , Masculino , Camundongos , Musicoterapia , Progesterona/sangue , Distribuição Aleatória , Fatores Sexuais , Estatísticas não ParamétricasRESUMO
Recent report (Maret, S., Franken, P., Dauvilliers, Y., Ghyselinck, N.B., Chambon, P., Tafti, M., 2005. Retinoic acid signaling affects cortical synchrony during sleep. Science 310, 111-113.) has suggested that vitamin A (retinol and its derivatives) is genetically involved in the electroencephalogram (EEG) delta oscillation during sleep. However, this finding has not yet been confirmed by other studies. In this study, we attempted to record the sleep EEG and behavior, and to quantify striatal monoamines in mice fed a vitamin A-deficient (VAD) diet for 4 weeks, in order to clarify the linkage between the delta oscillation and vitamin A. VAD mice demonstrated a significant decrease in the delta power of the EEG. However, 6-h sleep deprivation caused the recovery of the delta power in VAD mice to a level similar to that of the control. VAD also caused the decrease of spontaneous activity throughout 24-h period. Furthermore, dihydroxyphenylacetic acid, a metabolite of dopamine, was decreased significantly in the striatal tissue of VAD mice. Our present results suggest that the deficiency of vitamin A causes the attenuation of delta power in NREM sleep and spontaneous activity. These attenuations may be related to the alteration of striatal dopaminergic function.
Assuntos
Ritmo Delta , Sono/fisiologia , Deficiência de Vitamina A/fisiopatologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Análise de Variância , Animais , Comportamento Animal , Peso Corporal/fisiologia , Corpo Estriado/metabolismo , Dopamina/metabolismo , Comportamento Exploratório/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/fisiologia , Serotonina/metabolismo , Privação do Sono/fisiopatologia , Análise Espectral , Vitamina A/sangue , Deficiência de Vitamina A/sangue , Deficiência de Vitamina A/patologiaRESUMO
We have developed a chronic mild stress (MS) mouse model by simply rearing mice on a wire net for 3 weeks and investigated the effects of MS on glucose homeostasis and sleep. MS mice showed impaired glucose tolerance and disturbed sleep. One-week treatment with a histamine H1 receptor antagonist (H1RA) ameliorated the glucose intolerance and improved sleep quality in MS mice. MS mice showed an increased number of mast cells in both adipose tissue and the brain. Inhibition of mast cell function ameliorated the impairment in both glucose tolerance and sleep. Together, these findings indicate that mast cells may represent an important pathophysiological mediator in sleep and energy homeostasis.
Assuntos
Intolerância à Glucose/metabolismo , Glucose/metabolismo , Mastócitos/metabolismo , Transtornos do Sono-Vigília/metabolismo , Estresse Psicológico/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Doença Crônica , Modelos Animais de Doenças , Intolerância à Glucose/tratamento farmacológico , Intolerância à Glucose/patologia , Teste de Tolerância a Glucose , Antagonistas dos Receptores Histamínicos H1/farmacologia , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/patologia , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Distribuição Aleatória , Transtornos do Sono-Vigília/tratamento farmacológico , Transtornos do Sono-Vigília/patologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/patologiaRESUMO
Music has been suggested to have a beneficial effect on various types of performance in humans. However, the physiological and molecular mechanism of this effect remains unclear. We examined the effect of music exposure during the perinatal period on learning behavior in adult mice, and measured the levels of brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), which play critical roles in synaptic plasticity. In addition, we measured the levels of 3-phosphoinositide-dependent protein kinase-1 (PDK1) and mitogen-activated protein kinase (MAPK), downstream targets of two main pathways in BDNF/TrkB signaling. Music-exposed mice completed a maze learning task with fewer errors than the white noise-exposed mice and had lower levels of BDNF and higher levels of TrkB and PDK1 in the cortex. MAPK levels were unchanged. Furthermore, TrkB and PDK1 protein levels in the cortex showed a significant negative correlation with the number of errors on the maze. These results suggest that perinatal exposure of mice to music has an influence on BDNF/TrkB signaling and its intracellular signaling pathway targets, including PDK1, and thus may induce improved learning and memory functions.