RESUMO
Sleep and arousal are both important for animals. The neurotransmitter acetylcholine (ACh) has long been found to promote both sleep and arousal in mammals, an apparent paradox which has also been found to exist in flies, causing much confusion in understanding sleep and arousal. Here, we have systematically studied all 13 ACh receptors (AChRs) in Drosophila to understand mechanisms underlying ACh function in sleep and arousal. We found that exogenous stimuli-induced arousal was decreased in nAChRα3 mutants, whereas sleep was decreased in nAChRα2 and nAChRß2 mutants. nAChRα3 functions in dopaminergic neurons to promote exogenous stimuli-induced arousal, whereas nAChRα2 and ß2 function in octopaminergic neurons to promote sleep. Our studies have revealed that a single transmitter can promote endogenous sleep and exogenous stimuli-induced arousal through distinct receptors in different types of downstream neurons.
Assuntos
Nível de Alerta , Drosophila , Animais , Neurônios , Receptores Colinérgicos , SonoRESUMO
Natural D-serine (D-Ser) has been detected in animals more than two decades ago, but little is known about the physiological functions of D-Ser. Here we reveal sleep regulation by endogenous D-Ser. Sleep was decreased in mutants defective in D-Ser synthesis or its receptor the N-methyl-D-aspartic receptor 1 (NMDAR1), but increased in mutants defective in D-Ser degradation. D-Ser but not L-Ser rescued the phenotype of mutants lacking serine racemase (SR), the key enzyme for D-Ser synthesis. Pharmacological and triple gene knockout experiments indicate that D-Ser functions upstream of NMDAR1. Expression of SR was detected in both the nervous system and the intestines. Strikingly, reintroduction of SR into specific intestinal epithelial cells rescued the sleep phenotype of sr mutants. Our results have established a novel physiological function for endogenous D-Ser and a surprising role for intestinal cells.
Assuntos
Proteínas de Drosophila/metabolismo , Racemases e Epimerases/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Serina/metabolismo , Sono/fisiologia , Animais , Animais Geneticamente Modificados , Comportamento Animal/fisiologia , Drosophila/fisiologia , Proteínas de Drosophila/genética , Células Epiteliais/metabolismo , Feminino , Técnicas de Inativação de Genes , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Masculino , Modelos Animais , Racemases e Epimerases/genética , Receptores de N-Metil-D-Aspartato/genética , EstereoisomerismoRESUMO
We define the chemoconnectome (CCT) as the entire set of neurotransmitters, neuromodulators, neuropeptides, and their receptors underlying chemotransmission in an animal. We have generated knockout lines of Drosophila CCT genes for functional investigations and knockin lines containing Gal4 and other tools for examining gene expression and manipulating neuronal activities, with a versatile platform allowing genetic intersections and logic gates. CCT reveals the coexistence of specific transmitters but mutual exclusion of the major inhibitory and excitatory transmitters in the same neurons. One neuropeptide and five receptors were detected in glia, with octopamine ß2 receptor functioning in glia. A pilot screen implicated 41 genes in sleep regulation, with the dopamine receptor Dop2R functioning in neurons expressing the peptides Dilp2 and SIFa. Thus, CCT is a novel concept, chemoconnectomics a new approach, and CCT tool lines a powerful resource for systematic investigations of chemical-transmission-mediated neural signaling circuits underlying behavior and cognition.
