1. Nature—哈佛大學新發現！！未考慮晝夜節律可能是神經保護藥物在人類卒中臨床試驗中失敗的原因
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.
參考文獻：Potential circadian effects on translational failure for neuroprotection. Nature. 2020 Jun;582(7812):395-398.
2. Nature—飽食和飢餓狀態的記憶鞏固機制不同！！果蠅的飽食和飢餓狀態決定了其記憶的鞏固是否需要睡眠
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.
參考文獻：Availability of food determines the need for sleep in memory consolidation. Nature. 2020 Dec2.
3. Nature—你如何記住你的同伴？海馬CA2尖波漣漪重激活並促進社會性記憶
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.
參考文獻：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~興奮性神經元抑制覺醒！！基底前腦穀氨酸能神經元通過釋放腺苷以抑制覺醒？
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.
參考文獻：Regulation of sleep homeostasismediator adenosine by basal forebrain glutamatergic neurons. Science. 2020 Sep4;369(6508):eabb0556.
5. Nature—GABA是興奮性的！！高張鹽水通過OVLT-SCN(興奮性GABAergic)通路調控時鐘和體溫
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.
參考文獻：Sodium regulates clock time andoutput via an excitatory GABAergic pathway. Nature. 2020 Jul;583(7816):421-424.
6. Science—黑質網狀部GAD2陽性GABA能神經元是睡眠和運動的共同調控樞紐
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.
參考文獻：A common hub for sleep and motor control in the substantia nigra. Science. 2020 Jan 24;367(6476):440-445.
7. Cell—哈佛大學發現！！睡眠不足可能通過增加腸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.
參考文獻：Sleep Loss Can Cause Death throughAccumulation of Reactive Oxygen Species in the Gut. Cell. 2020 Jun11;181(6):1307-1328.e15.
8. Science—當科學家敲除了關鍵的時鐘基因Bmal1，你猜組織細胞分子的生物節律變不變？
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.
參考文獻：Circadian rhythms in the absence ofthe clock gene Bmal1. Science. 2020 Feb 14;367(6479):800-806.
9. Nature—爬行動物屏狀核是產生慢波睡眠中尖波漣漪的關鍵核團
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.
參考文獻：A claustrum in reptiles and its rolein slow-wave sleep. Nature. 2020 Feb;578(7795):413-418.
10. Nature—選擇性褪黑素受體MT1激動劑可能是調控晝夜節律的潛在候選藥物
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.
參考文獻：Virtual discovery of melatonin receptor ligands to modulate circadian rhythms. Nature. 2020Mar;579(7800):609-614.
語音解讀（具體見連結）
2020年十大研究進展名錄
2019年十大研究進展名錄
1. 年終盤點：2019年帕金森病十大基礎研究進展
2. 年終盤點：2019年帕金森病十大臨床研究進展
3. 年終盤點：2019年阿爾茨海默病十大基礎研究進展
4. 年終盤點：2019年阿爾茨海默病十大臨床研究進展
5. 年終盤點：2019年神經科學領域十大基礎研究進展
6. 年終盤點：2019年抑鬱症領域十大基礎研究進展（一半來自中國）
7. 年終盤點：2019年腦血管病領域十大基礎研究進展
8. 年終盤點：2019年神經炎症領域十大基礎研究進展
9. 年終盤點：2019年神經活動記錄十大基礎研究進展
10. 年終盤點：2019年ALS/FTD十大基礎研究進展
11. 年終盤點：2019年醫學和生物學領域深度學習和神經網絡十大基礎研究進展
12. 年終盤點：2019年神經內科十大臨床研究突破
13. 年終盤點：2019年疼痛防治和痛覺機制十大研究突破
14. 年終盤點：2019年睡眠和失眠領域十大研究突破
15.年終盤點：2019年神經發育及成年神經再生十大研究突破
16. 年終盤點：2019年大腦學習和記憶的十大研究突破
17. 年終盤點：2019年衰老和長壽十大研究突破
18. 年終盤點：2019年自閉症十大研究突破
2018年十大研究進展名錄
1.盤點2018年阿爾茨海默病十大研究突破
2.盤點2018年帕金森病十大研究突破
3. 盤點2018年神經科學二十大研究突破
4. 盤點2018年漸凍症（ALS）十大研究進展
5. 盤點2018年全球腦卒中十大研究進展
6. 盤點2018年神經影像十大研究進展
7. 盤點2018年神經炎症領域的十大研究突破
8. 盤點2018年神經變性痴呆十大研究突破
9. 2018年神經科學「學習和記憶」領域十大研究進展
10. 2018年抑鬱症領域的十大研究突破
11. 2018年痛覺和疼痛領域的十大研究突破
12. 2018年的神經幹細胞研究十大研究進展
13. 2018年的神經幹細胞研究十大研究進展
14. 2018年的十大睡眠研究突破
15. 2018年「衰老和長生不老」領域的十大研究突破
16. 2018年自閉症領域的十大研究突破
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20個神經科學領域的突破可能獲得諾貝爾獎
1. 意識研究：意識的本質、組成、運行機制及其物質載體；不同意識層次的操控和幹預，意識障礙性疾病的治療。
2. 學習和記憶的機制及其調控：記憶的形成和消退機制，記憶的人為移植和記憶的人為消除等；
3. 痴呆研究：阿爾茨海默病的機制和治療研究，血管性痴呆、額顳葉痴呆、路易體痴呆的機制研究和治療。
4. 睡眠和睡眠障礙的機制和幹預研究。
5. 情緒研究：喜、怒、哀、恐等基本情緒的機制和相關疾病的治療。
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9. 創造力、想像力和藝術文學創造的神經基礎研究。
10. 痛覺的神經科學基礎及其幹預研究
11. 性行為研究：性行為的神經科學基礎研究和性行為的調控和幹預。
12. 腦和脊髓損傷的機制及其幹預研究，包括腦卒中、脊髓損傷機制研究，神經幹細胞移植研究，新型神經修復技術，神經康復技術。
13. 精神類疾病的機制和幹預研究：自閉症、精分、抑鬱症、智能障礙、藥物成癮等；
14. 運動神經元病等神經變性病機制研究及其幹預。
15. 衰老的機制和永生研究，包括大腦衰老的機制和壽命延長研究。
16. 神經系統遺傳病的機制研究及基因治療。
17. 神經操縱和調控技術：光遺傳技術、藥物遺傳技術、基因編輯技術、經顱磁刺激、深部腦刺激和電刺激等。
18. 腦組織兼容性電子微晶片及腦機互動裝置研究，包括腦機接口、神經刺激晶片、記憶存儲晶片，意識存儲晶片，人腦非語言互動裝置等。
19. 半人半機器人的設計、完善和修復技術：包括任何機械肢體的人類移植，大腦移植入機器體內等。
20. 新型大腦成像和神經元活動記錄技術：高解析度成像技術、大型電極微陣列技術等。
臨床醫學前沿
專門解析最新的臨床指南和循證醫學證據
神經科學臨床和基礎
專門解析最新的神經科學基礎和臨床研究進展
臨床科研那些事
專門解析最新的臨床研究結果和觀點