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年终盘点：2019年睡眠和失眠领域十大研究突破
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2019年睡眠和失眠领域十大研究突破
1. Nat Genet—失眠是遗传的吗？全基因组关联研究发现一系列和人类失眠相关的基因变异
英文摘要1：
Insomniais a common disorder linked with adverse long-term medical and psychiatricoutcomes. The underlying pathophysiological processes and causal relationshipsof insomnia with disease are poorly understood. Here we identified 57 loci forself-reported insomnia symptoms in the UK Biobank (n = 453,379) and confirmedtheir effects on self-reported insomnia symptoms in the HUNT Study (n = 14,923cases and 47,610 controls), physician-diagnosed insomnia in the PartnersBiobank (n = 2,217 cases and 14,240 controls), and accelerometer-derivedmeasures of sleep efficiency and sleep duration in the UK Biobank (n = 83,726). Ourresults suggest enrichment of genes involved in ubiquitin-mediated proteolysisand of genes expressed in multiple brain regions, skeletal muscle, and adrenalglands. Evidence of shared genetic factors was found between frequent insomniasymptoms and restless legs syndrome, aging, and cardiometabolic, behavioral,psychiatric, and reproductive traits. Evidence was found for a possible causallink between insomnia symptoms and coronary artery disease, depressivesymptoms, and subjective well-being.
英文摘要2：
Insomniais the second most prevalent mental disorder, with no sufficient treatmentavailable. Despite substantial heritability, insight into the associated genesand neurobiological pathways remains limited. Here, we use a large geneticassociation sample (n = 1,331,010) to detect novel loci and gain insight intothe pathways, tissue and cell types involved in insomnia complaints. Weidentify 202 loci implicating 956 genes through positional, expressionquantitative trait loci, and chromatin mapping. The meta-analysis explained2.6% of the variance. We show gene set enrichments for the axonal part ofneurons, cortical and subcortical tissues, and specific cell types, includingstriatal, hypothalamic, and claustrum neurons. We found considerable geneticcorrelations with psychiatric traits and sleepduration, and modest correlations with other sleep-relatedtraits. Mendelian randomization identified the causal effects of insomnia ondepression, diabetes, and cardiovascular disease, and the protective effects ofeducational attainment and intracranial volume. Our findings highlight keybrain areas and cell types implicated in insomnia, and provide new treatmenttargets.
参考文献：
1.Lane et al (2019). Biological and clinical insightsfrom genetics of insomnia symptoms. Nat Genet. 2019 Mar;51(3):387-393.
2.Jansen et al (2019). Genome-wide analysis of insomnia in1,331,010 individuals identifies new risk loci and functional pathways. NatGenet. 2019 Mar;51(3):394-403.
2. Science—科学家证实人类睡眠中存在电生理、血流动力学和脑脊液流动的协同振荡
英文摘要：
Sleep is essential for both cognition and maintenance ofhealthy brain function. Slow waves in neural activity contribute to memoryconsolidation, whereas cerebrospinal fluid (CSF) clears metabolic wasteproducts from the brain. Whether these two processes are related is not known.We used accelerated neuroimaging to measure physiological and neural dynamicsin the human brain. We discovered a coherent pattern of oscillatingelectrophysiological, hemodynamic, and CSF dynamics that appears duringnon-rapid eye movement sleep. Neural slow wavesare followed by hemodynamic oscillations, which in turn are coupled to CSFflow. These results demonstrate that the sleeping brain exhibits waves of CSFflow on a macroscopic scale, and these CSF dynamics are interlinked with neuraland hemodynamic rhythms.
参考文献:
Fultz et al (2019). Coupled electrophysiological,hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science. 2019Nov 1;366(6465):628-631.
3. Science—Delta波的功能被阐明：Delta波通过隔离皮层计算以促进记忆巩固
英文摘要：
Deltawaves have been described as periods of generalized silence across the cortex,and their alternation with periods of endogenous activity results in the slowoscillation of slow-wave sleep. Despite evidencethat delta waves are instrumental for memory consolidation, their specific rolein reshaping cortical functional circuits remains puzzling. In a rat model, wefound that delta waves are not periods of complete silence and that theresidual activity is not mere neuronal noise. Instead, cortical cells involvedin learning a spatial memory task subsequently formed cell assemblies duringdelta waves in response to transient reactivation of hippocampal ensemblesduring ripples. This process occurred selectively during endogenous or inducedmemory consolidation. Thus, delta waves represent isolated corticalcomputations tightly related to ongoing information processing underlyingmemory consolidation.
参考文献：
Todorovaet al (2019). Isolated cortical computations during delta waves support memoryconsolidation. Science. 2019 Oct 18;366(6463):377-381.
4. Science—REM睡眠激活的MCH神经元参与海马依赖的记忆的遗忘
英文摘要：
Theneural mechanisms underlying memory regulation during sleepare not yet fully understood. We found that melanin concentratinghormone-producing neurons (MCH neurons) in the hypothalamus actively contributeto forgetting in rapid eye movement (REM) sleep.Hypothalamic MCH neurons densely innervated the dorsal hippocampus. Activationor inhibition of MCH neurons impaired or improved hippocampus-dependent memory,respectively. Activation of MCH nerve terminals in vitro reduced firing ofhippocampal pyramidal neurons by increasing inhibitory inputs. Wake- and REM sleep-active MCH neurons were distinct populations thatwere randomly distributed in the hypothalamus. REM sleepstate-dependent inhibition of MCH neurons impaired hippocampus-dependent memorywithout affecting sleep architecture or quality.REM sleep-active MCH neurons in the hypothalamusare thus involved in active forgetting in the hippocampus.
参考文献：
Izawa et al (2019). REM sleep-active MCH neurons areinvolved in forgetting hippocampus-dependent memories. Science. 2019 Sep20;365(6459):1308-1313.
5. Cell—中脑动眼神经核周区是重要的NREM睡眠调控中枢
英文摘要：
Theperioculomotor (pIII) region of the midbrain was postulated as a sleep-regulating center in the 1890s but largelyneglected in subsequent studies. Using activity-dependent labeling and geneexpression profiling, we identified pIII neurons that promote non-rapid eyemovement (NREM) sleep. Optrode recording showedthat pIII glutamatergic neurons expressing calcitonin gene-related peptidealpha (CALCA) are NREM-sleep active; optogeneticand chemogenetic activation/inactivation showed that they strongly promote NREMsleep. Within the pIII region, CALCA neuronsform reciprocal connections with another population of glutamatergic neuronsthat express the peptide cholecystokinin (CCK). Activation of CCK neurons alsopromoted NREM sleep. Both CALCA and CCK neuronsproject rostrally to the preoptic hypothalamus, whereas CALCA neurons alsoproject caudally to the posterior ventromedial medulla. Activation of eachprojection increased NREM sleep. Together, thesefindings point to the pIII region as an excitatory sleepcenter where different subsets of glutamatergic neurons promote NREM sleep through both local reciprocal connections andlong-range projections.
参考文献：
Zhang et al (2019). An Excitatory Circuit in thePerioculomotor Midbrain for Non-REM Sleep Control. Cell. 2019 May16;177(5):1293-1307.e16.
6.。 Nature—睡眠通过调控造血系统进而预防动脉粥样硬化
英文摘要：
Sleep is integral to life1. Althoughinsufficient or disrupted sleep increases the riskof multiple pathological conditions, including cardiovascular disease2,we know little about the cellular and molecular mechanisms by which sleep maintains cardiovascular health. Here we reportthat sleep regulates haematopoiesis and protectsagainst atherosclerosis in mice. We show that mice subjected to sleep fragmentation produce more Ly-6Chighmonocytes, develop larger atherosclerotic lesions and produce less hypocretin-astimulatory and wake-promoting neuropeptide-in the lateral hypothalamus.Hypocretin controls myelopoiesis by restricting the production of CSF1 byhypocretin-receptor-expressing pre-neutrophils in the bone marrow. Whereashypocretin-null and haematopoietic hypocretin-receptor-null mice developmonocytosis and accelerated atherosclerosis, sleep-fragmentedmice with either haematopoietic CSF1 deficiency or hypocretin supplementationhave reduced numbers of circulating monocytes and smaller atheroscleroticlesions. Together, these results identify a neuro-immune axis that links sleep to haematopoiesis and atherosclerosis.
参考文献：
McAlpine et al (2019). Sleep modulates haematopoiesis andprotects against atherosclerosis. Nature. 2019 Feb;566(7744):383-387.
7. Science—研究发现果蝇中促进睡眠的基因也具有抗微生物的作用
英文摘要：
Sleep remains a major mystery of biology. In particular,little is known about the mechanisms that account for the drive to sleep. In an unbiased screen of more than 12,000 Drosophilalines, we identified a single gene, nemuri, that induces sleep. The NEMURI protein is an antimicrobial peptidethat can be secreted ectopically to drive prolonged sleep(with resistance to arousal) and to promote survival after infection. Loss of nemuriincreased arousability during daily sleep andattenuated the acute increase in sleep induced by sleep deprivation or bacterial infection. Conditionsthat increase sleep drive induced expression of nemuriin a small number of fly brain neurons and targeted it to the sleep-promoting, dorsal fan-shaped body. We propose thatNEMURI is a bona fide sleep homeostasis factorthat is particularly important under conditions of high sleepneed; because these conditions include sickness, our findings provide a linkbetween sleep and immune function.
参考文献：
Toda et al (2019). A sleep-inducing gene, nemuri, linkssleep and immune function in Drosophila. Science. 2019 Feb 1;363(6426):509-515.
8. Science—睡眠觉醒周期调控细胞间液中tau蛋白水平，睡眠剥夺增加细胞间液中tau蛋白水平
英文摘要：
The sleep-wake cycle regulates interstitial fluid (ISF) andcerebrospinal fluid (CSF) levels of β-amyloid (Aβ) that accumulates in Alzheimer'sdisease (AD). Furthermore, chronic sleepdeprivation (SD) increases Aβ plaques. However, tau, not Aβ, accumulationappears to drive AD neurodegeneration. We tested whether ISF/CSF tau and tauseeding and spreading were influenced by the sleep-wakecycle and SD. Mouse ISF tau was increased ~90% during normal wakefulness versussleep and ~100% during SD. Human CSF tau alsoincreased more than 50% during SD. In a tau seeding-and-spreading model,chronic SD increased tau pathology spreading. Chemogenetically drivenwakefulness in mice also significantly increased both ISF Aβ and tau. Thus, thesleep-wake cycle regulates ISF tau, and SDincreases ISF and CSF tau as well as tau pathology spreading.
参考文献：
Holth et al (2019). The sleep-wake cycle regulates braininterstitial fluid tau in mice and CSF tau in humans. Science. 2019 Feb22;363(6429):880-884.
9. Science—睡眠觉醒周期驱动突触磷酸化动力学
英文摘要：
Thecircadian clock drives daily changes of physiology, including sleep-wake cycles, through regulation of transcription,protein abundance, and function. Circadian phosphorylation controls cellularprocesses in peripheral organs, but little is known about its role in brainfunction and synaptic activity. We applied advanced quantitativephosphoproteomics to mouse forebrain synaptoneurosomes isolated across 24hours, accurately quantifying almost 8000 phosphopeptides. Half of the synapticphosphoproteins, including numerous kinases, had large-amplitude rhythms peakingat rest-activity and activity-rest transitions. Bioinformatic analyses revealedglobal temporal control of synaptic function through phosphorylation, includingsynaptic transmission, cytoskeleton reorganization, and excitatory/inhibitorybalance. Sleep deprivation abolished 98% of allphosphorylation cycles in synaptoneurosomes, indicating that sleep-wake cycles rather than circadian signals are maindrivers of synaptic phosphorylation, responding to both sleepand wake pressures.
参考文献：
Brüning et al (2019). Sleep-wake cycles drive dailydynamics of synaptic phosphorylation. Science. 2019 Oct 11;366(6462).
10. Cell—慢波振荡和Delta波在睡眠依赖的记忆巩固中具有相反的作用
英文摘要：
Sleep has been implicated in both memory consolidationand forgetting of experiences. However, it is unclear what governs the balancebetween consolidation and forgetting. Here, we tested how activity-dependentprocessing during sleep might differentiallyregulate these two processes. We specifically examined how neural reactivationsduring non-rapid eye movement (NREM) sleep werecausally linked to consolidation versus weakening of the neural correlatesof neuroprosthetic skill. Strikingly, we found that slow oscillations (SOs) anddelta (δ) waves have dissociable and competing roles in consolidation versusforgetting. By modulating cortical spiking linked to SOs or δ waves using closed-loopoptogenetic methods, we could, respectively, weaken or strengthen consolidationand thereby bidirectionally modulate sleep-dependentperformance gains. We further found that changes in the temporal coupling ofspindles to SOs relative to δ waves could account for such effects. Thus, ourresults indicate that neural activity driven by SOs and δ waves have competingroles in sleep-dependent memory consolidation.
参考文献：
Kim et al (2019). Competing Roles of Slow Oscillationsand Delta Waves in Memory Consolidation versus Forgetting. Cell. 2019 Oct3;179(2):514-526.e13.
2019年十大研究进展名录
6. 年终盘点：2019年抑郁症领域十大基础研究进展（一半来自中国）
11. 年终盘点：2019年医学和生物学领域深度学习和神经网络十大基础研究进展
2018年十大研究进展名录
14. 2018年的十大睡眠研究突破
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