​1. Nature—ALS/FTD中肠道微生物是“坏”的？C9orf72抑制肠道微生物诱导的外周和中枢炎症

Abstract

A hexanucleotide-repeat expansion inC9ORF72 is the most common genetic variant that contributes to amyotrophiclateral sclerosis and frontotemporal dementia1,2. The C9ORF72 mutation actsthrough gain- and loss-of-function mechanisms to induce pathways that areimplicated in neural degeneration3-9. The expansion is transcribed into a longrepetitive RNA, which negatively sequesters RNA-binding proteins5 before itsnon-canonical translation into neural-toxic dipeptide proteins3,4. The failureof RNA polymerase to read through the mutation also reduces the abundance ofthe endogenous C9ORF72 gene product, which functions in endolysosomal pathwaysand suppresses systemic and neural inflammation6-9. Notably, the effects of therepeat expansion act with incomplete penetrance in families with a highprevalence of amyotrophic lateral sclerosis or frontotemporal dementia,indicating that either genetic or environmental factors modify the risk ofdisease for each individual. Identifying disease modifiers is of considerabletranslational interest, as it could suggest strategies to diminish the risk ofdeveloping amyotrophic lateral sclerosis or frontotemporal dementia, or to slowprogression. Here we report that an environment with reduced abundance ofimmune-stimulating bacteria10,11 protects C9orf72-mutant mice from prematuremortality and significantly ameliorates their underlying systemic inflammationand autoimmunity. Consistent with C9orf72 functioning to prevent microbiotafrom inducing a pathological inflammatory response, we found that reducing themicrobial burden in mutant mice with broad spectrum antibiotics-as well astransplanting gut microflora from a protective environment-attenuatedinflammatory phenotypes, even after their onset. Our studies provide furtherevidence that the microbial composition of our gut has an important role inbrain health and can interact in surprising ways with well-known genetic riskfactors for disorders of the nervous system.

参考文献：C9orf72 suppresses systemic andneural inflammation induced by gut bacteria. Nature. 2020 Jun;582(7810):89-94.

2. Cell—重建大脑中的小胶质细胞可以通过IL-6依赖的信号通路修复大脑创伤性损伤

Abstract

Cognitive dysfunction and reactivemicroglia are hallmarks of traumatic brain injury (TBI), yet whether these cellscontribute to cognitive deficits and secondary inflammatory pathology remainspoorly understood. Here, we show that removal of microglia from the mouse brainhas little effect on the outcome of TBI, but inducing the turnover of thesecells through either pharmacologic or genetic approaches can yield aneuroprotective microglial phenotype that profoundly aids recovery. Thebeneficial effects of these repopulating microglia are critically dependent oninterleukin-6 (IL-6) trans-signaling via the soluble IL-6 receptor (IL-6R) androbustly support adult neurogenesis, specifically by augmenting the survival ofnewborn neurons that directly support cognitive function. We conclude thatmicroglia in the mammalian brain can be manipulated to adopt a neuroprotectiveand pro-regenerative phenotype that can aid repair and alleviate the cognitivedeficits arising from brain injury.

参考文献：Repopulating Microglia Promote BrainRepair in an IL-6-Dependent Manner. Cell. 2020 Mar 5;180(5):833-846.e16.

3.Nature—阿尔茨海默病患者存在CD8+T细胞的单克隆扩增

Abstract

Alzheimer's disease is an incurableneurodegenerative disorder in which neuroinflammation has a critical function1.However, little is known about the contribution of the adaptive immune responsein Alzheimer's disease2. Here, using integrated analyses of multiple cohorts,we identify peripheral and central adaptive immune changes in Alzheimer'sdisease. First, we performed mass cytometry of peripheral blood mononuclearcells and discovered an immune signature of Alzheimer's disease that consistsof increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. In asecond cohort, we found that CD8+ TEMRA cells were negatively associated withcognition. Furthermore, single-cell RNA sequencing revealed that T cellreceptor (TCR) signalling was enhanced in these cells. Notably, by usingseveral strategies of single-cell TCR sequencing in a third cohort, wediscovered clonally expanded CD8+ TEMRA cells in the cerebrospinal fluid ofpatients with Alzheimer's disease. Finally, we used machine learning, cloningand peptide screens to demonstrate the specificity of clonally expanded TCRs inthe cerebrospinal fluid of patients with Alzheimer's disease to two separateEpstein-Barr virus antigens. These results reveal an adaptive immune responsein the blood and cerebrospinal fluid in Alzheimer's disease and provideevidence of clonal, antigen-experienced T cells patrolling the intrathecalspace of brains affected by age-related neurodegeneration.

参考文献：Clonally expanded CD8 T cells patrolthe cerebrospinal fluid in Alzheimer's disease. Nature. 2020Jan;577(7790):399-404.

4. Cell—渐冻症发病机制新突破！！ALS中TDP-43通过mPTP激发线粒体DNA释放并激活cGAS/STING通路

Abstract

Cytoplasmic accumulation of TDP-43 isa disease hallmark for many cases of amyotrophic lateral sclerosis (ALS),associated with a neuroinflammatory cytokine profile related to upregulation ofnuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we showthat this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosinemonophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria andreleases DNA via the permeability transition pore. Pharmacologic inhibition orgenetic deletion of cGAS and its downstream signaling partner STING preventsupregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotentstem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, wedocument elevated levels of the specific cGAS signaling metabolite cGAMP inspinal cord samples from patients, which may be a biomarker of mtDNA releaseand cGAS/STING activation in ALS. Our results identify mtDNA release andcGAS/STING activation as critical determinants of TDP-43-associated pathologyand demonstrate the potential for targeting this pathway in ALS.

参考文献：TDP-43 Triggers Mitochondrial DNARelease via mPTP to Activate cGAS/STING in ALS. Cell. 2020 Oct29;183(3):636-649.e18.

5.Nature biotechnology—PNS光遗传学来了！！ChR2光敏感通道刺激周围痛觉神经纤维可激活免疫系统并放大炎症

Abstract

Activation of nociceptor sensoryneurons by noxious stimuli both triggers pain and increases capillarypermeability and blood flow to produce neurogenic inflammation1,2, but whethernociceptors also interact with the immune system remains poorly understood.Here we report a neurotechnology for selective epineural optogeneticneuromodulation of nociceptors and demonstrate that nociceptor activationdrives both protective pain behavior and inflammation. The wirelessoptoelectronic system consists of sub-millimeter-scale light-emitting diodesembedded in a soft, circumneural sciatic nerve implant, powered and driven by aminiaturized head-mounted control unit. Photostimulation of axons in freelymoving mice that express channelrhodopsin only in nociceptors resulted inbehaviors characteristic of pain, reflecting orthodromic input to the spinalcord. It also led to immune reactions in the skin in the absence ofinflammation and potentiation of established inflammation, a consequence of theantidromic activation of nociceptor peripheral terminals. These results reveala link between nociceptors and immune cells, which might have implications forthe treatment of inflammation.

参考文献：Epineural optogenetic activation ofnociceptors initiates and amplifies inflammation. Nat Biotechnol. 2020 Sep 21.

6. Cell—CD4+T细胞是小胶质细胞成熟和大脑正常发育的关键

Abstract

The brain is a site of relativeimmune privilege. Although CD4 T cells have been reported in the centralnervous system, their presence in the healthy brain remains controversial, andtheir function remains largely unknown. We used a combination of imaging,single cell, and surgical approaches to identify a CD69+ CD4 T cell populationin both the mouse and human brain, distinct from circulating CD4 T cells. Thebrain-resident population was derived through in situ differentiation fromactivated circulatory cells and was shaped by self-antigen and the peripheralmicrobiome. Single-cell sequencing revealed that in the absence of murine CD4 Tcells, resident microglia remained suspended between the fetal and adultstates. This maturation defect resulted in excess immature neuronal synapsesand behavioral abnormalities. These results illuminate a role for CD4 T cellsin brain development and a potential interconnected dynamic between theevolution of the immunological and neurological systems. VIDEO ABSTRACT.

参考文献：Microglia Require CD4 T Cells toComplete the Fetal-to-Adult Transition. Cell. 2020 Aug 6;182(3):625-640.e24.

7.Nature—炎症可对抗自闭症？IL-17a改善自闭症小鼠的社交缺陷

Abstract

A subset of children with autismspectrum disorder appear to show an improvement in their behavioural symptomsduring the course of a fever, a sign of systemic inflammation1,2. Here weelucidate the molecular and neural mechanisms that underlie the beneficialeffects of inflammation on social behaviour deficits in mice. We compared anenvironmental model of neurodevelopmental disorders in which mice were exposedto maternal immune activation (MIA) during embryogenesis3,4 with mouse modelsthat are genetically deficient for contactin-associated protein-like 2(Cntnap2)5, fragile X mental retardation-1 (Fmr1)6 or Sh3 and multiple ankyrinrepeat domains 3 (Shank3)7. We establish that the social behaviour deficits inoffspring exposed to MIA can be temporarily rescued by the inflammatoryresponse elicited by the administration of lipopolysaccharide (LPS). Thisbehavioural rescue was accompanied by a reduction in neuronal activity in theprimary somatosensory cortex dysgranular zone (S1DZ), the hyperactivity ofwhich was previously implicated in the manifestation of behavioural phenotypesassociated with offspring exposed to MIA8. By contrast, we did not observe anLPS-induced rescue of social deficits in the monogenic models. We demonstratethat the differences in responsiveness to the LPS treatment between the MIA andthe monogenic models emerge from differences in the levels of cytokineproduction. LPS treatment in monogenic mutant mice did not induce amounts ofinterleukin-17a (IL-17a) comparable to those induced in MIA offspring;bypassing this difference by directly delivering IL-17a into S1DZ wassufficient to promote sociability in monogenic mutant mice as well as in MIAoffspring. Conversely, abrogating the expression of IL-17 receptor subunit a(IL-17Ra) in the neurons of the S1DZ eliminated the ability of LPS to reversethe sociability phenotypes in MIA offspring. Our data support a neuroimmune mechanismthat underlies neurodevelopmental disorders in which the production of IL-17aduring inflammation can ameliorate the expression of social behaviour deficitsby directly affecting neuronal activity in the central nervous system.

参考文献：IL-17a promotes sociability in mouse models of neurodevelopmental disorders. Nature. 2020 Jan;577(7789):249-253.

8. Nature—ALS/FTD致病基因C9orf72调节免疫新机制！！髓样细胞C9orf72抑制STING诱导的炎症

Abstract

Amyotrophic lateral sclerosis (ALS)and frontotemporal dementia (FTD) are neurodegenerative disorders that overlapin their clinical presentation, pathology and genetic origin. Autoimmunedisorders are also overrepresented in both ALS and FTD, but this remains an unexplainedepidemiologic observation1-3. Expansions of a hexanucleotide repeat (GGGGCC) inthe C9orf72 gene are the most common cause of familial ALS and FTD(C9-ALS/FTD), and lead to both repeat-containing RNA and dipeptideaccumulation, coupled with decreased C9orf72 protein expression in brain andperipheral blood cells4-6. Here we show in mice that loss of C9orf72 frommyeloid cells alone is sufficient to recapitulate the age-dependent lymphoidhypertrophy and autoinflammation seen in animals with a complete knockout ofC9orf72. Dendritic cells isolated from C9orf72-/- mice show marked earlyactivation of the type I interferon response, and C9orf72-/- myeloid cells areselectively hyperresponsive to activators of the stimulator of interferon genes(STING) protein-a key regulator of the innate immune response to cytosolic DNA.Degradation of STING through the autolysosomal pathway is diminished inC9orf72-/- myeloid cells, and blocking STING suppresses hyperactive type Iinterferon responses in C9orf72-/- immune cells as well as splenomegaly andinflammation in C9orf72-/- mice. Moreover, mice lacking one or both copies ofC9orf72 are more susceptible to experimental autoimmune encephalitis, mirroringthe susceptibility to autoimmune diseases seen in people with C9-ALS/FTD.Finally, blood-derived macrophages, whole blood and brain tissue from patientswith C9-ALS/FTD all show an elevated type I interferon signature compared withsamples from people with sporadic ALS/FTD; this increased interferon responsecan be suppressed with a STING inhibitor. Collectively, our results suggestthat patients with C9-ALS/FTD have an altered immunophenotype because theirreduced levels of C9orf72 cannot suppress the inflammation mediated by theinduction of type I interferons by STING.

参考文献：C9orf72 in myeloid cells suppressesSTING-induced inflammation. Nature. 2020 Sep;585(7823):96-101.

9. Cell—AD重磅新突破！！泛素连接酶COP1通过降解小胶质细胞中的c/EBPβ以抑制神经炎症

Abstract

Dysregulated microglia are intimatelyinvolved in neurodegeneration, including Alzheimer's disease (AD) pathogenesis,but the mechanisms controlling pathogenic microglial gene expression remainpoorly understood. The transcription factor CCAAT/enhancer binding protein beta(c/EBPβ) regulates pro-inflammatory genes in microglia and is upregulated inAD. We show expression of c/EBPβ in microglia is regulated post-translationallyby the ubiquitin ligase COP1 (also called RFWD2). In the absence of COP1,c/EBPβ accumulates rapidly and drives a potent pro-inflammatory andneurodegeneration-related gene program, evidenced by increased neurotoxicity inmicroglia-neuronal co-cultures. Antibody blocking studies reveal thatneurotoxicity is almost entirely attributable to complement. Remarkably, loss ofa single allele of Cebpb prevented the pro-inflammatory phenotype.COP1-deficient microglia markedly accelerated tau-mediated neurodegeneration ina mouse model where activated microglia play a deleterious role. Thus, COP1 isan important suppressor of pathogenic c/EBPβ-dependent gene expression programsin microglia.

参考文献：Ubiquitin Ligase COP1 SuppressesNeuroinflammation by Degrading c/EBPβ in Microglia. Cell. 2020 Sep3;182(5):1156-1169.e12.

10. Cell—神经免疫和炎症再获突破！！HLA-DR15肽段经B细胞提呈是MS中自身反应性T细胞活化的重要环节

Abstract

The HLA-DR15 haplotype is thestrongest genetic risk factor for multiple sclerosis (MS), but ourunderstanding of how it contributes to MS is limited. Because autoreactive CD4+T cells and B cells as antigen-presenting cells are involved in MSpathogenesis, we characterized the immunopeptidomes of the two HLA-DR15allomorphs DR2a and DR2b of human primary B cells and monocytes, thymus, and MSbrain tissue. Self-peptides from HLA-DR molecules, particularly from DR2a andDR2b themselves, are abundant on B cells and thymic antigen-presenting cells.Furthermore, we identified autoreactive CD4+ T cell clones that can cross-reactwith HLA-DR-derived self-peptides (HLA-DR-SPs), peptides from MS-associatedforeign agents (Epstein-Barr virus and Akkermansia muciniphila), andautoantigens presented by DR2a and DR2b. Thus, both HLA-DR15 allomorphs jointlyshape an autoreactive T cell repertoire by serving as antigen-presentingstructures and epitope sources and by presenting the same foreign peptides andautoantigens to autoreactive CD4+ T cells in MS.

参考文献：HLA-DR15 Molecules Jointly Shape anAutoreactive T Cell Repertoire in Multiple Sclerosis. Cell. 2020 Nov25;183(5):1264-1281.e20.

语音解读（具体见链接）

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

欢迎加入60个“神经科学临床和基础社群”

1、神经科学临床和基础主群（500人）已满；

2、神经科学临床和基础Alzheimer亚群；

3、神经科学临床和基础Parkinson亚群；

4、神经科学临床和基础cerebrovascular亚群；

5、神经科学临床和基础Depression亚群；

6、神经科学临床和基础Movement disorders亚群；

7、神经科学临床和基础Neuroimmunology亚群；

8、神经科学临床和基础Psychiatry亚群；

9、神经科学临床和基础Neuroimaging亚群；

10、神经科学临床和基础Neurogenetics亚群；

11、神经科学临床和基础Neurodegeneration亚群；

12、神经科学临床和基础Epilepsy亚群；

13、神经科学临床和基础Sleep亚群；

14、神经科学临床和基础Neural Development亚群；

15、神经科学临床和基础Electrophysiology亚群；

16、神经科学临床和基础Neural circuits亚群；

17、神经科学临床和基础神经调控和脑机接口亚群；

18、神经科学临床和基础人工智能亚群；

19、神经科学临床和基础重大疾病和疑难病亚群；

20、神经科学临床和基础衰老和永生亚群；

21、神经科学临床和基础周围神经病群；

22、神经科学临床和基础神经肌肉疾病群；

23、神经科学临床和基础视觉系统研究群；

24、神经科学临床和基础疼痛研究群；

25、神经科学临床和基础Emotion研究群；

26、神经科学临床和基础意识研究群；

27、神经科学临床和基础Learning & Memory亚群；

28、神经科学国自然基金申请交流群；

29、神经科学ALS/FTD交流群；

30、神经科学脑外伤和脊髓外伤研究群；

31、神经科学儿科神经病学交流群；

32、神经科学Autism & ADHD研究群；

33、神经科学大数据和组学研究群；

34、神经科学非编码RNA研究群；

35、神经科学schizophrenia研究群；

36、神经科学Non-human primate研究群；

37、神经科学神经损伤与修复研究群；

38、神经科学Epigenetics研究群；

39、神经科学神经介入和静脉溶栓亚群；

40、神经科学计算神经科学亚群；

41、神经科学基因治疗交流群；

42、神经科学细胞治疗交流群；

43、神经科学纳米药物治疗交流群；

44、神经科学中医药治疗交流群；

45、神经科学免疫调节治疗交流群；

46、神经科学类器官和类脑研究交流群；

47、神经科学语言研究交流群；

48、神经科学深度学习和神经网络交流群；

49、神经科学类神经元和类脑器件设计交流群；

50、神经科学半人半机器人交流群；

51、神经科学感染性疾病研究群；

52、神经科学神经系统肿瘤研究群；

53、神经科学星型和小胶质细胞研究群；

54、神经科学神经外科研究群;

55、神经科学系统论和复杂性研究交流群；

56、神经科学脑肠轴和Microbiota交流群；

57、神经科学虚拟现实、增强现实和混合现实交流群；

58、神经科学临床试验和流行病学研究交流群；

59、神经科学单细胞测序研究交流群；

60、神经科学蛋白质解析交流群。

如果想入群，请加我微信（qingyierjing），并回复要加入的群，我会将您拉入群中。

20个神经科学领域的突破可能获得诺贝尔奖

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。

16. 神经系统遗传病的机制研究及基因治疗。

17. 神经操纵和调控技术：光遗传技术、药物遗传技术、基因编辑技术、经颅磁刺激、深部脑刺激和电刺激等。

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。

临床医学前沿

专门解析最新的临床指南和循证医学证据 

神经科学临床和基础

专门解析最新的神经科学基础和临床研究进展 

临床科研那些事

专门解析最新的临床研究结果和观点