RESUMEN
Hibernation is an extreme state of seasonal energy conservation, reducing metabolic rate to as little as 1% of the active state. During the hibernation season, many species of hibernating mammals cycle repeatedly between the active (aroused) and hibernating (torpid) states (T-A cycling), using brown adipose tissue (BAT) to drive cyclical rewarming. The regulatory mechanisms controlling this process remain undefined but are presumed to involve thermoregulatory centres in the hypothalamus. Here, we used the golden hamster (Mesocricetus auratus), and high-resolution monitoring of BAT, core body temperature and ventilation rate, to sample at precisely defined phases of the T-A cycle. Using c-fos as a marker of cellular activity, we show that although the dorsomedial hypothalamus is active during torpor entry, neither it nor the pre-optic area shows any significant changes during the earliest stages of spontaneous arousal. Contrastingly, in three non-neuronal sites previously linked to control of metabolic physiology over seasonal and daily time scales - the choroid plexus, pars tuberalis and third ventricle tanycytes - peak c-fos expression is seen at arousal initiation. We suggest that through their sensitivity to factors in the blood or cerebrospinal fluid, these sites may mediate metabolic feedback-based initiation of the spontaneous arousal process.
Asunto(s)
Nivel de Alerta , Plexo Coroideo , Células Ependimogliales , Hibernación , Proteínas Proto-Oncogénicas c-fos , Letargo , Animales , Cricetinae , Masculino , Tejido Adiposo Pardo/metabolismo , Nivel de Alerta/genética , Plexo Coroideo/metabolismo , Células Ependimogliales/metabolismo , Hibernación/genética , Mesocricetus , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Letargo/genéticaRESUMEN
The ability to respond to light has profoundly shaped life. Animals with eyes overwhelmingly rely on their visual circuits for mediating light-induced coordinated movements. Building on previously reported behaviors, we report the discovery of an organized, eye-independent (extraocular), body-wide photosensory framework that allows even a head-removed animal to move like an intact animal. Despite possessing sensitive cerebral eyes and a centralized brain that controls most behaviors, head-removed planarians show acute, coordinated ultraviolet-A (UV-A) aversive phototaxis. We find this eye-brain-independent phototaxis is mediated by two noncanonical rhabdomeric opsins, the first known function for this newly classified opsin-clade. We uncover a unique array of dual-opsin-expressing photoreceptor cells that line the periphery of animal body, are proximal to a body-wide nerve net, and mediate UV-A phototaxis by engaging multiple modes of locomotion. Unlike embryonically developing cerebral eyes that are functional when animals hatch, the body-wide photosensory array matures postembryonically in "adult-like animals." Notably, apart from head-removed phototaxis, the body-wide, extraocular sensory organization also impacts physiology of intact animals. Low-dose UV-A, but not visible light (ocular-stimulus), is able to arouse intact worms that have naturally cycled to an inactive/rest-like state. This wavelength selective, low-light arousal of resting animals is noncanonical-opsin dependent but eye independent. Our discovery of an autonomous, multifunctional, late-maturing, organized body-wide photosensory system establishes a paradigm in sensory biology and evolution of light sensing.
Asunto(s)
Encéfalo/metabolismo , Ojo/metabolismo , Proteínas del Helminto/genética , Opsinas/genética , Células Fotorreceptoras de Invertebrados/metabolismo , Planarias/genética , Animales , Nivel de Alerta/genética , Nivel de Alerta/fisiología , Nivel de Alerta/efectos de la radiación , Encéfalo/crecimiento & desarrollo , Ojo/crecimiento & desarrollo , Perfilación de la Expresión Génica/métodos , Regulación del Desarrollo de la Expresión Génica , Proteínas del Helminto/clasificación , Proteínas del Helminto/metabolismo , Hibridación Fluorescente in Situ/métodos , Locomoción/genética , Locomoción/fisiología , Locomoción/efectos de la radiación , Movimiento/fisiología , Movimiento/efectos de la radiación , Opsinas/clasificación , Opsinas/metabolismo , Filogenia , Planarias/crecimiento & desarrollo , Planarias/metabolismo , Interferencia de ARN , Rayos UltravioletaRESUMEN
Hibernation consists of alternating periods of reduced metabolism (torpor) with brief periods of metabolism similar to summer euthermia (arousal). The function of the innate immune system is reduced during hibernation, of which the underlying mechanisms are incompletely understood. Here, we studied neutrophil functionality during hibernation in Syrian hamsters. The inflammatory response to LPS-induced endotoxemia is inhibited in hibernation, partly mediated by reduced IL-6 production in early arousal. Furthermore, neutrophil pathogen binding, phagocytosis and oxidative burst is profoundly reduced in early arousal. Functionality of both summer and early arousal neutrophils was repressed in plasma from early arousal and mixed plasma from early arousal and summer euthermic, but restored by summer euthermic plasma, signifying that a plasma factor in early arousal inhibits TLR-recognition. Identification of the inhibiting factor may offer a target to modulate neutrophil function with relevance to (auto-)inflammatory diseases.
Asunto(s)
Hibernación/inmunología , Inmunidad Innata/inmunología , Mesocricetus/inmunología , Neutrófilos/inmunología , Estaciones del Año , Proteínas de Fase Aguda/inmunología , Animales , Nivel de Alerta/genética , Nivel de Alerta/fisiología , Proteínas Portadoras/sangre , Proteínas Portadoras/inmunología , Citocinas/inmunología , Citocinas/metabolismo , Expresión Génica/inmunología , Hibernación/genética , Hibernación/fisiología , Inmunidad Innata/genética , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Interleucina-6/inmunología , Interleucina-6/metabolismo , Receptores de Lipopolisacáridos/sangre , Receptores de Lipopolisacáridos/inmunología , Receptores de Lipopolisacáridos/metabolismo , Lipopolisacáridos/inmunología , Lipopolisacáridos/metabolismo , Glicoproteínas de Membrana/sangre , Glicoproteínas de Membrana/inmunología , Mesocricetus/genética , Mesocricetus/metabolismo , FN-kappa B/inmunología , FN-kappa B/metabolismo , Neutrófilos/metabolismo , Neutrófilos/fisiología , Fagocitosis/inmunología , Estallido Respiratorio/inmunología , Estallido Respiratorio/fisiología , Factores de TiempoRESUMEN
Εpidemiological research during last decades has demonstrated the association of certain environmental variables with psychosis. Ιn parallel with understanding environmental contributors to schizophrenia, identification of those at high risk of psychosis has become a priority. These risk factors include adverse traumatic experiences, such as discrimination, social environment adversities, bullying, emigration and childhood trauma. For many years the possibility of a relationship of adverse traumatic experiences with schizophrenia was minimized in favor of a biological paradigm. However, there is evidence supporting that childhood adversities is one of the most significant environmental risk factors for psychosis, if not the most significant. Studies have demonstrated the validity and the reliability of retrospective reports of adverse traumatic experiences in psychotic patients. The question on the causal relationship between adverse traumatic experiences and psychosis has been raised for many years, but it has not yet been answered. Researchers have focused on the study of dysfunctional cognitive schemes being formed due to childhood adversities and interpreting the world as unfriendly and threatening. According to social defeat hypothesis, the patients do not experience more stressful life events but they experience them as less controllable. Furthermore, researchers study the mediator psychopathology associated directly with adverse traumatic experiences, such as anxiety, mood, dissociative and adaptation disorders, which possibly predispose to psychosis. Cannabis use and childhood adversities may interact to increase the risk of psychotic symptoms in adolescence, according to research findings. Several publications have positively linked the number of traumatic adverse experiences with the severity of mental health and possibly with high risk of psychosis in a dose-response relationship model. Taking note that it is important to have a plausible hypothesis of the biological mechanisms involved with the relationship between adverse traumatic experiences and psychosis, the putative systems being explored are: (1) the hypothalamus-pituitary-adrenal (HPA) axis because it mediates the principal adaptive response to perceived psychological or physiological stress and (2) the dopamine system, which is considered to be important in the development of psychosis. The biological and environmental risk factors are both important in the etiology of psychosis but the effects of some forms of childhood adversity act largely independently of pre-existing genetic liability to increase the risk of psychosis. A supposed differentiation of psychosis associated with adverse traumatic experiences from the classic neurodegenerative model possibly should be considered seriously by the clinician in order to design the best therapeutic plan.
Asunto(s)
Experiencias Adversas de la Infancia/psicología , Esquizofrenia/diagnóstico , Psicología del Esquizofrénico , Adolescente , Adulto , Nivel de Alerta/genética , Nivel de Alerta/fisiología , Niño , Correlación de Datos , Femenino , Predisposición Genética a la Enfermedad/genética , Predisposición Genética a la Enfermedad/psicología , Humanos , Sistema Hipotálamo-Hipofisario/fisiopatología , Masculino , Factores de Riesgo , Esquizofrenia/fisiopatología , Esquizofrenia/terapia , Medio Social , Adulto JovenRESUMEN
BACKGROUND: G protein signaling pathways are key neuromodulatory mechanisms for behaviors and neurological functions that affect the impact of ethanol (EtOH) on locomotion, arousal, and synaptic plasticity. Here, we report a novel role for the Drosophila G protein-coupled receptor kinase 2 (GPRK2) as a member of the GRK4/5/6 subfamily in modulating EtOH-induced behaviors. METHODS: We studied the requirement of Drosophila Gprk2 for naïve sensitivity to EtOH sedation and ability of the fly to develop rapid tolerance after a single exposure to EtOH, using the loss of righting reflex (LORR) and fly group activity monitor (FlyGrAM) assays. RESULTS: Loss-of-function Gprk2 mutants demonstrate an increase in alcohol-induced hyperactivity, reduced sensitivity to the sedative effects of EtOH, and diminished rapid tolerance after a single intoxicating exposure. The requirement for Gprk2 in EtOH sedation and rapid tolerance maps to ellipsoid body neurons within the Drosophila brain, suggesting that wild-type Gprk2 is required for modulation of locomotion and alertness. However, even though Gprk2 loss of function leads to decreased and fragmented sleep, this change in the sleep state does not depend on Gprk2 expression in the ellipsoid body. CONCLUSION: Our work on GPRK2 has established a role for this GRK4/5/6 subfamily member in EtOH sensitivity and rapid tolerance.
Asunto(s)
Encéfalo/metabolismo , Depresores del Sistema Nervioso Central/farmacología , Proteínas de Drosophila/genética , Tolerancia a Medicamentos/genética , Etanol/farmacología , Quinasa 2 del Receptor Acoplado a Proteína-G/genética , Neuronas/metabolismo , Animales , Nivel de Alerta/efectos de los fármacos , Nivel de Alerta/genética , Drosophila , Técnicas de Inactivación de Genes , Locomoción/efectos de los fármacos , Locomoción/genética , Mutación con Pérdida de Función , Mutación , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/genética , Reflejo de Enderezamiento/efectos de los fármacos , Sueño/efectos de los fármacos , Sueño/genéticaRESUMEN
RNA-binding proteins (RBPs) have important roles in transcription, pre-mRNA processing/transport, mRNA degradation, translation, and non-coding RNA processing, among others. RBPs that are expressed in response to cold stress, such as Cirp and Rbm3, could regulate RNA stability and translation in hibernating mammals that reduce their body temperatures from 37 °C to as low as 0-5 °C during torpor bouts. RBPs including Cirp, Rbm3, and stress-inducible HuR translocate from the nucleus to stabilize mRNAs in the cytoplasm, and thereby could regulate which mRNA transcripts are protected from degradation and are translated, versus stored, for future protein synthesis or degraded by nucleases during cell stress associated with metabolic rate depression. This is the first study to explore the transcriptional/translational regulation, and subcellular localization of cold-inducible RBPs in a model hibernator, the 13-lined ground squirrel (Ictidomys tridecemlineatus). Cirp protein levels were upregulated in liver, skeletal muscle, and brown adipose tissue throughout the torpor-arousal cycle whereas Rbm3 protein levels stayed constant or decreased, suggesting an important role for Cirp, but likely not Rbm3, in the hibernator stress response. Increased cytoplasmic localization of Cirp in liver and muscle and HuR in liver during torpor, but no changes in the relative levels of Rbm3 in the cytoplasm, emphasizes a role for Cirp and possibly HuR in regulating mRNA processing during torpor. This study informs our understanding of the natural adaptations that extreme animals use in the face of stress, and highlight natural stress response mediators that could be used to bolster cryoprotection of human organs donated for transplant.
Asunto(s)
Frío , Hibernación/genética , Especificidad de Órganos/genética , Procesamiento Postranscripcional del ARN/genética , Proteínas de Unión al ARN/genética , Sciuridae/genética , Sciuridae/fisiología , Animales , Nivel de Alerta/genética , Citoplasma/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Letargo/genéticaRESUMEN
The tonic model delineating the serotonin transporter polymorphism's (5-HTTLPR) modulatory effect on anxiety points towards a universal underlying mechanism involving a hyper-or-elevated baseline level of arousal even to non-threatening stimuli. However, to our knowledge, this mechanism has never been observed in non-clinical cohorts exhibiting high anxiety. Moreover, empirical support regarding said association is mixed, potentially because of publication bias with a relatively small sample size. Hence, how the 5-HTTLPR modulates neural correlates remains controversial. Here we show that 5-HTTLPR short-allele carriers had significantly increased baseline ERPs and reduced fearful MMN, phenomena which can nevertheless be reversed by acute anxiolytic treatment. This provides evidence that the 5-HTT affects the automatic processing of threatening and non-threatening voices, impacts broadly on social cognition, and conclusively asserts the heightened baseline arousal level as the universal underlying neural mechanism for anxiety-related susceptibilities, functioning as a spectrum-like distribution from high trait anxiety non-patients to anxiety patients.
Asunto(s)
Ansiedad/metabolismo , Nivel de Alerta , Encéfalo/metabolismo , Emociones , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Percepción del Habla , Calidad de la Voz , Estimulación Acústica , Adulto , Ansiolíticos/uso terapéutico , Ansiedad/genética , Ansiedad/prevención & control , Ansiedad/psicología , Nivel de Alerta/genética , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Estudios Cruzados , Método Doble Ciego , Electroencefalografía , Potenciales Evocados Auditivos , Femenino , Interacción Gen-Ambiente , Genotipo , Humanos , Lorazepam/uso terapéutico , Masculino , Persona de Mediana Edad , Medición de Riesgo , Factores de Riesgo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Adulto JovenRESUMEN
Tonic immobility (TI) is an effective anti-predator strategy. However, long immobility status on the ground increases the risk of being eaten by predators, and thus insects must rouse themselves when appropriate stimulation is provided. Here, the strength of vibration causing arousal from the state of TI was examined in strains artificially selected for longer duration of TI (L-strains: long sleeper) in a beetle. We provided different strengths of vibration stimuli to the long sleepers in Tribolium castaneum. Although immobilized beetles were never awakened by the stimuli from 0.01 to 0.12 mm in amplitude, almost of the beetles were aroused from immobilized status by the stimulus at 0.21 mm. There was a difference in sensitivity of individuals when the stimuli of 0.14 mm and 0.18 mm were provided. F2 individuals were also bred by crossing experiments of the strains selected for shorter and longer duration of TI. The arousal sensitivity to vibration was well separated in the F2 individuals. A positive relationship was observed between the duration of TI and the vibration amplitude, suggesting that immobilized beetles are difficult to arouse from a deep sleep, while light sleepers are easily aroused by even small vibrations. The results indicate a genetic basis for sensitivity to arousal from TI.
Asunto(s)
Nivel de Alerta/genética , Pérdida de Tono Postural/fisiología , Tribolium/fisiología , Animales , Nivel de Alerta/fisiología , Escarabajos/fisiología , Femenino , Masculino , Sueño/genética , Sueño/fisiología , VibraciónRESUMEN
The role of serotonin (5-HT) in sleep is controversial: early studies suggested a sleep-promoting role, but eventually the paradigm shifted toward a wake-promoting function for the serotonergic raphe. Here, we provide evidence from zebrafish and mice that the raphe are critical for the initiation and maintenance of sleep. In zebrafish, genetic ablation of 5-HT production by the raphe reduces sleep, sleep depth, and the homeostatic response to sleep deprivation. Pharmacological inhibition or ablation of the raphe reduces sleep, while optogenetic stimulation increases sleep. Similarly, in mice, ablation of the raphe increases wakefulness and impairs the homeostatic response to sleep deprivation, whereas tonic optogenetic stimulation at a rate similar to baseline activity induces sleep. Interestingly, burst optogenetic stimulation induces wakefulness in accordance with previously described burst activity of the raphe during arousing stimuli. These results indicate that the serotonergic system promotes sleep in both diurnal zebrafish and nocturnal rodents. VIDEO ABSTRACT.
Asunto(s)
Ratones/fisiología , Núcleos del Rafe/fisiología , Serotonina/fisiología , Sueño/fisiología , Pez Cebra/fisiología , Animales , Nivel de Alerta/genética , Nivel de Alerta/fisiología , Buspirona/farmacología , Ritmo Circadiano/fisiología , Fenclonina/farmacología , Homeostasis , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Optogenética , Quipazina/farmacología , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/fisiología , Serotonina/biosíntesis , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Privación de Sueño/genética , Privación de Sueño/fisiopatología , Triptófano Hidroxilasa/deficiencia , Triptófano Hidroxilasa/genética , Vigilia/genética , Vigilia/fisiología , Proteínas de Pez Cebra/deficiencia , Proteínas de Pez Cebra/genéticaRESUMEN
Posttraumatic stress disorder is developed by exposure to a threatening and/or a horrifying event and characterized by the presence of anxiety, hyperarousal, avoidance, and sleep abnormality for a prolonged period of time. To elucidate the potential molecular mechanisms, we constructed a mouse model by electric foot shock followed by situational reminders and performed transcriptome analysis in brain tissues. The stressed mice acquired anxiety-like behavior after 2 weeks and exaggerated startle response after 4 weeks. Avoidance latency and freezing behavior were sustained up to 5 weeks post stress and abnormal static behavior was observed during the sleep period. RNA sequencing was performed in two of the emotional regulatory regions, anterior cingulate cortex and amygdala, at 2 and 5 weeks post stress. More than 1000 differentially expressed genes were identified at 2 weeks in both regions. The number of the regulated genes remained constant in amygdala at 5 weeks post stress, whereas those in anterior cingulate cortex were plummeted. Although synaptic remodeling and endocrine system were the most enriched signaling pathways in both anterior cingulate cortex and amygdala, the individual gene expression profile was regulated in a region- and time-dependent manner. In addition, several genes associated with PTSD involved in Hypothalamic-Pituitary-Adrenal axis were differentially regulated. These findings suggested that global gene expression profile was dynamically regulated in accordance with the disease development stage, and therefore targeting the distinct signaling molecules in different region and development stage might be critical for effective treatment to PTSD.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Regulación de la Expresión Génica , Giro del Cíngulo/metabolismo , Trastornos por Estrés Postraumático/genética , Amígdala del Cerebelo/fisiopatología , Animales , Ansiedad/complicaciones , Ansiedad/genética , Ansiedad/fisiopatología , Nivel de Alerta/genética , Reacción de Prevención , Conducta Animal , Modelos Animales de Enfermedad , Reacción Cataléptica de Congelación , Perfilación de la Expresión Génica , Ontología de Genes , Giro del Cíngulo/fisiopatología , Inmovilización , Masculino , Aprendizaje por Laberinto , Memoria , Ratones Endogámicos C57BL , Tiempo de Reacción/genética , Reflejo de Sobresalto , Sueño , Trastornos por Estrés Postraumático/fisiopatología , Factores de TiempoRESUMEN
STUDY OBJECTIVES: This study examines the associations between overall pre-sleep arousal, its cognitive and somatic subscales and insomnia symptoms. Furthermore, the relative contribution of genetic and environmental influences on overall pre-sleep arousal, cognitive pre-sleep arousal, somatic pre-sleep arousal, and insomnia symptoms and the association between these variables is estimated. METHODS: The cross-sectional data came from G1219 (wave 5), a twin/sibling study which comprised 862 individuals (aged 22-32 years, 34% males). Pre-sleep arousal was measured using the pre-sleep arousal scale and insomnia symptoms using the insomnia symptoms questionnaire. RESULTS: Both cognitive and somatic pre-sleep arousal were significant, independent factors associated with insomnia symptoms. Overall and somatic pre-sleep arousal showed a significant, substantial genetic influence (47% and 49% respectively) and non-shared environmental influence. For cognitive pre-sleep arousal and insomnia symptoms, non-shared environment appeared to be most important (74% and 61% respectively), and familiality was indicated. A strong, significant association of the genetic influences on overall pre-sleep arousal and insomnia symptoms was found (genetic correlation = .88). Strong, significant genetic correlations were found between cognitive pre-sleep arousal, somatic pre-sleep arousal and insomnia symptoms (genetic correlations .93 to 1). Non-shared environmental influences between these three variables were moderately, significantly correlated (non-shared environmental correlation .22 to .41). CONCLUSION: The large overlap of genetic influences between pre-sleep arousal and insomnia symptoms provides novel insight into the associations between these variables. The results indicate that those with cognitive and/or somatic pre-sleep arousal may also have a genetic vulnerability to insomnia symptoms.
Asunto(s)
Nivel de Alerta/genética , Hermanos , Trastornos del Inicio y del Mantenimiento del Sueño/diagnóstico , Trastornos del Inicio y del Mantenimiento del Sueño/genética , Sueño/genética , Gemelos/genética , Adulto , Estudios Transversales , Femenino , Humanos , Estudios Longitudinales , Masculino , Trastornos del Inicio y del Mantenimiento del Sueño/fisiopatología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
PURPOSE: Patients with sickle cell disease (SCD) regularly experience abnormal sleep, characterized by frequent arousals and reduced total sleep time. However, obstructive sleep apnea syndrome (OSAS) is a common comorbidity of SCD, making it unclear whether the disease per se is impacting sleep, or sleep disruption is secondary to the presence of OSAS. Thus, we assessed sleep, independent of OSAS, using a mouse model of SCD. METHODS: Sleep was compared between 10-to-12-week-old Townes knockout-transgenic mice with the sickle cell phenotype SS (n = 6) and Townes mice with sickle cell trait AS (n = 6; control). The mice underwent chronic polysomnographic electrode implantation (4EEG/2EMG) to assess sleep architecture. RESULTS: The SS mice had significantly lower hemoglobin concentration compared to control AS mice (7.3 ± 1.3 vs. 12.9 ± 1.7 g/dL; p < 0.01), consistent with the expected SCD phenotype. SS mice exhibited significantly decreased total NREM sleep time (45.0 ± 0.7 vs. 53.0 ± 1.3% 24 h sleep time; p < 0.01), but no change in total REM sleep time compared to the AS mice. The SS mice took longer to resume sleep after a wake period compared to the AS mice (3.2 ± 0.3 min vs. 1.9 ± 0.2 min; p < 0.05). Unexpectedly, SS mice experienced fewer arousals compared to AS mice (19.0 ± 0.9 vs. 23.3 ± 2.1 arousals/h of sleep; p = 0.031). CONCLUSIONS: The presence of decreased total NREM sleep associated with reduced arousals, in the absence of OSAS, suggests a distinctive underlying sleep phenotype in a mouse model of SCD.
Asunto(s)
Anemia de Células Falciformes/genética , Modelos Animales de Enfermedad , Fenotipo , Apnea Obstructiva del Sueño/genética , Privación de Sueño/genética , Animales , Nivel de Alerta/genética , Hemoglobinometría , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Polisomnografía , Rasgo Drepanocítico/genética , Sueño de Onda Lenta/genética , Vigilia/genéticaRESUMEN
Arousal affects cognition, emotion, and behavior and has been implicated in the etiology of psychiatric disorders. Although environmental conditions substantially contribute to the level of arousal, stable interindividual characteristics are well-established and a genetic basis has been suggested. Here we investigated the molecular genetics of brain arousal in the resting state by conducting a genome-wide association study (GWAS). We selected N = 1877 participants from the population-based LIFE-Adult cohort. Participants underwent a 20-min eyes-closed resting state EEG, which was analyzed using the computerized VIGALL 2.1 (Vigilance Algorithm Leipzig). At the SNP-level, GWAS analyses revealed no genome-wide significant locus (p < 5E-8), although seven loci were suggestive (p < 1E-6). The strongest hit was an expression quantitative trait locus (eQTL) of TMEM159 (lead-SNP: rs79472635, p = 5.49E-8). Importantly, at the gene-level, GWAS analyses revealed significant evidence for TMEM159 (p = 0.013, Bonferroni-corrected). By mapping our SNPs to the GWAS results from the Psychiatric Genomics Consortium, we found that all corresponding markers of TMEM159 showed nominally significant associations with Major Depressive Disorder (MDD; 0.006 ≤ p ≤ 0.011). More specifically, variants associated with high arousal levels have previously been linked to an increased risk for MDD. In line with this, the MetaXcan database suggests increased expression levels of TMEM159 in MDD, as well as Autism Spectrum Disorder, and Alzheimer's Disease. Furthermore, our pathway analyses provided evidence for a role of sodium/calcium exchangers in resting state arousal. In conclusion, the present GWAS identifies TMEM159 as a novel candidate gene which may modulate the risk for psychiatric disorders through arousal mechanisms. Our results also encourage the elaboration of the previously reported interrelations between ion-channel modulators, sleep-wake behavior, and psychiatric disorders.
Asunto(s)
Nivel de Alerta/genética , Adulto , Algoritmos , Enfermedad de Alzheimer/genética , Nivel de Alerta/fisiología , Trastorno del Espectro Autista/genética , Encéfalo/metabolismo , Estudios de Cohortes , Trastorno Depresivo Mayor/genética , Electroencefalografía/métodos , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genética , Descanso/fisiologíaRESUMEN
Dysregulated physiological stress reactivity has been suggested to impact the development of children and adolescents with important health consequences throughout the life span. Both environmental adversity and genetic predispositions can lead to physiological imbalances in stress systems, which in turn lead to developmental differences. We investigated genetic and environmental contributions to autonomic nervous system reactivity to a psychosocial stressor. Furthermore, we tested whether these effects were consistent with the differential susceptibility framework. Composite measures of adverse life events combined with socioeconomic status were constructed. Effects of these adversity scores in interaction with a polygenic score summarizing six genetic variants, which were hypothesized to work as susceptibility factors, were tested on autonomic nervous system measures as indexed by heart rate and heart rate variability. Results showed that carriers of more genetic variants and exposed to high adversity manifested enhanced heart rate variability reactivity to a psychosocial stressor compared to carriers of fewer genetic variants. Conversely, the stress procedure elicited a more moderate response in these individuals compared to carriers of fewer variants when adversity was low.
Asunto(s)
Nivel de Alerta/fisiología , Sistema Nervioso Autónomo/fisiopatología , Interacción Gen-Ambiente , Estrés Psicológico/fisiopatología , Adolescente , Nivel de Alerta/genética , Niño , Femenino , Tamización de Portadores Genéticos , Predisposición Genética a la Enfermedad/genética , Frecuencia Cardíaca/genética , Frecuencia Cardíaca/fisiología , Humanos , Acontecimientos que Cambian la Vida , Masculino , Herencia Multifactorial/genética , Herencia Multifactorial/fisiología , Clase Social , Estrés Fisiológico , Estrés Psicológico/genéticaRESUMEN
The Met allele of the human brain-derived neurotrophic factor (BDNF) gene might be a risk factor for anxiety disorders and is associated with reduced hippocampal volume. Notably, hippocampus plays a crucial role in contextual learning and generalization. The role of the BDNF gene variation in human context-conditioning and generalization is still unknown. We investigated 33 carriers of the Met allele (18 females) and 32 homozygous carriers of the Val allele (15 females) with a virtual-reality context-conditioning paradigm. Electric stimulations (unconditioned stimulus, US) were unpredictably delivered in one virtual office (CTX+), but never in another virtual office (CTX-). During generalization, participants revisited CTX+ and CTX- and a generalization office (G-CTX), which was a mix of the other two. Rating data indicated successful conditioning (more negative valence, higher arousal, anxiety and contingency ratings for CTX+ than CTX-), and generalization of conditioned anxiety by comparable ratings for G-CTX and CTX+. The startle data indicated discriminative learning for Met allele carriers, but not for Val homozygotes. Moreover, a trend effect suggests that startle responses of only the Met carriers were slightly potentiated in G-CTX versus CTX-. In sum, the BDNF polymorphism did not affect contextual learning and its generalization on a verbal level. However, the physiological data suggest that Met carriers are characterized by fast discriminative contextual learning and a tendency to generalize anxiety responses to ambiguous contexts. We propose that such learning may be related to reduced hippocampal functionality and the basis for the risk of Met carriers to develop anxiety disorders.
Asunto(s)
Trastornos de Ansiedad/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Generalización Psicológica , Adulto , Alelos , Ansiedad/genética , Nivel de Alerta/genética , Condicionamiento Clásico , Condicionamiento Psicológico , Miedo , Femenino , Hipocampo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Reflejo de Sobresalto/genéticaRESUMEN
An essential characteristic of sleep is heightened arousal threshold, with decreased behavioral response to external stimuli. The molecular and cellular mechanisms underlying arousal threshold changes during sleep are not fully understood. We report that loss of UNC-7 or UNC-9 innexin function dramatically reduced sleep and decreased arousal threshold during developmentally timed sleep in Caenorhabditiselegans UNC-7 function was required in premotor interneurons and UNC-9 function was required in motor neurons in this paradigm. Simultaneous transient overexpression of UNC-7 and UNC-9 was sufficient to induce anachronistic sleep in adult animals. Moreover, loss of UNC-7 or UNC-9 suppressed the increased sleep of EGL-4 gain-of-function animals, which have increased cyclic-GMP-dependent protein kinase activity. These results suggest C. elegans gap junctions may act downstream of previously identified sleep regulators. In other paradigms, the NCA cation channels act upstream of gap junctions. Consistent with this, diminished NCA channel activity in C. elegans robustly increased arousal thresholds during sleep bouts in L4-to-adult developmentally timed sleep. Total time in sleep bouts was only modestly increased in animals lacking NCA channel auxiliary subunit UNC-79, whereas increased channel activity dramatically decreased sleep. Loss of EGL-4 or innexin proteins suppressed UNC-79 loss-of-function sleep and arousal defects. In Drosophila, the ion channel narrow abdomen, an ortholog of the C. elegans NCA channels, drive the pigment dispersing factor (PDF) neuropeptide release, regulating circadian behavior. However, in C. elegans, we found that loss of the PDF receptor PDFR-1 did not suppress gain-of-function sleep defects, suggesting an alternative downstream pathway. This study emphasizes the conservation and importance of neuronal activity modulation during sleep, and unequivocally demonstrates that gap junction function is critical for normal sleep.
Asunto(s)
Nivel de Alerta/genética , Proteínas de Caenorhabditis elegans/genética , Neuropéptidos/genética , Receptores Acoplados a Proteínas G/genética , Sueño/genética , Animales , Nivel de Alerta/fisiología , Caenorhabditis elegans/genética , Ritmo Circadiano/genética , Proteínas Quinasas Dependientes de GMP Cíclico/genética , Drosophila/genética , Drosophila/fisiología , Uniones Comunicantes/genética , Proteínas de la Membrana/genética , Neuronas Motoras/fisiología , Sueño/fisiologíaRESUMEN
The central part of the medial preoptic nucleus (MPNc) is associated with sexual arousal induction in male rats. However, it is largely unclear how males are sexually aroused and achieve their first copulation. We previously reported that more MPNc neurons activate during the first copulation than the second copulation. In this study, to explore the molecules responsible for sexual arousal induction, we performed DNA microarray of the MPNc in sexually naive males and males after they copulated for their first and second times. We then performed quantitative PCR analyses to validate the results of the DNA microarray. Six genes were identified. Their expression increased following copulation and was higher in males after they copulated for the first time than after the second time. The genes encode transcription factors (Fos, Nfil3, and Nr4a3), a serine/threonine kinase (Sik1), an antioxidant protein (Srxn1), and a neuropeptide precursor VGF (Vgf), which may be the candidate genes responsible for sexual arousal induction. We examined the effects of Vgf knockdown in the MPNc on sexual partner preference and sexual behavior in sexually inexperienced and experienced males to determine the role of VGF in sexual arousal induction. A preference for estrous female rats was reinforced, and the latency of mount and intromission became short after sexually inexperienced males copulated for the first time. However, Vgf knockdown disrupted these phenomena. Vgf knockdown did not have any significant effect in sexually experienced males. VGF-derived neuropeptides presumably serve as an effector molecule to increase sexual activity following sexual arousal induction.
Asunto(s)
Nivel de Alerta/genética , Neuropéptidos/fisiología , Área Preóptica/metabolismo , Conducta Sexual Animal/fisiología , Animales , Copulación/fisiología , Femenino , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Masculino , Neuropéptidos/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Ratas , Ratas Transgénicas , Ratas Wistar , Factores SexualesRESUMEN
Hibernation is an exceptional physiological response to a hostile environment, characterized by a seasonal period of torpor cycles involving dramatic reductions of body temperature and metabolism, and arousal back to normothermia. As the mechanisms regulating hibernation are still poorly understood, here we analysed the expression of genes involved in energy homeostasis, torpor regulation, and daily or seasonal timing using digital droplet PCR in various central and peripheral tissues sampled at different stages of torpor/arousal cycles in the European hamster. During torpor, the hypothalamus exhibited strongly down-regulated gene expression, suggesting that hypothalamic functions were reduced during this period of low metabolic activity. During both torpor and arousal, many structures (notably the brown adipose tissue) exhibited altered expression of deiodinases, potentially leading to reduced tissular triiodothyronine availability. During the arousal phase, all analysed tissues showed increased expression of the core clock genes Per1 and Per2. Overall, our data indicated that the hypothalamus and brown adipose tissue were the tissues most affected during the torpor/arousal cycle, and that clock genes may play critical roles in resetting the body's clocks at the beginning of the active period.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Nivel de Alerta/genética , Cricetulus/genética , Metabolismo Energético/genética , Hibernación/genética , Hipotálamo/metabolismo , Proteínas Circadianas Period/genética , Animales , Ritmo Circadiano/genética , Cricetulus/metabolismo , Europa (Continente) , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Ontología de Genes , Yoduro Peroxidasa/genética , Yoduro Peroxidasa/metabolismo , Masculino , Anotación de Secuencia Molecular , Proteínas Circadianas Period/metabolismo , Triyodotironina/metabolismoRESUMEN
Arginine vasopressin (AVP) has recently been implicated in juvenile and adolescent social development. How AVP influences social development, however, is not understood. Adolescent homozygous Brattleboro rats (Hom), which lack AVP due to a mutation in the Avp gene, exhibit fewer active social behaviors (e.g., social play) but more passive social behaviors (e.g., huddling) than their wild type and heterozygous (Het) littermates, raising the possibility that AVP impacts social development through an arousal mechanism. Here, we test whether the atypical social phenotype of adolescent Hom rats is associated with altered behavioral arousal, social approach, or affective behaviors and whether Brattleboro mothers impact these behavioral phenotypes. Male and female Het and Hom adolescents born to Het or Hom mothers were tested in social interaction, open field, novelty-seeking, social approach, and marble burying tests. As reported previously, Hom rats played less and emitted fewer 50â¯kHz ultrasonic vocalizations while huddling more than their Het littermates. No genotype differences were detected in novelty seeking or social approach, nor were consistent differences found between offspring from Het and Hom mothers. However, Hom rats were less active in the open field and buried fewer marbles than Het rats indicating a hypoaroused, low anxiety phenotype. Open field activity correlated with levels of social play indicating that the effects of the Brattleboro mutation on arousal and social behavior are linked. These data demonstrate that chronic AVP deficiency impacts behavioral arousal during adolescence and support the hypothesis that AVP influences adolescent social development, in part, through its regulation of arousal.
Asunto(s)
Afecto/fisiología , Nivel de Alerta , Conducta Animal/fisiología , Locomoción/fisiología , Conducta Social , Vasopresinas/fisiología , Animales , Nivel de Alerta/genética , Conducta Exploratoria/fisiología , Femenino , Estudios de Asociación Genética , Genotipo , Locomoción/genética , Masculino , Ratas , Ratas Brattleboro/genética , Ratas Long-Evans , Maduración Sexual/genética , Maduración Sexual/fisiologíaRESUMEN
In the central nervous system the neuropeptide oxytocin mediates a range of behaviors related primarily to emotionality. One factor that influences oxytocinergic communication in the human brain and correlates with emotional behaviors is the single nucleotide polymorphism rs53576 on the oxytocin receptor gene (OXTR). For example, variations in this OXTR genotype are related to parental, altruistic, and other prosocial behaviors. Electroencephalographic waveforms of visually evoked response potentials recorded at the midline parietal electrode site display a prominent component putatively involved with attention allocation called the late positive potential. The magnitude of the late positive potential was found to be significantly higher in homozygous G allele individuals compared with A allele carriers when viewing negative emotionally charged images. Inversely, A allele carriers rated these negative images as more arousing, when measured by the Self-Assessment Manikin rating scale. These data suggest that OXTR functioning contributes to visual processing and subjective experience of negative stimuli.