RESUMEN
Early-life obesity predisposes to obesity in adulthood, a condition with broad medical implications including sleep disorders, which can exacerbate metabolic disturbances and disrupt cognitive and affective behaviors. In this study, we examined the long-term impact of transient peripubertal diet-induced obesity (ppDIO, induced between 4 and 10 weeks of age) on sleep-wake behavior in male mice. EEG and EMG recordings revealed that ppDIO increases sleep during the active phase but reduces resting-phase sleep quality. This impaired sleep phenotype persisted for up to 1 year, although animals were returned to a non-obesiogenic diet from postnatal week 11 onwards. To better understand the mechanisms responsible for the ppDIO-induced alterations in sleep, we focused on the lateral hypothalamus (LH). Mice exposed to ppDIO did not show altered mRNA expression levels of orexin and melanin-concentrating hormone, two peptides that are important for sleep-wake behavior and food intake. Conversely, the LH of ppDIO-exposed mice had reduced contents of serotonin (5-hydroxytryptamine, 5-HT), a neurotransmitter involved in both sleep-wake and satiety regulation. Interestingly, an acute peripheral injection of the satiety-signaling peptide YY 3-36 increased 5-HT turnover in the LH and ameliorated the ppDIO-induced sleep disturbances, suggesting the therapeutic potential of this peptide. These findings provide new insights into how sleep-wake behavior is programmed during early life and how peripheral and central signals are integrated to coordinate sleep.SIGNIFICANCE STATEMENT Adult physiology and behavior are strongly influenced by dynamic reorganization of the brain during puberty. The present work shows that obesity during puberty leads to persistently dysregulated patterns of sleep and wakefulness by blunting serotonergic signaling in the lateral hypothalamus. It also shows that pharmacological mimicry of satiety with peptide YY3-36 can reverse this neurochemical imbalance and acutely restore sleep composition. These findings add insight into how innate behaviors such as feeding and sleep are integrated and suggest a novel mechanism through which diet-induced obesity during puberty imposes its long-lasting effects on sleep-wake behavior.
Asunto(s)
Área Hipotalámica Lateral/metabolismo , Obesidad/complicaciones , Serotonina/metabolismo , Trastornos del Sueño-Vigilia/etiología , Animales , Homeostasis/fisiología , Área Hipotalámica Lateral/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Fragmentos de Péptidos/farmacología , Péptido YY/farmacología , Trastornos del Sueño-Vigilia/metabolismoRESUMEN
Meis homeobox 1 (Meis1) is a transcription factor functioning in the development of the nervous system and the cardiovascular system. Both common and rare variants within the gene have been associated with restless legs syndrome (RLS), while its association with symptoms of insomnia has also been discovered recently. RLS is associated with sleep disturbances, and while Meis1 haploinsufficiency is one of the most promising strategies for an RLS animal model, sleep phenotyping of Meis1 knockout mice has never been conducted. We report a detailed sleep analysis of heterozygous Meis1 knockout mice and challenge it with pramipexole, a dopamine agonist used in the treatment of RLS. At baseline, the Meis1-haploinsufficient mice had a trend towards lower delta power in the electroencephalogram (EEG) during sleep compared to the wild-type littermates, possibly indicating reduced sleep quality, but not sleep fragmentation. Pramipexole had a sleep disrupting effect in both genotype groups. In addition, it exerted differential effects on the EEG power spectra of the two mouse lines, remarkably elevating the theta power of the mutant mice during recovery more than that of the wild-types. In conclusion, Meis1 haploinsufficiency seems to have only a modest effect on sleep, but the gene may interact with the sleep-disrupting effect of dopamine agonists.
Asunto(s)
Agonistas de Dopamina/toxicidad , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide/genética , Pramipexol/toxicidad , Síndrome de las Piernas Inquietas/inducido químicamente , Síndrome de las Piernas Inquietas/genética , Sueño/fisiología , Animales , Haploinsuficiencia/efectos de los fármacos , Haploinsuficiencia/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Síndrome de las Piernas Inquietas/fisiopatología , Sueño/efectos de los fármacosRESUMEN
FK506-binding protein 51 (FKBP51) is a co-chaperone of the glucocorticoid receptor, functionally linked to its activity via an ultra-short negative feedback loop. Thus, FKBP51 plays an important regulatory role in the hypothalamic-pituitary-adrenocortical (HPA) axis necessary for stress adaptation and recovery. Previous investigations illustrated that HPA functionality is influenced by polymorphisms in the gene encoding FKBP51, which are associated with both increased protein levels and depressive episodes. Because FKBP51 is a key molecule in stress responses, we hypothesized that its deletion impacts sleep. To study FKBP51-involved changes in sleep, polysomnograms of FKBP51 knockout (KO) mice and wild-type (WT) littermates were compared at baseline and in the recovery phase after 6-h sleep deprivation (SD) and 1-h restraint stress (RS). Using another set of animals, the 24-h profiles of hippocampal free corticosterone levels were also determined. The most dominant effect of FKBP51 deletion appeared as increased nocturnal wake, where the bout length was significantly extended while non-rapid eye movement sleep (NREMS) and rapid eye movement sleep were rather suppressed. After both SD and RS, FKBP51KO mice exhibited less recovery or rebound sleep than WTs, although slow-wave activity during NREMS was higher in KOs, particularly after SD. Sleep compositions of KOs were nearly opposite to sleep profiles observed in human depression. This might result from lower levels of free corticosterone in FKBP51KO mice, confirming reduced HPA reactivity. The results indicate that an FKBP51 deletion yields a pro-resilience sleep phenotype. FKBP51 could therefore be a therapeutic target for stress-induced mood and sleep disorders.
Asunto(s)
Privación de Sueño/metabolismo , Privación de Sueño/fisiopatología , Sueño , Proteínas de Unión a Tacrolimus/metabolismo , Animales , Corticosterona/sangre , Trastorno Depresivo/metabolismo , Humanos , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Ratones , Ratones Noqueados , Sistema Hipófiso-Suprarrenal/metabolismo , Polimorfismo Genético , Polisomnografía , Privación de Sueño/sangre , Trastornos del Sueño-Vigilia/metabolismo , Trastornos del Sueño-Vigilia/fisiopatología , Sueño REM , Proteínas de Unión a Tacrolimus/deficiencia , Proteínas de Unión a Tacrolimus/genéticaRESUMEN
Adverse events in early life can modulate the response to additional stressors later in life and increase the risk of developing psychiatric disorders. The underlying molecular mechanisms responsible for these effects remain unclear. Here, we uncover that early life adversity (ELA) in mice leads to social subordination. Using single-cell RNA sequencing (scRNA-seq), we identified cell type-specific changes in the transcriptional state of glutamatergic and GABAergic neurons in the ventral hippocampus of ELA mice after exposure to acute social stress in adulthood. These findings were reflected by an alteration in excitatory and inhibitory synaptic transmission induced by ELA in response to acute social stress. Finally, enhancing the inhibitory network function through transient diazepam treatment during an early developmental sensitive period reversed the ELA-induced social subordination. Collectively, this study significantly advances our understanding of the molecular, physiological, and behavioral alterations induced by ELA, uncovering a previously unknown cell type-specific vulnerability to ELA.
Asunto(s)
Experiencias Adversas de la Infancia , Trastornos Mentales , Humanos , Ratones , Animales , Transcriptoma , Estrés Psicológico/genética , Estrés Psicológico/psicología , HipocampoRESUMEN
A single sub-anesthetic dose of ketamine produces a rapid and sustained antidepressant response, yet the molecular mechanisms responsible for this remain unclear. Here, we identified cell-type-specific transcriptional signatures associated with a sustained ketamine response in mice. Most interestingly, we identified the Kcnq2 gene as an important downstream regulator of ketamine action in glutamatergic neurons of the ventral hippocampus. We validated these findings through a series of complementary molecular, electrophysiological, cellular, pharmacological, behavioral, and functional experiments. We demonstrated that adjunctive treatment with retigabine, a KCNQ activator, augments ketamine's antidepressant-like effects in mice. Intriguingly, these effects are ketamine specific, as they do not modulate a response to classical antidepressants, such as escitalopram. These findings significantly advance our understanding of the mechanisms underlying the sustained antidepressant effects of ketamine, with important clinical implications.
Asunto(s)
Ketamina , Animales , Antidepresivos/farmacología , Hipocampo , Canal de Potasio KCNQ2/genética , Ketamina/farmacología , Ketamina/uso terapéutico , Ratones , Proteínas del Tejido Nervioso , NeuronasRESUMEN
In response to infectious stimuli, enhanced non-rapid eye movement sleep (NREMS) occurs, which is driven by pro-inflammatory cytokines. Those cytokines further elicit the release of corticotropin-releasing hormone (CRH), resulting in the activation of the hypothalamic-pituitary-adrenocortical axis. Signals of CRH are mediated by two receptor types, namely CRH-R1 and -R2. The role of CRH-R1 in wake-promoting effects of CRH has been rather clarified, whereas the involvement of CRH-R2 in sleep-wake regulation is poorly understood. To investigate whether CRH-R2 interferes with sleep responses to immune challenge, this study examined effects of bacterial lipopolysaccharide (LPS) on sleep in CRH-R2 deficient (KO) mice. CRH-R2 KO mice and control littermates (CL) were implanted with electrodes for recording electroencephalogram (EEG) and electromyogram. After recovery, LPS was applied by intraperitoneal injection at doses of 0.1, 1.0, or 10 µg at dark onset. In response to LPS injection NREMS of both genotypes was enhanced in a dose-dependent manner. However, CRH-R2 KO mice showed a larger increase, in particular after 10 µg of LPS compared to CL mice. During postinjection, reduced delta power for NREMS was detected in both genotypes after each dose, but the highest dose evoked a marked elevation of EEG activity in a limited frequency band (4 Hz). However, the EEG power of lower frequencies (1-2 Hz) increased more in CRH-R2 KO than in CL mice. The results indicated that CRH-R2 KO mice show greater NREMS responses to LPS, providing evidence that CRH-R2 participates in sleep-wake regulation via an interaction with the activated immune system.
Asunto(s)
Lipopolisacáridos/farmacología , Receptores de Hormona Liberadora de Corticotropina/deficiencia , Receptores de Hormona Liberadora de Corticotropina/genética , Sueño/genética , Sueño/fisiología , Animales , Corticosterona/sangre , Ritmo Delta/efectos de los fármacos , Electroencefalografía , Electromiografía , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Polisomnografía , Sueño/efectos de los fármacos , Fases del Sueño/efectos de los fármacos , Fases del Sueño/genética , Sueño REM/efectos de los fármacos , Sueño REM/genéticaRESUMEN
STUDY OBJECTIVES: Corticotropin-releasing hormone (CRH) is the major activator of the hypothalamic-pituitary-adrenocortical (HPA) system and orchestrates the neuroendocrine, autonomous as well as behavioral responses to stress. Many studies suggest an influence of CRH on sleep-wake regulation even in the absence of stressors. However, none of these studies yet clearly distinguished between central and peripheral effects of CRH. Therefore, we investigated in CNS-specific CRH receptor type 1 deficient mice whether centrally administered CRH could induce its sleep-wake modulatory effects without peripheral induction of HPA activity. DESIGN: Male mice (C57BL/6J, CNS-specific CRH-R1 knockout [CKO] mice and their control littermates [CL]) were intracerebroventricularily (i.c.v.) injected with vehicle or 3 different doses of CRH shortly before the beginning of the light period. Electroencephalogram (EEG) and electromyogram (EMG) were monitored to compare the effects of CRH on vigilance states with or without presence of central CRH-R1. To quantify HPA-axis reactivity to CRH injections in CKO and CL animals, blood samples were analyzed to determine plasma corticosterone concentrations. RESULTS: I.c.v. injections of CRH promoted wakefulness while decreasing NREMS in C57BL/6J and CRH-R1 CL animals, whereas such changes were not exerted in CKO mice. However, REMS suppression after CRH application persisted in all animals. I.c.v. injected CRH increased plasma corticosterone levels in both CL and CKO mice. CONCLUSIONS: The results demonstrated that CRH has a major impact on wake and NREMS regulation which is predominantly mediated through central CRH-R1. Peripheral actions of CRH, i.e., elevated HPA activity, may interfere with its central effects on REMS but not on NREMS suppression.
Asunto(s)
Hormona Liberadora de Corticotropina/administración & dosificación , Receptores de Hormona Liberadora de Corticotropina/deficiencia , Sueño REM/efectos de los fármacos , Animales , Nivel de Alerta/efectos de los fármacos , Corticosterona/sangre , Hormona Liberadora de Corticotropina/sangre , Relación Dosis-Respuesta a Droga , Electroencefalografía/métodos , Electromiografía/métodos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Receptores de Hormona Liberadora de Corticotropina/sangre , Fases del Sueño/efectos de los fármacos , Factores de Tiempo , Vigilia/efectos de los fármacosRESUMEN
Sex differences and social context independently contribute to the development of stress-related disorders. However, less is known about how their interplay might influence behavior and physiology. Here we focused on social hierarchy status, a major component of the social environment in mice, and whether it influences behavioral adaptation to chronic stress in a sex-specific manner. We used a high-throughput automated behavioral monitoring system to assess social dominance in same-sex, group-living mice. We found that position in the social hierarchy at baseline was a significant predictor of multiple behavioral outcomes following exposure to chronic stress. Crucially, this association carried opposite consequences for the two sexes. This work demonstrates the importance of recognizing the interplay between sex and social factors and enhances our understating of how individual differences shape the stress response.
Most people experience chronic stress at some point in their life, which may increase their chances of developing depression or anxiety. There is evidence that chronic stress may more negatively impact the well-being of women, placing them as higher risk of developing these mental health conditions. The biological factors that underlie these differences are not well understood, which leaves clinicians and scientists struggling to develop and provide effective treatments. The social environment has a powerful influence on how people experience and cope with stress. For example, a person's social and socioeconomic status can change their perception of and reaction to everyday stress. Researchers have found differences in how men and women relate to their social standing. One way for scientists to learn more about the biological processes involved is to study the effect of social standing and chronic stress in male and female mice. Now, Karamihalev, Brivio et al. show that social status influences the behavior of stressed mice in a sex-specific way. In the experiments, an automated observation system documented the behavior of mice living in all female or male groups. Karamihalev, Brivio et al. determined where each animal fit into the social structure of their group. Then, they exposed some groups of mice to mild chronic stress and compared their behaviors to groups of mice housed in normal conditions. They found that both the sex and social status of each played a role in how they responded to stress. For example, subordinate males displayed more anxious behavior under stressful circumstances, while dominant females acted bolder and less anxious. More studies in mice are needed to understand the biological basis of these social- and sex-based differences in stress response. Learning more may help scientists understand why some individuals are more susceptible to the effects of stress and lead to the development of personalized prevention or treatment strategies for anxiety and depression.
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Predominio Social , Estrés Psicológico/fisiopatología , Estrés Psicológico/psicología , Adaptación Fisiológica , Animales , Femenino , Jerarquia Social , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Caracteres SexualesRESUMEN
In socially-living species, sleep patterns are often subject to group influences, as individuals adjust to the presence, daily rhythms, and social pressures of cohabitation. However, sleep studies in mice are typically conducted in single-housed individuals. Here, we investigated sleep in a semi-naturalistic environment with freely-moving, group-housed mice using wireless electroencephalographic (EEG) monitoring and video tracking. We found evidence of in-group synchrony of sleep state patterns and effects of social dominance status on sleep quality. These findings highlight the importance of exploring sleep in a social context and are a step toward more informative research on the interplay between social functioning and sleep.
Asunto(s)
Movimiento/fisiología , Sueño/fisiología , Predominio Social , Animales , Masculino , Ratones Endogámicos ICRRESUMEN
Personality traits can offer considerable insight into the biological basis of individual differences. However, existing approaches toward understanding personality across species rely on subjective criteria and limited sets of behavioral readouts, which result in noisy and often inconsistent outcomes. Here we introduce a mathematical framework for describing individual differences along dimensions with maximum consistency and discriminative power. We validate this framework in mice, using data from a system for high-throughput longitudinal monitoring of group-housed male mice that yields a variety of readouts from across the behavioral repertoire of individual animals. We demonstrate a set of stable traits that capture variability in behavior and gene expression in the brain, allowing for better-informed mechanistic investigations into the biology of individual differences.
Asunto(s)
Individualidad , Modelos Teóricos , Personalidad , Conducta Social , Animales , Conducta Animal , Jerarquia Social , Masculino , RatonesRESUMEN
Forced swimming is a behavioural stress model increasingly used to investigate the neurocircuitry of stress responses. Although forced swim stress clearly is a psychological stressor (anxiety, panic), its physical aspects are often neglected. There are indications that behavioural and neurochemical responses to swim stress depend on the water temperature. Thus, we investigated the responsiveness of hippocampal serotonergic neurotransmission (important in the coordination of stress responses), and of behaviour and core body temperature to forced swimming at different water temperatures (19, 25 and 35 degrees C). In vivo microdialysis and biotelemetry in freely-behaving rats were used. Dialysates were analysed for serotonin (5-HT) and its metabolite 5-HIAA (5-hydroxyindoleacetic acid) by HPLC with electrochemical detection. Forced swimming in water at 25 and 19 degrees C decreased core body temperature by 8 and 12 degrees C, respectively. A rapid and pronounced increase in hippocampal 5-HT and 5-HIAA was found in rats that swam at 35 degrees C, whereas biphasic responses in 5-HT and 5-HIAA were observed at 25 and 19 degrees C. Also swim stress behaviour and post-stress home cage behaviour depended on the water temperature. Comparing the serotonergic and core body temperature changes revealed that a combination of two different 5-HT and 5-HIAA responses seems to shape the neurotransmitter response. Swimming-induced increases in hippocampal extracellular concentrations of 5-HT and 5-HIAA occurred at all water temperatures, but these increases were temporarily quenched, or concentrations were transistently decreased, when core body temperature fell below 31 degrees C in water at 25 or 19 degrees C. These data demonstrate that water temperature is a key factor determining the impact of forced swim stress on behaviour and neurochemistry, and underscore that changes in these parameters should be interpreted in the light of the autonomic responses induced by this stressor.
Asunto(s)
Conducta Animal/fisiología , Estrés Psicológico/fisiopatología , Natación/psicología , Animales , Temperatura Corporal/fisiología , Hipocampo/metabolismo , Ácido Hidroxiindolacético/metabolismo , Masculino , Microdiálisis , Actividad Motora/fisiología , Ratas , Ratas Wistar , Serotonina/metabolismo , Telemetría , TemperaturaRESUMEN
The cannabinoid receptor type 1 (CB1) and its endogenous ligands, the endocannabinoids, are involved in the regulation of food intake. Here we show that the lack of CB1 in mice with a disrupted CB1 gene causes hypophagia and leanness. As compared with WT (CB1+/+) littermates, mice lacking CB1 (CB1-/-) exhibited reduced spontaneous caloric intake and, as a consequence of reduced total fat mass, decreased body weight. In young CB1-/- mice, the lean phenotype is predominantly caused by decreased caloric intake, whereas in adult CB1-/- mice, metabolic factors appear to contribute to the lean phenotype. No significant differences between genotypes were detected regarding locomotor activity, body temperature, or energy expenditure. Hypothalamic CB1 mRNA was found to be coexpressed with neuropeptides known to modulate food intake, such as corticotropin-releasing hormone (CRH), cocaine-amphetamine-regulated transcript (CART), melanin-concentrating hormone (MCH), and preproorexin, indicating a possible role for endocannabinoid receptors within central networks governing appetite. CB1-/- mice showed significantly increased CRH mRNA levels in the paraventricular nucleus and reduced CART mRNA levels in the dorsomedial and lateral hypothalamic areas. CB1 was also detected in epidydimal mouse adipocytes, and CB1-specific activation enhanced lipogenesis in primary adipocyte cultures. Our results indicate that the cannabinoid system is an essential endogenous regulator of energy homeostasis via central orexigenic as well as peripheral lipogenic mechanisms and might therefore represent a promising target to treat diseases characterized by impaired energy balance.
Asunto(s)
Apetito/fisiología , Cannabinoides/metabolismo , Metabolismo Energético , Ácidos Grasos Insaturados/fisiología , Lípidos/biosíntesis , Receptores de Droga/fisiología , Adipocitos/metabolismo , Animales , Moduladores de Receptores de Cannabinoides , Hormona Liberadora de Corticotropina/genética , Hormona Liberadora de Corticotropina/fisiología , Ingestión de Alimentos/fisiología , Expresión Génica , Hipotálamo/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuropéptidos/genética , Neuropéptidos/fisiología , Obesidad/fisiopatología , Obesidad/terapia , Fenotipo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Cannabinoides , Receptores de Droga/deficiencia , Receptores de Droga/genética , Delgadez/fisiopatologíaRESUMEN
Although total sleep deprivation is frequently used in sleep research, the techniques used such as gentle handling are labor consuming and not standardized (and boring). In order to minimize these limitations, we developed a fully automated setup, which can be used for total sleep deprivation. A shortfall of individually adjustable thresholds of electromyogram (EMG) signals from sleep deprived animals was used online to switch running wheels incorporated into the home cages. Randomized direction of rotations, adaptable rotational speed and automatic deactivation of the running wheels during quiet waking of the animals provided robust and standardized sleep deprivation without increased stress, when compared to gentle handling. The setup can easily be introduced to a variety of home cages and is individually adaptable to each animal to be sleep deprived.
Asunto(s)
Modelos Animales de Enfermedad , Equipos y Suministros , Privación de Sueño/fisiopatología , Sueño/fisiología , Animales , Electroencefalografía/métodos , Electromiografía/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/fisiologíaRESUMEN
STUDY OBJECTIVES: The CACNA1C gene encodes the alpha 1C (α1C) subunit of the Cav1.2 voltage-dependent L-type calcium channel (LTCC). Some of the other voltage-dependent calcium channels, e.g., P-/Q-type, Cav2.1; N-type, Cav2.2; E-/R-type, Cav2.3; and T-type, Cav3.3 have been implicated in sleep modulation. However, the contribution of LTCCs to sleep remains largely unknown. Based on recent genome-wide association studies, CACNA1C emerged as one of potential candidate genes associated with both sleep and psychiatric disorders. Indeed, most patients with mental illnesses have sleep problems and vice versa. DESIGN: To investigate an impact of Cav1.2 on sleep-wake behavior and electroencephalogram (EEG) activity, polysomnography was performed in heterozygous Cacna1c (HET) knockout mice and their wild-type (WT) littermates under baseline and challenging conditions (acute sleep deprivation and restraint stress). MEASUREMENTS AND RESULTS: HET mice displayed significantly lower EEG spectral power than WT mice across high frequency ranges (beta to gamma) during wake and rapid eye movement (REM) sleep. Although HET mice spent slightly more time asleep in the dark period, daily amounts of sleep did not differ between the two genotypes. However, recovery sleep after exposure to both types of challenging stress conditions differed markedly; HET mice exhibited reduced REM sleep recovery responses compared to WT mice. CONCLUSIONS: These results suggest the involvement of Cacna1c (Cav1.2) in fast electroencephalogram oscillations and REM sleep regulatory processes. Lower spectral gamma activity, slightly increased sleep demands, and altered REM sleep responses found in heterozygous Cacna1c knockout mice may rather resemble a sleep phenotype observed in schizophrenia patients.
Asunto(s)
Canales de Calcio Tipo L/metabolismo , Electroencefalografía , Ritmo Gamma/fisiología , Sueño REM/fisiología , Animales , Canales de Calcio Tipo L/genética , Heterocigoto , Masculino , Ratones , Ratones Noqueados , Polisomnografía , Restricción Física , Privación de Sueño/fisiopatología , Vigilia/fisiologíaRESUMEN
Antagonists of the corticotropin-releasing hormone receptor type 1 (CRH-R1) are regarded as promising tools for the treatment of stress-related psychiatric disorders. Owing to the intricate relationship between CRH and serotonin (5-HT), we studied the effects of chronic oral treatment of C57Bl6/N mice with the CRH-R1 antagonist NBI 30775 (formerly known as R121919) on hippocampal serotonergic neurotransmission during basal (on 15th day of treatment) and stress (forced swimming; on 16th day of treatment) conditions by in vivo microdialysis. Given the important role of CRH in the regulation of hypothalamic-pituitary-adrenocortical (HPA) axis activity and behavior, the effects of NBI 30775 on dialysate-free corticosterone levels, and on home cage and forced swimming-related behavior were also assessed. Chronic administration of NBI 30775 (18.4+/-0.9 mg/kg/day) did not result in alterations in food consumption and body weight. NBI 30775 caused complex changes in hippocampal serotonergic neurotransmission. Whereas no effects on the diurnal rhythms of 5-HT and its metabolite 5-hydroxyindoleacetic acid were found, the responses of the neurotransmitter and its metabolite to 10 min of forced swim stress were reduced and prolonged, respectively. NBI 30775 did not change free corticosterone levels over the diurnal rhythm. Moreover, NBI 30775-treated mice showed a similar forced swim stress-induced increase in corticosterone as observed in the control group. No effects of NBI 30775 on home cage, and swim stress-related active behaviors (climbing, swimming) and immobility were found. Thus, whereas chronic antagonism of CRH-R1 did not compromise HPA axis performance and behavior, distinct changes in serotonergic neurotransmission developed. Owing to the important role of 5-HT in the pathophysiology of mood and anxiety disorders, the latter observation may contribute to the therapeutical efficacy of CRH-R1 antagonists in these illnesses.
Asunto(s)
Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Pirimidinas/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Serotonina/metabolismo , Administración Oral , Animales , Conducta Animal/efectos de los fármacos , Ritmo Circadiano/efectos de los fármacos , Corticosterona/metabolismo , Espacio Extracelular/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ácido Hidroxiindolacético/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microdiálisis , Sistema Hipófiso-Suprarrenal/metabolismo , Radioinmunoensayo , Estrés Fisiológico/metabolismo , Natación , Factores de TiempoRESUMEN
Methylglyoxal (MG), an essential by-product of glycolysis, is a highly reactive endogenous α-oxoaldehyde. Although high levels of MG are cytotoxic, physiological doses of MG were shown to reduce anxiety-related behavior through selective activation of γ-aminobutyric acid type A (GABAA) receptors. Because the latter play a major role in sleep induction, this study examined the potential of MG to regulate sleep. Specifically, we assessed how MG influences sleep-wake behavior in CD1 mice that received intracerebroventricular injections of either vehicle or 0.7 µmol MG at onset of darkness. We used electroencephalogram (EEG) and electromyogram (EMG) recordings to monitor changes in vigilance states, sleep architecture and the EEG spectrum, for 24 h after receipt of injections. Administration of MG rapidly induced non-rapid eye movement sleep (NREMS) and, concomitantly, decreased wakefulness and suppressed EEG delta power during NREMS. In addition, MG robustly enhanced the amount and number of episodes of an unclassified state of vigilance in which EMG, as well as EEG delta and theta power, were very low. MG did not affect overall rapid eye movement sleep (REMS) in a given 24-h period, but significantly reduced the power of theta activity during REMS. Our results provide the first evidence that MG can exert sleep-promoting properties by triggering low-amplitude NREMS.
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Nivel de Alerta/efectos de los fármacos , Glucosa/metabolismo , Piruvaldehído/metabolismo , Piruvaldehído/farmacología , Fases del Sueño/efectos de los fármacos , Animales , Ondas Encefálicas/efectos de los fármacos , Electromiografía/efectos de los fármacos , Infusiones Intraventriculares , Masculino , Ratones , Piruvaldehído/administración & dosificaciónRESUMEN
BACKGROUND: There is accumulating evidence that anxiety impairs sleep. However, due to high sleep variability in anxiety disorders, it has been difficult to state particular changes in sleep parameters caused by anxiety. Sleep profiling in an animal model with extremely high vs. low levels of trait anxiety might serve to further define sleep patterns associated with this psychopathology. METHODOLOGY/PRINCIPAL FINDINGS: Sleep-wake behavior in mouse lines with high (HAB), low (LAB) and normal (NAB) anxiety-related behaviors was monitored for 24 h during baseline and recovery after 6 h sleep deprivation (SD). The amounts of each vigilance state, sleep architecture, and EEG spectral variations were compared between the mouse lines. In comparison to NAB mice, HAB mice slept more and exhibited consistently increased delta power during non-rapid eye movement (NREM) sleep. Their sleep patterns were characterized by heavy fragmentation, reduced maintenance of wakefulness, and frequent intrusions of rapid eye movement (REM) sleep. In contrast, LAB mice showed a robust sleep-wake rhythm with remarkably prolonged sleep latency and a long, persistent period of wakefulness. In addition, the accumulation of delta power after SD was impaired in the LAB line, as compared to HAB mice. CONCLUSIONS/SIGNIFICANCE: Sleep-wake patterns were significantly different between HAB and LAB mice, indicating that the genetic predisposition to extremes in trait anxiety leaves a biological scar on sleep quality. The enhanced sleep demand observed in HAB mice, with a strong drive toward REM sleep, may resemble a unique phenotype reflecting not only elevated anxiety but also a depression-like attribute.
Asunto(s)
Trastornos de Ansiedad/fisiopatología , Carácter Cuantitativo Heredable , Sueño/fisiología , Animales , Modelos Animales de Enfermedad , Electroencefalografía , Homeostasis , Período de Latencia Psicosexual , Masculino , Ratones , Fenotipo , Privación de Sueño/fisiopatología , Sueño REM/fisiología , Vigilia/fisiologíaRESUMEN
It is widely accepted that orexin (hypocretin) bears wake-promoting effects. While under normal conditions the circadian rhythm of orexin release has a clear circadian distribution, the amplitude of orexin fluctuation is dampened in depression. Interestingly, clinical symptoms of depression include several sleep disturbances. In this disease, corticotropin-releasing hormone (CRH) seems to be another factor influencing sleep. As neurophysiological interactions and anatomical connections between the orexinergic and the CRH system point to mutual influences of these two neuropeptides, we examined whether a dysfunctional CRH-receptor system in two different CRH receptor knock out models alters general wake-promoting effects of orexin applied exogenously. Orexin was injected intracerebroventricularlly into CNS-restricted CRH-receptor type 1 knockout mice (CRH-R1 KO) and CRH-receptor type 2 knockout mice (CRH-R2 KO) and baseline sleep was recorded from the freely behaving mice. A third experiment included antisauvagine-30 injections (CRH-R2 antagonist) into CRH-R1 KO animals. Orexin had similar wake-promoting effects in CRH-R1KO mice, in CRH-R2 KO animals and in CRH-R1KO mice treated with antisauvagine-30. Consistent results were obtained from all corresponding control littermate experiments. According to our results we conclude that the wake-promoting effects of orexin are not influenced by a possible contribution of CRH.
Asunto(s)
Nivel de Alerta/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/farmacología , Neuropéptidos/farmacología , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Simpatomiméticos/farmacología , Animales , Nivel de Alerta/genética , Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/genética , Ritmo Circadiano/fisiología , Electroencefalografía , Electromiografía , Inhibidores Enzimáticos/farmacología , Proteínas de Filamentos Intermediarios/genética , Meloxicam , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Nestina , Orexinas , Fragmentos de Péptidos/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Hormona Liberadora de Corticotropina/deficiencia , Tiazinas/farmacología , Tiazoles/farmacología , Factores de TiempoRESUMEN
Plasminogen activator inhibitor-type 1 (PAI-1) is involved in the fibrinolytic system and shows its increased levels in diseases, e.g., obesity and sleep apnea syndrome. The aim of the study is to investigate whether PAI-1 affects sleep-wake patterns in mice. When recombinant mouse PAI-1 was administered intraperitoneally, only rapid but short increases in time spent awake were observed after 20 or 100 µg/kg, although its plasma concentration was kept high for an hour. The results suggest that PAI-1 may serve its role rather as a marker than an initiator of disturbed sleep.
Asunto(s)
Inhibidor 1 de Activador Plasminogénico/farmacología , Vigilia/efectos de los fármacos , Análisis de Varianza , Animales , Ondas Encefálicas/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Electroencefalografía/métodos , Electromiografía/métodos , Inyecciones Intraperitoneales/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Inhibidor 1 de Activador Plasminogénico/sangre , Sueño , Factores de TiempoRESUMEN
Wake-promoting effects of orexins and corticotropin-releasing hormone (CRH) are well documented. Neuronal interactions between these two systems and anatomical data point to a reciprocal influence of these neuropeptides. We examined in how far an impaired CRH system may influence the circadian rhythm of extracellular orexin levels in mice. The basal levels of orexin were collected unilaterally from the lateral hypothalamus over 24 h in conditional CNS-specific CRH receptor type 1 (CRH-R1) knockout animals and control littermates. No significant differences were obtained between both groups suggesting that under basal conditions the circadian variation of hypothalamic orexin is not mediated by CRH, at least not via CRH-R1.