​1. Nature—哈佛大学新发现！！未考虑昼夜节律可能是神经保护药物在人类卒中临床试验中失败的原因

Abstract

Neuroprotectant strategies that haveworked in rodent models of stroke have failed to provide protection in clinicaltrials. Here we show that the opposite circadian cycles in nocturnal rodentsversus diurnal humans1,2 may contribute to this failure in translation. Wetested three independent neuroprotective approaches-normobaric hyperoxia, thefree radical scavenger α-phenyl-butyl-tert-nitrone (αPBN), and theN-methyl-D-aspartic acid (NMDA) antagonist MK801-in mouse and rat models offocal cerebral ischaemia. All three treatments reduced infarction in day-time(inactive phase) rodent models of stroke, but not in night-time (active phase)rodent models of stroke, which match the phase (active, day-time) during whichmost strokes occur in clinical trials. Laser-speckle imaging showed that thepenumbra of cerebral ischaemia was narrower in the active-phase mouse modelthan in the inactive-phase model. The smaller penumbra was associated with alower density of terminal deoxynucleotidyl transferase dUTP nick end labelling(TUNEL)-positive dying cells and reduced infarct growth from 12 to 72 h. Whenwe induced circadian-like cycles in primary mouse neurons, deprivation ofoxygen and glucose triggered a smaller release of glutamate and reactive oxygenspecies, as well as lower activation of apoptotic and necroptotic mediators, in'active-phase' than in 'inactive-phase' rodent neurons. αPBN and MK801 reducedneuronal death only in 'inactive-phase' neurons. These findings suggest thatthe influence of circadian rhythm on neuroprotection must be considered fortranslational studies in stroke and central nervous system diseases.

参考文献：Potential circadian effects on translational failure for neuroprotection. Nature. 2020 Jun;582(7812):395-398.

2. Nature—饱食和饥饿状态的记忆巩固机制不同！！果蝇的饱食和饥饿状态决定了其记忆的巩固是否需要睡眠

Abstract

Sleep remains a major mystery ofbiology, with little understood about its basic function. One of the mostcommonly proposed functions of sleep is the consolidation of memory1-3.However, as conditions such as starvation require the organism to be awake andactive4, the ability to switch to a memory consolidation mechanism that is notcontingent on sleep may confer an evolutionary advantage. Here we identify anadaptive circuit-based mechanism that enables Drosophila to formsleep-dependent and sleep-independent memory. Flies fed after appetitiveconditioning needed increased sleep for memory consolidation, but flies starvedafter training did not require sleep to form memories. Memory in fed flies ismediated by the anterior-posterior α'/β' neurons of the mushroom body, whilememory under starvation is mediated by medial α'/β' neurons. Sleep-dependent andsleep-independent memory rely on distinct dopaminergic neurons andcorresponding mushroom body output neurons. However, sleep and memory arecoupled such that mushroom body neurons required for sleep-dependent memoryalso promote sleep. Flies lacking Neuropeptide F display sleep-dependent memoryeven when starved, suggesting that circuit selection is determined by hunger.This plasticity in memory circuits enables flies to retain essentialinformation in changing environments.

参考文献：Availability of food determines the need for sleep in memory consolidation. Nature. 2020 Dec2.

3. Nature—你如何记住你的同伴？海马CA2尖波涟漪重激活并促进社会性记忆

Abstract

The consolidation of spatial memorydepends on the reactivation ('replay') of hippocampal place cells that wereactive during recent behaviour. Such reactivation is observed during sharp-waveripples (SWRs)-synchronous oscillatory electrical events that occur duringnon-rapid-eye-movement (non-REM) sleep1-8 and whose disruption impairs spatialmemory3,5,6,8. Although the hippocampus also encodes a wide range ofnon-spatial forms of declarative memory, it is not yet known whether SWRs arenecessary for such memories. Moreover, although SWRs can arise from either theCA3 or the CA2 region of the hippocampus7,9, the relative importance of SWRsfrom these regions for memory consolidation is unknown. Here we examine therole of SWRs during the consolidation of social memory-the ability of an animalto recognize and remember a member of the same species-focusing on CA2 becauseof its essential role in social memory10-12. We find that ensembles of CA2pyramidal neurons that are active during social exploration of previouslyunknown conspecifics are reactivated during SWRs. Notably, disruption orenhancement of CA2 SWRs suppresses or prolongs social memory, respectively.Thus, SWR-mediated reactivation of hippocampal firing related to recentexperience appears to be a general mechanism for binding spatial, temporal andsensory information into high-order memory representations, including socialmemory.

参考文献：Hippocampal CA2 sharp-wave ripplesreactivate and promote social memory. Nature. 2020 Nov;587(7833):264-269.

4. Science—睡眠研究重大突破~兴奋性神经元抑制觉醒！！基底前脑谷氨酸能神经元通过释放腺苷以抑制觉醒？

Abstract

Sleep and wakefulness arehomeostatically regulated by a variety of factors, including adenosine.However, how neural activity underlying the sleep-wake cycle controls adenosinerelease in the brain remains unclear. Using a newly developed geneticallyencoded adenosine sensor, we found an activity-dependent rapid increase in theconcentration of extracellular adenosine in mouse basal forebrain (BF), acritical region controlling sleep and wakefulness. Although the activity ofboth BF cholinergic and glutamatergic neurons correlated with changes in theconcentration of adenosine, optogenetic activation of these neurons atphysiological firing frequencies showed that glutamatergic neurons contributedmuch more to the adenosine increase. Mice with selective ablation of BFglutamatergic neurons exhibited a reduced adenosine increase and impaired sleephomeostasis regulation. Thus, cell type-specific neural activity in the BFdynamically controls sleep homeostasis.

参考文献：Regulation of sleep homeostasismediator adenosine by basal forebrain glutamatergic neurons. Science. 2020 Sep4;369(6508):eabb0556.

5. Nature—GABA是兴奋性的！！高张盐水通过OVLT-SCN(兴奋性GABAergic)通路调控时钟和体温

Abstract

The suprachiasmatic nucleus (SCN)serves as the body's master circadian clock that adaptively coordinates changesin physiology and behaviour in anticipation of changing requirements throughoutthe 24-h day-night cycle1-4. For example, the SCN opposes overnight adipsia bydriving water intake before sleep5,6, and by driving the secretion ofanti-diuretic hormone7,8 and lowering body temperature9,10 to reduce water lossduring sleep11. These responses can also be driven by central osmo-sodiumsensors to oppose an unscheduled rise in osmolality during the activephase12-16. However, it is unknown whether osmo-sodium sensors requireclock-output networks to drive homeostatic responses. Here we show that asystemic salt injection (hypertonic saline) given at Zeitgeber time 19-a timeat which SCNVP (vasopressin) neurons are inactive-excited SCNVP neurons anddecreased non-shivering thermogenesis (NST) and body temperature. The effectsof hypertonic saline on NST and body temperature were prevented by chemogeneticinhibition of SCNVP neurons and mimicked by optogenetic stimulation of SCNVPneurons in vivo. Combined anatomical and electrophysiological experimentsrevealed that osmo-sodium-sensing organum vasculosum lamina terminalis (OVLT)neurons expressing glutamic acid decarboxylase (OVLTGAD) relay this informationto SCNVP neurons via an excitatory effect of γ-aminobutyric acid (GABA).Optogenetic activation of OVLTGAD neuron axon terminals excited SCNVP neuronsin vitro and mimicked the effects of hypertonic saline on NST and bodytemperature in vivo. Furthermore, chemogenetic inhibition of OVLTGAD neuronsblunted the effects of systemic hypertonic saline on NST and body temperature.Finally, we show that hypertonic saline significantly phase-advanced thecircadian locomotor activity onset of mice. This effect was mimicked byoptogenetic activation of the OVLTGAD→ SCNVP pathway and was prevented bychemogenetic inhibition of OVLTGAD neurons. Collectively, our findings providedemonstration that clock time can be regulated by non-photic physiologicallyrelevant cues, and that such cues can drive unscheduled homeostatic responsesvia clock-output networks.

参考文献：Sodium regulates clock time andoutput via an excitatory GABAergic pathway. Nature. 2020 Jul;583(7816):421-424.

6. Science—黑质网状部GAD2阳性GABA能神经元是睡眠和运动的共同调控枢纽

Abstract

The arousal state of the braincovaries with the motor state of the animal. How these state changes arecoordinated remains unclear. We discovered that sleep-wake brain states andmotor behaviors are coregulated by shared neurons in the substantia nigra parsreticulata (SNr). Analysis of mouse home-cage behavior identified four stateswith different levels of brain arousal and motor activity: locomotion,nonlocomotor movement, quiet wakefulness, and sleep; transitions occurred notrandomly but primarily between neighboring states. The glutamic aciddecarboxylase 2 but not the parvalbumin subset of SNr γ-aminobutyric acid(GABA)-releasing (GABAergic) neurons was preferentially active in states of lowmotor activity and arousal. Their activation or inactivation biased thedirection of natural behavioral transitions and promoted or suppressed sleep,respectively. These GABAergic neurons integrate wide-ranging inputs andinnervate multiple arousal-promoting and motor-control circuits throughextensive collateral projections.

参考文献：A common hub for sleep and motor control in the substantia nigra. Science. 2020 Jan 24;367(6476):440-445.

7. Cell—哈佛大学发现！！睡眠不足可能通过增加肠道活性氧化合物加速衰老，甚至引起“英年早逝”

Abstract

The view that sleep is essential forsurvival is supported by the ubiquity of this behavior, the apparent existenceof sleep-like states in the earliest animals, and the fact that severe sleeploss can be lethal. The cause of this lethality is unknown. Here we show, usingflies and mice, that sleep deprivation leads to accumulation of reactive oxygenspecies (ROS) and consequent oxidative stress, specifically in the gut. ROS arenot just correlates of sleep deprivation but drivers of death: their neutralizationprevents oxidative stress and allows flies to have a normal lifespan withlittle to no sleep. The rescue can be achieved with oral antioxidant compoundsor with gut-targeted transgenic expression of antioxidant enzymes. We concludethat death upon severe sleep restriction can be caused by oxidative stress,that the gut is central in this process, and that survival without sleep ispossible when ROS accumulation is prevented. VIDEO ABSTRACT.

参考文献：Sleep Loss Can Cause Death throughAccumulation of Reactive Oxygen Species in the Gut. Cell. 2020 Jun11;181(6):1307-1328.e15.

8. Science—当科学家敲除了关键的时钟基因Bmal1，你猜组织细胞分子的生物节律变不变？

Abstract

Circadian (~24 hour) clocks have afundamental role in regulating daily physiology. The transcription factor BMAL1is a principal driver of a molecular clock in mammals. Bmal1 deletion abolishes24-hour activity patterning, one measure of clock output. We determined whetherBmal1 function is necessary for daily molecular oscillations in skinfibroblasts and liver slices. Unexpectedly, in Bmal1 knockout mice, bothtissues exhibited 24-hour oscillations of the transcriptome, proteome, andphosphoproteome over 2 to 3 days in the absence of any exogenous drivers suchas daily light or temperature cycles. This demonstrates a competent 24-hourmolecular pacemaker in Bmal1 knockouts. We suggest that such oscillations mightbe underpinned by transcriptional regulation by the recruitment of ETS familytranscription factors, and nontranscriptionally by co-opting redoxoscillations.

参考文献：Circadian rhythms in the absence ofthe clock gene Bmal1. Science. 2020 Feb 14;367(6479):800-806.

9. Nature—爬行动物屏状核是产生慢波睡眠中尖波涟漪的关键核团

Abstract

The mammalian claustrum, owing to itswidespread connectivity with other forebrain structures, has been hypothesizedto mediate functions that range from decision-making to consciousness1. Here wereport that a homologue of the claustrum, identified by single-celltranscriptomics and viral tracing of connectivity, also exists in a reptile-theAustralian bearded dragon Pogona vitticeps. In Pogona, the claustrum underliesthe generation of sharp waves during slow-wave sleep. The sharp waves, togetherwith superimposed high-frequency ripples2, propagate to the entire neighbouringpallial dorsal ventricular ridge (DVR). Unilateral or bilateral lesions of theclaustrum suppress the production of sharp-wave ripples during slow-wave sleepin a unilateral or bilateral manner, respectively, but do not affect theregular and rapidly alternating sleep rhythm that is characteristic of sleep inthis species3. The claustrum is thus not involved in the generation of thesleep rhythm itself. Tract tracing revealed that the reptilian claustrumprojects widely to a variety of forebrain areas, including the cortex, and thatit receives converging inputs from, among others, areas of the mid- andhindbrain that are known to be involved in wake-sleep control in mammals4-6.Periodically modulating the concentration of serotonin in the claustrum, forexample, caused a matching modulation of sharp-wave production there and in theneighbouring DVR. Using transcriptomic approaches, we also identified aclaustrum in the turtle Trachemys scripta, a distant reptilian relative oflizards. The claustrum is therefore an ancient structure that was probablyalready present in the brain of the common vertebrate ancestor of reptiles andmammals. It may have an important role in the control of brain states owing tothe ascending input it receives from the mid- and hindbrain, its widespreadprojections to the forebrain and its role in sharp-wave generation duringslow-wave sleep.

参考文献：A claustrum in reptiles and its rolein slow-wave sleep. Nature. 2020 Feb;578(7795):413-418.

10. Nature—选择性褪黑素受体MT1激动剂可能是调控昼夜节律的潜在候选药物

Abstract

The neuromodulator melatoninsynchronizes circadian rhythms and related physiological functions through theactions of two G-protein-coupled receptors: MT1 and MT2. Circadian release of melatonin at night from the pineal gland activates melatonin receptors in thesuprachiasmatic nucleus of the hypothalamus, synchronizing the physiology andbehaviour of animals to the light-dark cycle1-4. The two receptors areestablished drug targets for aligning circadian phase to this cycle indisorders of sleep5,6 and depression1-4,7-9. Despite their importance, few invivo active MT1-selective ligands have been reported2,8,10-12, hampering boththe understanding of circadian biology and the development of targetedtherapeutics. Here we docked more than 150 million virtual molecules to an MT1crystal structure, prioritizing structural fit and chemical novelty. Of thesecompounds, 38 high-ranking molecules were synthesized and tested, revealingligands with potencies ranging from 470 picomolar to 6 micromolar.Structure-based optimization led to two selective MT1 inverse agonists-whichwere topologically unrelated to previously explored chemotypes-that acted asinverse agonists in a mouse model of circadian re-entrainment. Notably, we found that these MT1-selective inverse agonists advanced the phase of the mousecircadian clock by 1.3-1.5 h when given at subjective dusk, an agonist-likeeffect that was eliminated in MT1- but not in MT2-knockout mice. This study illustrates the opportunities for modulating melatonin receptor biology throughMT1-selective ligands and for the discovery of previously undescribed, in vivoactive chemotypes from structure-based screens of diverse, ultralargelibraries.

参考文献：Virtual discovery of melatonin receptor ligands to modulate circadian rhythms. Nature. 2020Mar;579(7800):609-614.

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2020年十大研究进展名录

2019年十大研究进展名录

1. 年终盘点：2019年帕金森病十大基础研究进展

2. 年终盘点：2019年帕金森病十大临床研究进展

3. 年终盘点：2019年阿尔茨海默病十大基础研究进展

4. 年终盘点：2019年阿尔茨海默病十大临床研究进展

5. 年终盘点：2019年神经科学领域十大基础研究进展

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）

7. 年终盘点：2019年脑血管病领域十大基础研究进展

8. 年终盘点：2019年神经炎症领域十大基础研究进展

9. 年终盘点：2019年神经活动记录十大基础研究进展

10. 年终盘点：2019年ALS/FTD十大基础研究进展

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

12. 年终盘点：2019年神经内科十大临床研究突破

13. 年终盘点：2019年疼痛防治和痛觉机制十大研究突破

14. 年终盘点：2019年睡眠和失眠领域十大研究突破

15.年终盘点：2019年神经发育及成年神经再生十大研究突破

16. 年终盘点：2019年大脑学习和记忆的十大研究突破

17. 年终盘点：2019年衰老和长寿十大研究突破

18. 年终盘点：2019年自闭症十大研究突破

2018年十大研究进展名录

1.盘点2018年阿尔茨海默病十大研究突破

2.盘点2018年帕金森病十大研究突破

3. 盘点2018年神经科学二十大研究突破

4. 盘点2018年渐冻症（ALS）十大研究进展

5. 盘点2018年全球脑卒中十大研究进展

6. 盘点2018年神经影像十大研究进展

7. 盘点2018年神经炎症领域的十大研究突破

8. 盘点2018年神经变性痴呆十大研究突破

9. 2018年神经科学“学习和记忆”领域十大研究进展

10. 2018年抑郁症领域的十大研究突破

11. 2018年痛觉和疼痛领域的十大研究突破

12. 2018年的神经干细胞研究十大研究进展

13. 2018年的神经干细胞研究十大研究进展

14. 2018年的十大睡眠研究突破

15. 2018年“衰老和长生不老”领域的十大研究突破

16. 2018年自闭症领域的十大研究突破

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13. 精神类疾病的机制和干预研究：自闭症、精分、抑郁症、智能障碍、药物成瘾等；

14. 运动神经元病等神经变性病机制研究及其干预。

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