​1.Science—这是否算新的synapse？小胶质细胞通过与神经元胞体形成嘌呤能连接以监测和保护神经元功能

Abstract

Microglia are the main immune cellsin the brain and have roles in brain homeostasis and neurological diseases.Mechanisms underlying microglia-neuron communication remain elusive. Here, weidentified an interaction site between neuronal cell bodies and microglialprocesses in mouse and human brain. Somatic microglia-neuron junctions have a specializednanoarchitecture optimized for purinergic signaling. Activity of neuronalmitochondria was linked with microglial junction formation, which was inducedrapidly in response to neuronal activation and blocked by inhibition of P2Y12receptors. Brain injury-induced changes at somatic junctions triggered P2Y12receptor-dependent microglial neuroprotection, regulating neuronal calcium loadand functional connectivity. Thus, microglial processes at these junctionscould potentially monitor and protect neuronal functions.

参考文献：Microgliamonitor and protect neuronal function through specialized somatic purinergicjunctions.Science. 2020 Jan 31;367(6477):528-537.

2.Nature—小胶质细胞促进损伤脊髓“无瘢痕”修复！！小胶质细胞在新生鼠脊髓损伤后无瘢痕修复过程中扮演关键角色

Abstract

Spinal cord injury in mammals isthought to trigger scar formation with little regeneration of axons1-4. Here weshow that a crush injury to the spinal cord in neonatal mice leads to scar-freehealing that permits the growth of long projecting axons through the lesion.Depletion of microglia in neonatal mice disrupts this healing process andstalls the regrowth of axons, suggesting that microglia are critical fororchestrating the injury response. Using single-cell RNA sequencing andfunctional analyses, we find that neonatal microglia are transiently activatedand have at least two key roles in scar-free healing. First, they transientlysecrete fibronectin and its binding proteins to form bridges of extracellularmatrix that ligate the severed ends of the spinal cord. Second, neonatal-butnot adult-microglia express several extracellular and intracellular peptidaseinhibitors, as well as other molecules that are involved in resolvinginflammation. We transplanted either neonatal microglia or adult microgliatreated with peptidase inhibitors into spinal cord lesions of adult mice, andfound that both types of microglia significantly improved healing and axonregrowth. Together, our results reveal the cellular and molecular basis of thenearly complete recovery of neonatal mice after spinal cord injury, and suggeststrategies that could be used to facilitate scar-free healing in the adultmammalian nervous system.

参考文献：Microglia-organized scar-free spinalcord repair in neonatal mice. Nature. 2020 Nov;587(7835):613-618.

3.Nature—重磅！！小胶质细胞反馈抑制神经元活动，消除小胶质细胞促进癫痫发生，ATP-腺苷-A1R通路介导其反馈抑制作用

Abstract

Microglia, the brain's residentmacrophages, help to regulate brain function by removing dying neurons, pruningnon-functional synapses, and producing ligands that support neuronal survival1.Here we show that microglia are also critical modulators of neuronal activityand associated behavioural responses in mice. Microglia respond to neuronalactivation by suppressing neuronal activity, and ablation of microgliaamplifies and synchronizes the activity of neurons, leading to seizures.Suppression of neuronal activation by microglia occurs in a highly region-specificfashion and depends on the ability of microglia to sense and catabolizeextracellular ATP, which is released upon neuronal activation by neurons andastrocytes. ATP triggers the recruitment of microglial protrusions and isconverted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMPis then converted into adenosine by CD73, which is expressed on microglia aswell as other brain cells. Microglial sensing of ATP, the ensuingmicroglia-dependent production of adenosine, and the adenosine-mediatedsuppression of neuronal responses via the adenosine receptor A1R are essentialfor the regulation of neuronal activity and animal behaviour. Our findingssuggest that this microglia-driven negative feedback mechanism operatessimilarly to inhibitory neurons and is essential for protecting the brain fromexcessive activation in health and disease.

参考文献：Negative feedback control of neuronalactivity by microglia. Nature. 2020 Oct;586(7829):417-423.

4.Nature—神经变性研究重磅！！Progranulin缺陷诱导神经毒性小胶质细胞引发TDP-43蛋白病

Abstract

Aberrant aggregation of theRNA-binding protein TDP-43 in neurons is a hallmark of frontotemporal lobardegeneration caused by haploinsufficiency in the gene encoding progranulin1,2.However, the mechanism leading to TDP-43 proteinopathy remains unclear. Here weuse single-nucleus RNA sequencing to show that progranulin deficiency promotesmicroglial transition from a homeostatic to a disease-specific state thatcauses endolysosomal dysfunction and neurodegeneration in mice. These defectspersist even when Grn-/- microglia are cultured ex vivo. In addition,single-nucleus RNA sequencing reveals selective loss of excitatory neurons atdisease end-stage, which is characterized by prominent nuclear and cytoplasmicTDP-43 granules and nuclear pore defects. Remarkably, conditioned media fromGrn-/- microglia are sufficient to promote TDP-43 granule formation, nuclearpore defects and cell death in excitatory neurons via the complement activationpathway. Consistent with these results, deletion of the genes encoding C1qa andC3 mitigates microglial toxicity and rescues TDP-43 proteinopathy andneurodegeneration. These results uncover previously unappreciated contributionsof chronic microglial toxicity to TDP-43 proteinopathy duringneurodegeneration.

参考文献：Neurotoxic microglia promote TDP-43proteinopathy in progranulin deficiency. Nature. 2020 Dec;588(7838):459-465.

5.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, lossof a 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.

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.Cell—小胶质细胞促进突触可塑性！！海马神经元产生的IL-33通过诱导小胶质细胞重构细胞外基质以促进突触可塑性

Abstract

Synapse remodeling is essential toencode experiences into neuronal circuits. Here, we define a molecularinteraction between neurons and microglia that drives experience-dependentsynapse remodeling in the hippocampus. We find that the cytokine interleukin-33(IL-33) is expressed by adult hippocampal neurons in an experience-dependentmanner and defines a neuronal subset primed for synaptic plasticity. Loss ofneuronal IL-33 or the microglial IL-33 receptor leads to impaired spineplasticity, reduced newborn neuron integration, and diminished precision ofremote fear memories. Memory precision and neuronal IL-33 are decreased in agedmice, and IL-33 gain of function mitigates age-related decreases in spineplasticity. We find that neuronal IL-33 instructs microglial engulfment of theextracellular matrix (ECM) and that its loss leads to impaired ECM engulfmentand a concomitant accumulation of ECM proteins in contact with synapses. Thesedata define a cellular mechanism through which microglia regulateexperience-dependent synapse remodeling and promote memory consolidation.

参考文献：Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity. Cell. 2020 Jul23;182(2):388-403.e15.

8.Cell—研究发现大脑中的两类巨噬细胞具有不同的发育起源

Abstract

Central nervous system (CNS)macrophages comprise microglia and border-associated macrophages (BAMs)residing in the meninges, the choroid plexus, and the perivascular spaces. MostCNS macrophages emerge during development, with the exception of choroid plexusand dural macrophages, which are replaced by monocytes in adulthood. Whethermicroglia and BAMs share a developmental program or arise from separatelineages remains unknown. Here, we identified two phenotypically,transcriptionally, and locally distinct brain macrophages throughoutdevelopment, giving rise to either microglia or BAMs. Two macrophagepopulations were already present in the yolk sac suggesting an earlysegregation. Fate-mapping models revealed that BAMs mostly derived from earlyerythro-myeloid progenitors in the yolk sac. The development of microglia wasdependent on TGF-β, whereas the genesis of BAMs occurred independently of thiscytokine. Collectively, our data show that developing parenchymal andnon-parenchymal brain macrophages are separate entities in terms of ontogeny,gene signature, and requirement for TGF-β.

参考文献：Early Fate Defines Microglia and Non-parenchymal Brain Macrophage Development. Cell. 2020 Apr30;181(3):557-573.e18.

9.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 thesecells contribute to cognitive deficits and secondary inflammatory pathologyremains poorly understood. Here, we show that removal of microglia from themouse brain has little effect on the outcome of TBI, but inducing the turnoverof these cells 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 neuroprotective andpro-regenerative phenotype that can aid repair and alleviate the cognitivedeficits arising from brain injury.

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

10.Science—小胶质细胞通过补体系统消除突触以介导遗忘？对于Fig4的矛盾，MEM不是促进记忆以治疗老年性痴呆的药物吗？

Abstract

Synapses between engram cells arebelieved to be substrates for memory storage, and the weakening or loss ofthese synapses leads to the forgetting of related memories. We found engulfmentof synaptic components by microglia in the hippocampi of healthy adult mice.Depletion of microglia or inhibition of microglial phagocytosis preventedforgetting and the dissociation of engram cells. By introducing CD55 to inhibit complement pathways, specifically in engram cells, we further demonstrated that microglia regulated forgetting in a complement- and activity-dependent manner.Additionally, microglia were involved in both neurogenesis-related andneurogenesis-unrelated memory degradation. Together, our findings revealedcomplement-dependent synapse elimination by microglia as a mechanism underlyingthe forgetting of remote memories.

参考文献：Microglia mediate forgetting via complement-dependent synaptic elimination. Science. 2020 Feb7;367(6478):688-694.

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2020年十大研究进展名录

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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

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5. 年终盘点：2019年神经科学领域十大基础研究进展

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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

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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

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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

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