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年终盘点：2019年神经科学领域十大基础研究进展
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2019年神经科学领域十大基础研究进展
1. Nature—这是人类在体外长期维持大脑活性的第一次成功尝试：关键是灌流系统、灌流液和截断了的神经纤维
英文摘要：
Thebrains of humans and other mammals are highly vulnerable to interruptions inblood flow and decreases in oxygen levels. Here we describe the restoration andmaintenance of microcirculation and molecular and cellular functions of theintact pig brain under ex vivo normothermic conditions up to four hourspost-mortem. We have developed an extracorporeal pulsatile-perfusion system anda haemoglobin-based, acellular, non-coagulative, echogenic, and cytoprotectiveperfusate that promotes recovery from anoxia, reduces reperfusion injury,prevents oedema, and metabolically supports the energy requirements of thebrain. With this system, we observed preservation of cytoarchitecture;attenuation of cell death; and restoration of vascular dilatory and glial inflammatoryresponses, spontaneous synaptic activity, and active cerebral metabolism in theabsence of global electrocorticographic activity. These findings demonstratethat under appropriate conditions the isolated, intact large mammalian brainpossesses an underappreciated capacity for restoration of microcirculation andmolecular and cellular activity after a prolonged post-mortem interval.
参考文献：
Vrseljaet al (2019). Restoration of brain circulation and cellular functions hourspost-mortem. Nature. 2019 Apr;568(7752):336-343.
2. Science—神经元和小胶质细胞之间形成了突触结构了吗？问题是这不是经典的突触结构。
英文摘要：
Microgliaare the main immune cells in the brain with roles in brain homeostasis andneurological diseases. Mechanisms underlying microglia-neuron communicationremain elusive. Here, we identified an interaction site between neuronal cellbodies and microglial processes in mouse and human brain. Somaticmicroglia-neuron junctions possessed specialized nanoarchitecture optimized forpurinergic signaling. Activity of neuronal mitochondria was linked withmicroglial junction formation, which was induced rapidly in response toneuronal activation and blocked by inhibition of P2Y12 receptors (P2Y12R).Brain injury-induced changes at somatic junctions triggered P2Y12R-dependentmicroglial neuroprotection, regulating neuronal calcium load and functionalconnectivity. Thus, microglial processes at these junctions could potentiallymonitor and protect neuronal functions.
参考文献：
Cserépet al (2019). Microglia monitor and protect neuronal function via specializedsomatic purinergic junctions. Science. 2019 Dec 12. pii: eaax6752.
3. Nature—肠道微生物-肠-脑轴理论逐步确立：肠道微生物调节大脑功能和人类记忆
英文摘要：
Multicellularorganisms have co-evolved with complex consortia of viruses, bacteria, fungiand parasites, collectively referred to as the microbiota1. In mammals, changesin the composition of the microbiota can influence many physiologic processes(including development, metabolism and immune cell function) and are associatedwith susceptibility to multiple diseases2. Alterations in the microbiota canalso modulate host behaviours-such as social activity, stress, andanxiety-related responses-that are linked to diverse neuropsychiatricdisorders3. However, the mechanisms by which the microbiota influence neuronalactivity and host behaviour remain poorly defined. Here we show thatmanipulation of the microbiota in antibiotic-treated or germ-free adult miceresults in significant deficits in fear extinction learning. Single-nucleus RNAsequencing of the medial prefrontal cortex of the brain revealed significantalterations in gene expression in excitatory neurons, glia and other celltypes. Transcranial two-photon imaging showed that deficits in extinctionlearning after manipulation of the microbiota in adult mice were associatedwith defective learning-related remodelling of postsynaptic dendritic spinesand reduced activity in cue-encoding neurons in the medial prefrontal cortex.In addition, selective re-establishment of the microbiota revealed a limitedneonatal developmental window in which microbiota-derived signals can restorenormal extinction learning in adulthood. Finally, unbiased metabolomic analysisidentified four metabolites that were significantly downregulated in germ-freemice and have been reported to be related to neuropsychiatric disorders inhumans and mouse models, suggesting that microbiota-derived compounds maydirectly affect brain function and behaviour. Together, these data indicatethat fear extinction learning requires microbiota-derived signals both duringearly postnatal neurodevelopment and in adult mice, with implications for ourunderstanding of how diet, infection, and lifestyle influence brain health andsubsequent susceptibility to neuropsychiatric disorders.
参考文献：
Chu et al (2019). The microbiota regulate neuronalfunction and fear extinction learning. Nature. 2019 Oct;574(7779):543-548.
4. Science—记忆插入逐步变成现实：科学家首次在鸟类大脑中实现外来记忆的插入
英文摘要：
Animalslearn many complex behaviors by emulating the behavior of more experiencedindividuals. This essential, yet still poorly understood, form of learningrelies on the ability to encode lasting memories of observed behaviors. Weidentified a vocal-motor pathway in the zebra finch where memories that guidelearning of song-element durations can be implanted. Activation of synapses inthis pathway seeds memories that guide learning of song-element duration andcan override learning from social interactions with other individuals. Geneticlesions of this circuit after memory formation, however, do not disruptsubsequent song imitation, which suggests that these memories are stored atdownstream synapses. Thus, activity at these sensorimotor synapses can bypasslearning from auditory and social experience and embed memories that guidelearning of song timing.
参考文献：
Zhao et al(2019). Inception of memories that guide vocallearning in the songbird. Science. 2019 Oct 4;366(6461):83-89.
5. Nature—神经元和肿瘤细胞之间形成突触结构并加剧肿瘤的扩散和恶化
英文摘要1：
High-gradegliomas are lethal brain cancers whose progression is robustly regulated byneuronal activity. Activity-regulated release of growth factors promotes gliomagrowth, but this alone is insufficient to explain the effect that neuronalactivity exerts on glioma progression. Here we show that neuron and gliomainteractions include electrochemical communication through bona fide AMPAreceptor-dependent neuron-glioma synapses. Neuronal activity also evokesnon-synaptic activity-dependent potassium currents that are amplified by gapjunction-mediated tumour interconnections, forming an electrically couplednetwork. Depolarization of glioma membranes assessed by in vivo optogeneticspromotes proliferation, whereas pharmacologically or genetically blockingelectrochemical signalling inhibits the growth of glioma xenografts and extendsmouse survival. Emphasizing the positive feedback mechanisms by which gliomasincrease neuronal excitability and thus activity-regulated glioma growth, humanintraoperative electrocorticography demonstrates increased corticalexcitability in the glioma-infiltrated brain. Together, these findings indicatethat synaptic and electrical integration into neural circuits promotes gliomaprogression.
英文摘要2：
Anetwork of communicating tumour cells that is connected by tumour microtubesmediates the progression of incurable gliomas. Moreover, neuronal activity canfoster malignant behaviour of glioma cells by non-synaptic paracrine andautocrine mechanisms. Here we report a direct communication channel betweenneurons and glioma cells in different disease models and human tumours:functional bona fide chemical synapses between presynaptic neurons andpostsynaptic glioma cells. These neurogliomal synapses show a typical synapticultrastructure, are located on tumour microtubes, and produce postsynapticcurrents that are mediated by glutamate receptors of the AMPA subtype. Neuronalactivity including epileptic conditions generates synchronised calciumtransients in tumour-microtube-connected glioma networks. Glioma-cell-specificgenetic perturbation of AMPA receptors reduces calcium-related invasiveness oftumour-microtube-positive tumour cells and glioma growth. Invasion and growthare also reduced by anaesthesia and the AMPA receptor antagonist perampanel,respectively. These findings reveal a biologically relevant direct synapticcommunication between neurons and glioma cells with potential clinicalimplications.
英文摘要3：
Metastasis-thedisseminated growth of tumours in distant organs-underlies cancer mortality.Breast-to-brain metastasis (B2BM) is a common and disruptive form of cancer andis prevalent in the aggressive basal-like subtype, but is also found at varyingfrequencies in all cancer subtypes. Previous studies revealed parameters ofbreast cancer metastasis to the brain, but its preference for this site remainsan enigma. Here we show that B2BM cells co-opt a neuronal signalling pathwaythat was recently implicated in invasive tumour growth, involving activation byglutamate ligands of N-methyl-D-aspartate receptors (NMDARs), which is key inmodel systems for metastatic colonization of the brain and is associated withpoor prognosis. Whereas NMDAR activation is autocrine in some primary tumourtypes, human and mouse B2BM cells express receptors but secrete insufficientglutamate to induce signalling, which is instead achieved by the formation ofpseudo-tripartite synapses between cancer cells and glutamatergic neurons,presenting a rationale for brain metastasis.
参考文献：
1.Venkatesh et al (2019). Electrical and synaptic integration of glioma intoneural circuits. Nature. 2019 Sep;573(7775):539-545.
2.Venkataramani et al (2019). Glutamatergic synaptic input to glioma cells drivesbrain tumour progression. Nature. 2019 Sep;573(7775):532-538.
3.Zeng et al (2019). Synaptic proximity enables NMDAR signalling to promote brainmetastasis. Nature. 2019 Sep;573(7775):526-531.
6.Science—同性性行为的遗传学研究揭示遗传因素可能对同性性行为的影响没那么大
英文摘要：
Twinand family studies have shown that same-sex sexual behavior is partlygenetically influenced, but previous searches for specific genes involved havebeen underpowered. We performed a genome-wide association study (GWAS) on477,522 individuals, revealing five loci significantly associated with same-sexsexual behavior. In aggregate, all tested genetic variants accounted for 8 to25% of variation in same-sex sexual behavior, only partially overlapped betweenmales and females, and do not allow meaningful prediction of an individual'ssexual behavior. Comparing these GWAS results with those for the proportion ofsame-sex to total number of sexual partners among nonheterosexuals suggeststhat there is no single continuum from opposite-sex to same-sex sexualbehavior. Overall, our findings provide insights into the genetics underlyingsame-sex sexual behavior and underscore the complexity of sexuality.
参考文献：
Gannaet al (2019). Large-scale GWAS reveals insights into the genetic architectureof same-sex sexual behavior. Science. 2019 Aug 30;365(6456).
7.Science—万事万物相生相克：科学家发现一个孤儿型抗阿片肽系统受体
英文摘要：
Opioidstarget the μ-opioid receptor (MOR) to produce unrivaled pain management, buttheir addictive properties can lead to severe abuse. We developed awhole-animal behavioral platform for unbiased discovery of genes influencingopioid responsiveness. Using forward genetics in Caenorhabditis elegans,we identified a conserved orphan receptor, GPR139, with anti-opioid activity.GPR139 is coexpressed with MOR in opioid-sensitive brain circuits, binds toMOR, and inhibits signaling to heterotrimeric guanine nucleotide-bindingproteins (G proteins). Deletion of GPR139 in mice enhanced opioid-inducedinhibition of neuronal firing to modulate morphine-induced analgesia, reward,and withdrawal. Thus, GPR139 could be a useful target for increasing opioidsafety. These results also demonstrate the potential of C. elegans as ascalable platform for genetic discovery of G protein-coupled receptor signalingprinciples.
参考文献：
Wanget al (2019). Genetic behavioral screen identifies an orphan anti-opioidsystem. Science. 2019 Sep 20;365(6459):1267-1273.
8．Nature—清华大学研发第一个将人工神经网络和神经生物网络相结合的电子芯片
英文摘要：
Thereare two general approaches to developing artificial general intelligence (AGI)1:computer-science-oriented and neuroscience-oriented.Because of the fundamental differences in their formulations and codingschemes, these two approaches rely on distinct and incompatible platforms2-8,retarding the development of AGI. A general platform that could support theprevailing computer-science-based artificial neural networks as well as neuroscience-inspired models and algorithms is highlydesirable. Here we present the Tianjic chip, which integrates the twoapproaches to provide a hybrid, synergistic platform. The Tianjic chip adopts amany-core architecture, reconfigurable building blocks and a streamlineddataflow with hybrid coding schemes, and can not only accommodatecomputer-science-based machine-learning algorithms, but also easily implementbrain-inspired circuits and several coding schemes. Using just one chip, wedemonstrate the simultaneous processing of versatile algorithms and models inan unmanned bicycle system, realizing real-time object detection, tracking,voice control, obstacle avoidance and balance control. Our study is expected tostimulate AGI development by paving the way to more generalized hardwareplatforms.
参考文献：
Peiet al (2019). Towards artificial general intelligence with hybrid Tianjic chiparchitecture. Nature. 2019 Aug;572(7767):106-111.
9.Science—长时程海马尖波涟漪的功能被阐明：长时程海马尖波涟漪促进记忆
英文摘要：
Hippocampalsharp wave ripples (SPW-Rs) have been hypothesized as a mechanism for memoryconsolidation and action planning. The duration of ripples shows a skeweddistribution with a minority of long-duration events. We discovered thatlong-duration ripples are increased in situations demanding memory in rats.Prolongation of spontaneously occurring ripples by optogenetic stimulation, butnot randomly induced ripples, increased memory during maze learning. Theneuronal content of randomly induced ripples was similar to short-durationspontaneous ripples and contained little spatial information. The spike contentof the optogenetically prolonged ripples was biased by the ongoing, naturallyinitiated neuronal sequences. Prolonged ripples recruited new neurons thatrepresented either arm of the maze. Long-duration hippocampal SPW-Rs replayinglarge parts of planned routes are critical for memory.
参考文献：
Fernández-Ruizet al (2019). Long-duration hippocampal sharp wave ripples improve memory. Science.2019 Jun 14;364(6445):1082-1086.
10.Science—小脑不仅仅是一个运动调控中枢，也是一个奖赏和社会行为的调控中枢
英文摘要：
Thecerebellum has been implicated in a number of nonmotor mental disorders such asautism spectrum disorder, schizophrenia, and addiction. However, itscontribution to these disorders is not well understood. In mice, we found thatthe cerebellum sends direct excitatory projections to the ventral tegmentalarea (VTA), one of the brain regions that processes and encodes reward.Optogenetic activation of the cerebello-VTA projections was rewarding and, in athree-chamber social task, these projections were more active when the animalexplored the social chamber. Intriguingly, activity in the cerebello-VTApathway was required for the mice to show social preference in this task. Ourdata delineate a major, previously unappreciated role for the cerebellum incontrolling the reward circuitry and social behavior.
参考文献：
Cartaet al (2019). Cerebellar modulation of the reward circuitry and socialbehavior. Science. 2019 Jan 18;363(6424).
2019年十大研究进展名录
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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1. 意识研究：意识的本质、组成、运行机制及其物质载体；不同意识层次的操控和干预，意识障碍性疾病的治疗。
2. 学习和记忆的机制及其调控：记忆的形成和消退机制，记忆的人为移植和记忆的人为消除等；
3. 痴呆研究：阿尔茨海默病的机制和治疗研究，血管性痴呆、额颞叶痴呆、路易体痴呆的机制研究和治疗。
4. 睡眠和睡眠障碍的机制和干预研究。
5. 情绪研究：喜、怒、哀、恐等基本情绪的机制和相关疾病的治疗。
6. 计算和逻辑推理的神经科学基础研究。
7. 语言的神经科学基础研究。
8. 视觉图像形成和运用的神经科学基础研究。
9. 创造力、想象力和艺术文学创造的神经基础研究。
10. 痛觉的神经科学基础及其干预研究
11. 性行为研究：性行为的神经科学基础研究和性行为的调控和干预。
12. 脑和脊髓损伤的机制及其干预研究，包括脑卒中、脊髓损伤机制研究，神经干细胞移植研究，新型神经修复技术，神经康复技术。
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。
15. 衰老的机制和永生研究，包括大脑衰老的机制和寿命延长研究。
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18. 脑组织兼容性电子微芯片及脑机互动装置研究，包括脑机接口、神经刺激芯片、记忆存储芯片，意识存储芯片，人脑非语言互动装置等。
19. 半人半机器人的设计、完善和修复技术：包括任何机械肢体的人类移植，大脑移植入机器体内等。
20. 新型大脑成像和神经元活动记录技术：高分辨率成像技术、大型电极微阵列技术等。
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