RESUMEN
Sleep relates to numerous biological functions, including metabolism. Both dietary conditions and genes related to metabolism are known to affect sleep behavior. Insulin signaling is well conserved across species including the fruit fly and relates to both metabolism and sleep. However, the neural mechanism of sleep regulation by insulin signaling is poorly understood. Here, we report that insulin signaling in specific neurons regulates sleep in Drosophila melanogaster. We analyzed the sleep behavior of flies with the mutation in insulin-like ligands expressed in the brain and found that three insulin-like ligands participate in sleep regulation with some redundancy. We next used 21 Gal4 drivers to express a dominant-negative form of the insulin receptor (InR DN) in various neurons including circadian clock neurons, which express the clock gene, and the pars intercerebralis (PI). Inhibition of insulin signaling in the anterior dorsal neuron group 1 (DN1a) decreased sleep. Additionally, the same manipulation in PI also decreased sleep. Pan-neuronal induced expression of InR DN also decreased sleep. These results suggested that insulin signaling in DN1a and PI regulates sleep.
Asunto(s)
Relojes Circadianos , Drosophila melanogaster/metabolismo , Insulina/metabolismo , Neuronas/metabolismo , Transducción de Señal , Sueño/fisiología , Animales , Proteínas de Drosophila/metabolismo , Receptor de Insulina/metabolismoRESUMEN
Although diurnal animals displaying monophasic sleep patterns exhibit periodic cycles of alternating slow-wave sleep (SWS) and rapid eye movement sleep (REMS), the regulatory mechanisms underlying these regular sleep cycles remain unclear. Here, we report that in the Australian dragon Pogona vitticeps exposed to constant darkness (DD), sleep behavior and sleep-related neuronal activity emerged over a 24-h cycle. However, the regularity of the REMS/SWS alternation was disrupted under these conditions. Notably, when the lizards were then exposed to 12â h of light after DD, the regularity of the sleep stages was restored. These results suggest that sleep-related neuronal activity in lizards is regulated by circadian rhythms and that the regularity of REMS and SWS cycling is influenced by daytime light exposure.
RESUMEN
Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.
Asunto(s)
Trastorno Bipolar , Temperatura Corporal , Cadherinas , Modelos Animales de Enfermedad , Locomoción , Ratones Noqueados , Animales , Masculino , Ratones , Conducta Animal , Trastorno Bipolar/genética , Trastorno Bipolar/fisiopatología , Cadherinas/genética , Ritmo Circadiano/genética , Ritmo Circadiano/fisiología , Locomoción/genética , Ratones Endogámicos C57BL , Inhibición Prepulso/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , ProtocadherinasRESUMEN
Microglia, as macrophages in the brain, are responsible for immune responses and synaptic remodeling. Although the function of microglia is regulated by circadian rhythms, it is still unclear whether microglia are involved in the generation and light entrainment of circadian rhythms of behavior. Here, we report that microglial depletion does not alter behavioral circadian rhythms. We depleted ~ 95% of microglia in the mouse brain by PLX3397, a CSF1R inhibitor, and analyzed the effect on the spontaneous behaviors of mice. We found that neither the free-running period under constant darkness nor light entrainment under jet-lag circumstances were influenced by the ablation of microglia. Our results demonstrate that the circadian rhythms of locomotor activity, an important output of the circadian clock in the brain, are likely a phenomenon not produced by microglia.
Asunto(s)
Microglía , Núcleo Supraquiasmático , Ratones , Animales , Núcleo Supraquiasmático/fisiología , Ritmo Circadiano , Oscuridad , LocomociónRESUMEN
Circadian rhythm is well conserved across species and relates to numerous biological functions. Circadian misalignment impairs metabolic function. Insulin signaling is a key modulator of metabolism in the fruit fly as well as mammals and its defects cause metabolic disease. Daily diet timing affects both circadian rhythmicities of behavior and metabolism. However, the relationship between the circadian clock and insulin signaling is still elusive. Here, we report that insulin signaling regulates circadian rhythm in Drosophila melanogaster. We found the insulin receptor substrate mutant, chico1, showed a shorter free-running circadian period. The knockdown of insulin receptor (InR), or another signaling molecule downstream of InR, dp110, or the expression of a dominant-negative form of InR resulted in the shortening of the circadian period and diminished its amplitude. The impairment of insulin signaling both in all neurons and restricted circadian clock neurons altered circadian period length, indicating that the insulin signaling plays a role in the regulation of circadian rhythm in clock cells. Among 3 insulin-like ligands expressed in the brain, dilp5 showed the largest effect on circadian phenotype when deleted. These results suggested that insulin signaling contributes to the robustness of the circadian oscillation and coordinates metabolism and behavior.