​ 1. Cell—可标记和操控被激活神经元的技术

摘要

Theability to record transient cellular events in the DNA or RNA of cells would enableprecise, large-scale analysis, selection, and reprogramming of heterogeneouscell populations. Here, we report a molecular technology for stable genetictagging of cells that exhibit activity-related increases in intracellularcalcium concentration (FLiCRE). We used FLiCRE to transcriptionally labelactivated neural ensembles in the nucleus accumbens of the mouse brain duringbrief stimulation of aversive inputs. Using single-cell RNA sequencing, wedetected FLiCRE transcripts among the endogenous transcriptome, providingsimultaneous readout of both cell-type and calcium activation history. Weidentified a cell type in the nucleus accumbens activated downstream oflong-range excitatory projections. Taking advantage of FLiCRE's modular design,we expressed an optogenetic channel selectively in this cell type and showedthat direct recruitment of this otherwise genetically inaccessible populationelicits behavioral aversion. The specificity and minute resolution of FLiCREenables molecularly informed characterization, manipulation, and reprogrammingof activated cellular ensembles.

参考文献：AMolecular Calcium Integrator Reveals a Striatal Cell Type Driving Aversion. Cell.2020 Dec 4;S0092-8674(20)31532-4.

2. Science—哈佛科学家开发Perturb-Seq技术大规模研究自闭症谱系病和神经发育迟滞相关风险基因的生物学效应

摘要

The numberof disease risk genes and loci identified through human genetic studies faroutstrips the capacity to systematically study their functions. We applied ascalable genetic screening approach, in vivo Perturb-Seq, to functionallyevaluate 35 autism spectrum disorder/neurodevelopmental delay (ASD/ND) de novoloss-of-function risk genes. Using CRISPR-Cas9, we introduced frameshiftmutations in these risk genes in pools, within the developing mouse brain inutero, followed by single-cell RNA-sequencing of perturbed cells in thepostnatal brain. We identified cell type-specific and evolutionarily conservedgene modules from both neuronal and glial cell classes. Recurrent gene modulesand cell types are affected across this cohort of perturbations, representingkey cellular effects across sets of ASD/ND risk genes. In vivo Perturb-Seqallows us to investigate how diverse mutations affect cell types and states inthe developing organism.

参考文献：In vivoPerturb-Seq reveals neuronal and glial abnormalities associated with autism riskgenes. Science. 2020 Nov 27;370(6520):eaaz6063.

3. Nature—单细胞膜片钳测序技术来了！！科学家实现对小鼠运动皮层神经元的形态学、电生理学和转录组学的精确分类和解析

摘要

Corticalneurons exhibit extreme diversity in gene expression as well as inmorphological and electrophysiological properties1,2. Most existing neuraltaxonomies are based on either transcriptomic3,4 or morpho-electric5,6criteria, as it has been technically challenging to study both aspects ofneuronal diversity in the same set of cells7. Here we used Patch-seq8 tocombine patch-clamp recording, biocytin staining, and single-cell RNAsequencing of more than 1,300 neurons in adult mouse primary motor cortex,providing a morpho-electric annotation of almost all transcriptomically definedneural cell types. We found that, although broad families of transcriptomictypes (those expressing Vip, Pvalb, Sst and so on) had distinct and essentiallynon-overlapping morpho-electric phenotypes, individual transcriptomic typeswithin the same family were not well separated in the morpho-electric space.Instead, there was a continuum of variability in morphology andelectrophysiology, with neighbouring transcriptomic cell types showing similarmorpho-electric features, often without clear boundaries between them. Ourresults suggest that neuronal types in the neocortex do not always formdiscrete entities. Instead, neurons form a hierarchy that consists of distinctnon-overlapping branches at the level of families, but can form continuous andcorrelated transcriptomic and morpho-electrical landscapes within families.

参考文献：Phenotypicvariation of transcriptomic cell types in mouse motor cortex. Nature. 2020 Nov12. doi: 10.1038/s41586-020-2907-3.

4. Nature—脑-肠轴和脑膜免疫学再突破！！科学家发现脑膜静脉窦周围存在肠道来源的IgA+浆细胞，其可抵抗血源性病菌侵袭入脑

摘要

Thecentral nervous system has historically been viewed as an immune-privilegedsite, but recent data have shown that the meninges-the membranes that surroundthe brain and spinal cord-contain a diverse population of immune cells1. Sofar, studies have focused on macrophages and T cells, but have not included adetailed analysis of meningeal humoral immunity. Here we show that, duringhomeostasis, the mouse and human meninges contain IgA-secreting plasma cells.These cells are positioned adjacent to dural venous sinuses: regions of slowblood flow with fenestrations that can potentially permit blood-borne pathogensto access the brain2. Peri-sinus IgA plasma cells increased with age andfollowing a breach of the intestinal barrier. Conversely, they were scarce ingerm-free mice, but their presence was restored by gut re-colonization. B cellreceptor sequencing confirmed that meningeal IgA+ cells originated in theintestine. Specific depletion of meningeal plasma cells or IgA deficiencyresulted in reduced fungal entrapment in the peri-sinus region and increasedspread into the brain following intravenous challenge, showing that meningealIgA is essential for defending the central nervous system at this vulnerablevenous barrier surface.

参考文献：Gut-educatedIgA plasma cells defend the meningeal venous sinuses. Nature. 2020Nov;587(7834):472-476.

5. Nature—经济学和神经科学的交叉再获突破！！科学家发现眶额皮层编码的主观价值和经济决策存在因果关联

摘要

In theeighteenth century, Daniel Bernoulli, Adam Smith and Jeremy Bentham proposedthat economic choices rely on the computation and comparison of subjectivevalues1. This hypothesis continues to inform modern economic theory2 andresearch in behavioural economics3, but behavioural measures are ultimately notsufficient to verify the proposal4. Consistent with the hypothesis, when agentsmake choices, neurons in the orbitofrontal cortex (OFC) encode the subjectivevalue of offered and chosen goods5. Value-encoding cells integrate multipledimensions6-9, variability in the activity of each cell group correlates withvariability in choices10,11 and the population dynamics suggests the formationof a decision12. However, it is unclear whether these neural processes arecausally related to choices. More generally, the evidence linking economicchoices to value signals in the brain13-15 remains correlational16. Here weshow that neuronal activity in the OFC is causal to economic choices. Weconducted two experiments using electrical stimulation in rhesus monkeys(Macaca mulatta). Low-current stimulation increased the subjective value ofindividual offers and thus predictably biased choices. Conversely, high-currentstimulation disrupted both the computation and the comparison of subjectivevalues, and thus increased choice variability. These results demonstrate acausal chain linking subjective values encoded in OFC to valuation and choice.

参考文献：Values encodedin orbitofrontal cortex are causally related to economic choices. Nature. 2020Dec;588(7838):450-453.

6. Nature—两种“渴觉”的神经细胞机制来了：Rxfp1+神经元调控“高渗透压性”渴觉，Pdyn+神经元调控“低容量性”渴觉

摘要

Fluidintake is an essential innate behaviour that is mainly caused by two distincttypes of thirst1-3. Increased blood osmolality induces osmotic thirst thatdrives animals to consume pure water. Conversely, the loss of body fluidinduces hypovolaemic thirst, in which animals seek both water and minerals(salts) to recover blood volume. Circumventricular organs in the laminaterminalis are critical sites for sensing both types of thirst-inducingstimulus4-6. However, how different thirst modalities are encoded in the brainremains unknown. Here we employed stimulus-to-cell-type mapping usingsingle-cell RNA sequencing to identify the cellular substrates that underliedistinct types of thirst. These studies revealed diverse types of excitatoryand inhibitory neuron in each circumventricular organ structure. We show thatunique combinations of these neuron types are activated under osmotic andhypovolaemic stresses. These results elucidate the cellular logic thatunderlies distinct thirst modalities. Furthermore, optogenetic gain of functionin thirst-modality-specific cell types recapitulated water-specific andnon-specific fluid appetite caused by the two distinct dipsogenic stimuli.Together, these results show that thirst is a multimodal physiological state,and that different thirst states are mediated by specific neuron types in themammalian brain.

参考文献：Thecellular basis of distinct thirst modalities. Nature. 2020Dec;588(7836):112-117.

7. Nature biotechnology—微创光遗传学来了！！Karl Deisseroth组开发不开颅深部脑光遗传学调控技术

摘要

Achievingtemporally precise, noninvasive control over specific neural cell types in thedeep brain would advance the study of nervous system function. Here we use thepotent channelrhodopsin ChRmine to achieve transcranial photoactivation ofdefined neural circuits, including midbrain and brainstem structures, atunprecedented depths of up to 7 mm with millisecond precision. Using systemicviral delivery of ChRmine, we demonstrate behavioral modulation withoutsurgery, enabling implant-free deep brain optogenetics.

参考文献：Deep brainoptogenetics without intracranial surgery. Nat Biotechnol. 2020 Oct 5. doi:10.1038/s41587-020-0679-9.

8. 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

摘要

Microglia,the brain's resident macrophages, help to regulate brain function by removingdying neurons, pruning non-functional synapses, and producing ligands thatsupport neuronal survival1. Here we show that microglia are also criticalmodulators of neuronal activity and associated behavioural responses in mice.Microglia respond to neuronal activation by suppressing neuronal activity, andablation of microglia amplifies and synchronizes the activity of neurons,leading to seizures. Suppression of neuronal activation by microglia occurs ina highly region-specific fashion and depends on the ability of microglia tosense and catabolize extracellular ATP, which is released upon neuronalactivation by neurons and astrocytes. ATP triggers the recruitment ofmicroglial protrusions and is converted by the microglial ATP/ADP hydrolysingectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, whichis expressed on microglia as well as other brain cells. Microglial sensing ofATP, the ensuing microglia-dependent production of adenosine, and theadenosine-mediated suppression of neuronal responses via the adenosine receptorA1R are essential for the regulation of neuronal activity and animal behaviour.Our findings suggest that this microglia-driven negative feedback mechanismoperates similarly to inhibitory neurons and is essential for protecting thebrain from excessive activation in health and disease.

参考文献：Negativefeedback control of neuronal activity by microglia. Nature. 2020Oct;586(7829):417-423.

9.Nature—为啥Fos蛋白是印记神经元的marker？原因之一：Fos神经元网络PV+和CCK+中间能神经元的双向抑制可塑性

摘要

Behaviouralexperiences activate the FOS transcription factor in sparse populations ofneurons that are critical for encoding and recalling specific events1-3.However, there is limited understanding of the mechanisms by which experiencedrives circuit reorganization to establish a network of Fos-activated cells. Itis also not known whether FOS is required in this process beyond serving as amarker of recent neural activity and, if so, which of its many gene targetsunderlie circuit reorganization. Here we demonstrate that when mice engage inspatial exploration of novel environments, perisomatic inhibition ofFos-activated hippocampal CA1 pyramidal neurons by parvalbumin-expressinginterneurons is enhanced, whereas perisomatic inhibition bycholecystokinin-expressing interneurons is weakened. This bidirectionalmodulation of inhibition is abolished when the function of the FOS transcriptionfactor complex is disrupted. Single-cell RNA-sequencing, ribosome-associatedmRNA profiling and chromatin analyses, combined with electrophysiology, revealthat FOS activates the transcription of Scg2, a gene that encodes multipledistinct neuropeptides, to coordinate these changes in inhibition. Asparvalbumin- and cholecystokinin-expressing interneurons mediate distinctfeatures of pyramidal cell activity4-6, the SCG2-dependent reorganization ofinhibitory synaptic input might be predicted to affect network function invivo. Consistent with this prediction, hippocampal gamma rhythms and pyramidalcell coupling to theta phase are significantly altered in the absence of Scg2.These findings reveal an instructive role for FOS and SCG2 in establishing anetwork of Fos-activated neurons via the rewiring of local inhibition to form aselectively modulated state. The opposing plasticity mechanisms acting ondistinct inhibitory pathways may support the consolidation of memories overtime.

参考文献：Bidirectionalperisomatic inhibitory plasticity of a Fos neuronal network. Nature. 2020 Dec9. doi: 10.1038/s41586-020-3031-0.

10. Nature—孕鼠肠道微生物调控小鼠胎儿神经发育，尤其是丘脑-皮层轴突发生

摘要

'Dysbiosis'of the maternal gut microbiome, in response to challenges such as infection1,altered diet2 and stress3 during pregnancy, has been increasingly associatedwith abnormalities in brain function and behaviour of the offspring4. However,it is unclear whether the maternal gut microbiome influences neurodevelopmentduring critical prenatal periods and in the absence of environmentalchallenges. Here we investigate how depletion and selective reconstitution ofthe maternal gut microbiome influences fetal neurodevelopment in mice. Embryosfrom antibiotic-treated and germ-free dams exhibited reduced brain expressionof genes related to axonogenesis, deficient thalamocortical axons and impairedoutgrowth of thalamic axons in response to cell-extrinsic factors. Gnotobioticcolonization of microbiome-depleted dams with a limited consortium of bacteriaprevented abnormalities in fetal brain gene expression and thalamocorticalaxonogenesis. Metabolomic profiling revealed that the maternal microbiomeregulates numerous small molecules in the maternal serum and the brains offetal offspring. Select microbiota-dependent metabolites promoted axonoutgrowth from fetal thalamic explants. Moreover, maternal supplementation withthese metabolites abrogated deficiencies in fetal thalamocortical axons.Manipulation of the maternal microbiome and microbial metabolites duringpregnancy yielded adult offspring with altered tactile sensitivity in twoaversive somatosensory behavioural tasks, but no overt differences in manyother sensorimotor behaviours. Together, our findings show that the maternalgut microbiome promotes fetal thalamocortical axonogenesis, probably throughsignalling by microbially modulated metabolites to neurons in the developingbrain.

参考文献：Thematernal microbiome modulates fetal neurodevelopment in mice. Nature. 2020Oct;586(7828):281-286.

 11. Science—“分子刀手术”来了！！日本科学家给突触做“搭桥手术”以修复神经系统疾病中的谷氨酸能神经环路

摘要

Neuronalsynapses undergo structural and functional changes throughout life, which areessential for nervous system physiology. However, these changes may alsoperturb the excitatory-inhibitory neurotransmission balance and triggerneuropsychiatric and neurological disorders. Molecular tools to restore thisbalance are highly desirable. Here, we designed and characterized CPTX, asynthetic synaptic organizer combining structural elements from cerebellin-1and neuronal pentraxin-1. CPTX can interact with presynaptic neurexins andpostsynaptic AMPA-type ionotropic glutamate receptors and induced the formationof excitatory synapses both in vitro and in vivo. CPTX restored synapticfunctions, motor coordination, spatial and contextual memories, and locomotionin mouse models for cerebellar ataxia, Alzheimer's disease, and spinal cordinjury, respectively. Thus, CPTX represents a prototype for structure-guidedbiologics that can efficiently repair or remodel neuronal circuits.

参考文献：Asynthetic synaptic organizer protein restores glutamatergic neuronal circuits. Science.2020 Aug 28;369(6507):eabb4853.

12. 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？

摘要

Sleep andwakefulness are homeostatically regulated by a variety of factors, includingadenosine. However, how neural activity underlying the sleep-wake cyclecontrols adenosine release in the brain remains unclear. Using a newlydeveloped genetically encoded adenosine sensor, we found an activity-dependentrapid increase in the concentration of extracellular adenosine in mouse basalforebrain (BF), a critical region controlling sleep and wakefulness. Althoughthe activity of both BF cholinergic and glutamatergic neurons correlated withchanges in the concentration of adenosine, optogenetic activation of theseneurons at physiological firing frequencies showed that glutamatergic neuronscontributed much more to the adenosine increase. Mice with selective ablationof BF glutamatergic neurons exhibited a reduced adenosine increase and impairedsleep homeostasis regulation. Thus, cell type-specific neural activity in theBF dynamically controls sleep homeostasis.

参考文献：Regulationof sleep homeostasis mediator adenosine by basal forebrain glutamatergicneurons. Science. 2020 Sep 4;369(6508):eabb0556.

13. Cell—重磅研究解码递推推理的神经生物学机制！！人类和小鼠推理的神经计算方式可能相似：海马前瞻性编码和海马涟漪很关键

摘要

Every daywe make decisions critical for adaptation and survival. We repeat actions withknown consequences. But we also draw on loosely related events to infer andimagine the outcome of entirely novel choices. These inferential decisions arethought to engage a number of brain regions; however, the underlying neuronalcomputation remains unknown. Here, we use a multi-day cross-species approach inhumans and mice to report the functional anatomy and neuronal computationunderlying inferential decisions. We show that during successful inference, themammalian brain uses a hippocampal prospective code to forecast temporallystructured learned associations. Moreover, during resting behavior,coactivation of hippocampal cells in sharp-wave/ripples represent inferredrelationships that include reward, thereby "joining-the-dots" betweenevents that have not been observed together but lead to profitable outcomes.Computing mnemonic links in this manner may provide an important mechanism tobuild a cognitive map that stretches beyond direct experience, thus supportingflexible behavior.

参考文献：NeuronalComputation Underlying Inferential Reasoning in Humans and Mice. Cell. 2020 Oct1;183(1):228-243.e21.

14. Science—外周-中枢交互再获突破（有视频）！！身体锻炼诱导肝脏产生Gpld1进而促进衰老大脑神经新生并改善认知功能

摘要

Reversingbrain aging may be possible through systemic interventions such as exercise. Wefound that administration of circulating blood factors in plasma from exercisedaged mice transferred the effects of exercise on adult neurogenesis andcognition to sedentary aged mice. Plasma concentrations ofglycosylphosphatidylinositol (GPI)-specific phospholipase D1 (Gpld1), aGPI-degrading enzyme derived from liver, were found to increase after exerciseand to correlate with improved cognitive function in aged mice, andconcentrations of Gpld1 in blood were increased in active, healthy elderlyhumans. Increasing systemic concentrations of Gpld1 in aged mice amelioratedage-related regenerative and cognitive impairments by altering signalingcascades downstream of GPI-anchored substrate cleavage. We thus identify aliver-to-brain axis by which blood factors can transfer the benefits ofexercise in old age.

参考文献：Bloodfactors transfer beneficial effects of exercise on neurogenesis and cognitionto the aged brain.

Science.2020 Jul 10;369(6500):167-173.

15. Nature—外周中枢交互再获突破！！生理性血-脑间蛋白转运随着衰老过程中BBB跨细胞运输功能的下降而下降

摘要

Thevascular interface of the brain, known as the blood-brain barrier (BBB), isunderstood to maintain brain function in part via its low transcellularpermeability1-3. Yet, recent studies have demonstrated that brain ageing issensitive to circulatory proteins4,5. Thus, it is unclear whether permeabilityto individually injected exogenous tracers-as is standard in BBB studies-fullyrepresents blood-to-brain transport. Here we label hundreds of proteinsconstituting the mouse blood plasma proteome, and upon their systemicadministration, study the BBB with its physiological ligand. We find thatplasma proteins readily permeate the healthy brain parenchyma, with transportmaintained by BBB-specific transcriptional programmes. Unlike IgG antibody,plasma protein uptake diminishes in the aged brain, driven by an age-relatedshift in transport from ligand-specific receptor-mediated to non-specificcaveolar transcytosis. This age-related shift occurs alongside a specific lossof pericyte coverage. Pharmacological inhibition of the age-upregulatedphosphatase ALPL, a predicted negative regulator of transport, enhances brainuptake of therapeutically relevant transferrin, transferrin receptor antibodyand plasma. These findings reveal the extent of physiological proteintranscytosis to the healthy brain, a mechanism of widespread BBB dysfunctionwith age and a strategy for enhanced drug delivery.

参考文献：Physiologicalblood-brain transport is impaired with age by a shift in transcytosis. Nature.2020 Jul;583(7816):425-430.

16. Nature—神经生物大分子结构解析再获突破！！科学家揭示代谢型GABA受体激活时的构象改变基础

摘要

Stimulationof the metabotropic GABAB receptor by γ-aminobutyric acid (GABA) results inprolonged inhibition of neurotransmission, which is central to brainphysiology1. GABAB belongs to family C of the G-protein-coupled receptors,which operate as dimers to transform synaptic neurotransmitter signals into acellular response through the binding and activation of heterotrimeric Gproteins2,3. However, GABAB is unique in its function as an obligateheterodimer in which agonist binding and G-protein activation take place ondistinct subunits4,5. Here we present cryo-electron microscopy structures ofheterodimeric and homodimeric full-length GABAB receptors. Complemented bycellular signalling assays and atomistic simulations, these structures revealthat extracellular loop 2 (ECL2) of GABAB has an essential role in relayingstructural transitions by ordering the linker that connects the extracellularligand-binding domain to the transmembrane region. Furthermore, the ECL2 ofeach of the subunits of GABAB caps and interacts with the hydrophilic head of aphospholipid that occupies the extracellular half of the transmembrane domain,thereby providing a potentially crucial link between ligand binding and thereceptor core that engages G proteins. These results provide a startingframework through which to decipher the mechanistic modes of signaltransduction mediated by GABAB dimers, and have important implications forrational drug design that targets these receptors.

参考文献：Structuresof metabotropic GABA B receptor. Nature. 2020 Aug;584(7820):310-314.

 17. Nature—肠道细菌竟产生神经递质！！肠道细菌产生的神经递质调控宿主嗅觉反射行为

摘要

Animalscoexist in commensal, pathogenic or mutualistic relationships with complexcommunities of diverse organisms, including microorganisms1. Some bacteriaproduce bioactive neurotransmitters that have previously been proposed tomodulate nervous system activity and behaviours of their hosts2,3. However, themechanistic basis of this microbiota-brain signalling and its physiological relevanceare largely unknown. Here we show that in Caenorhabditis elegans, theneuromodulator tyramine produced by commensal Providencia bacteria, whichcolonize the gut, bypasses the requirement for host tyramine biosynthesis andmanipulates a host sensory decision. Bacterially produced tyramine is probablyconverted to octopamine by the host tyramine β-hydroxylase enzyme. Octopamine,in turn, targets the OCTR-1 octopamine receptor on ASH nociceptive neurons tomodulate an aversive olfactory response. We identify the genes that arerequired for tyramine biosynthesis in Providencia, and show that these genesare necessary for the modulation of host behaviour. We further find that C.elegans colonized by Providencia preferentially select these bacteria in foodchoice assays, and that this selection bias requires bacterially producedtyramine and host octopamine signalling. Our results demonstrate that aneurotransmitter produced by gut bacteria mimics the functions of the cognatehost molecule to override host control of a sensory decision, and therebypromotes fitness of both the host and the microorganism.

参考文献：Aneurotransmitter produced by gut bacteria modulates host sensory behaviour. Nature.2020 Jul;583(7816):415-420.

18. 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

摘要

Neuroprotectantstrategies that have worked in rodent models of stroke have failed to provideprotection in clinical trials. Here we show that the opposite circadian cyclesin nocturnal rodents versus diurnal humans1,2 may contribute to this failure intranslation. We tested three independent neuroprotective approaches-normobarichyperoxia, the free radical scavenger α-phenyl-butyl-tert-nitrone (αPBN), andthe N-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：Potentialcircadian effects on translational failure for neuroprotection. Nature. 2020Jun;582(7812):395-398.

 19. Nature—神经-脾脏免疫轴再获突破！！大脑CeA和PVN通过脾脏神经丛调控脾脏B细胞免疫反应

摘要

It hasbeen speculated that brain activities might directly control adaptive immuneresponses in lymphoid organs, although there is little evidence for this. Herewe show that splenic denervation in mice specifically compromises the formationof plasma cells during a T cell-dependent but not T cell-independent immuneresponse. Splenic nerve activity enhances plasma cell production in a mannerthat requires B-cell responsiveness to acetylcholine mediated by the α9nicotinic receptor, and T cells that express choline acetyl transferase1,2probably act as a relay between the noradrenergic nerve andacetylcholine-responding B cells. We show that neurons in the central nucleusof the amygdala (CeA) and the paraventricular nucleus (PVN) that expresscorticotropin-releasing hormone (CRH) are connected to the splenic nerve;ablation or pharmacogenetic inhibition of these neurons reduces plasma cellformation, whereas pharmacogenetic activation of these neurons increases plasmacell abundance after immunization. In a newly developed behaviour regimen, miceare made to stand on an elevated platform, leading to activation of CeA and PVNCRH neurons and increased plasma cell formation. In immunized mice, theelevated platform regimen induces an increase in antigen-specific IgGantibodies in a manner that depends on CRH neurons in the CeA and PVN, anintact splenic nerve, and B cell expression of the α9 acetylcholine receptor.By identifying a specific brain-spleen neural connection that autonomicallyenhances humoral responses and demonstrating immune stimulation by a bodilybehaviour, our study reveals brain control of adaptive immunity and suggeststhe possibility to enhance immunocompetency by behavioural intervention.

参考文献：Braincontrol of humoral immune responses amenable to behavioural modulation. Nature.2020 May;581(7807):204-208.

20. Cell—这个小鼠脑模板用途很大！！Allen脑研究所发布高分辨率标准小鼠脑模板

摘要

Recentlarge-scale collaborations are generating major surveys of cell types andconnections in the mouse brain, collecting large amounts of data acrossmodalities, spatial scales, and brain areas. Successful integration of thesedata requires a standard 3D reference atlas. Here, we present the Allen MouseBrain Common Coordinate Framework (CCFv3) as such a resource. We constructed anaverage template brain at 10 μm voxel resolution by interpolating highresolution in-plane serial two-photon tomography images with 100 μm z-samplingfrom 1,675 young adult C57BL/6J mice. Then, using multimodal reference data, weparcellated the entire brain directly in 3D, labeling every voxel with a brainstructure spanning 43 isocortical areas and their layers, 329 subcortical graymatter structures, 81 fiber tracts, and 8 ventricular structures. CCFv3 can beused to analyze, visualize, and integrate multimodal and multiscale datasets in3D and is openly accessible (https://atlas.brain-map.org/).

参考文献：The AllenMouse Brain Common Coordinate Framework: A 3D Reference Atlas. Cell. 2020 May14;181(4):936-953.e20.

21. Cell—如何让无感瘫痪肢体既恢复运动功能又恢复触觉？科学家通过使用多路解码脑机接口恢复脊髓完全损伤患者的触觉和运动功能

摘要

Paralyzedmuscles can be reanimated following spinal cord injury (SCI) using abrain-computer interface (BCI) to enhance motor function alone. Importantly,the sense of touch is a key component of motor function. Here, we demonstratethat a human participant with a clinically complete SCI can use a BCI tosimultaneously reanimate both motor function and the sense of touch, leveragingresidual touch signaling from his own hand. In the primary motor cortex (M1),residual subperceptual hand touch signals are simultaneously demultiplexed fromongoing efferent motor intention, enabling intracortically controlledclosed-loop sensory feedback. Using the closed-loop demultiplexing BCI almostfully restored the ability to detect object touch and significantly improvedseveral sensorimotor functions. Afferent grip-intensity levels are also decodedfrom M1, enabling grip reanimation regulated by touch signaling. These resultsdemonstrate that subperceptual neural signals can be decoded from the cortexand transformed into conscious perception, significantly augmenting function.

参考文献：Restoringthe Sense of Touch Using a Sensorimotor Demultiplexing Neural Interface. Cell.2020 May 14;181(4):763-773.e12.

22. Cell—新研究改变传统神经解剖学观念！！！运动前皮层的把手区神经元以组合的方式表征整个身体及其运动模式

摘要

Decadesafter the motor homunculus was first proposed, it is still unknown howdifferent body parts are intermixed and interrelated in human motor corticalareas at single-neuron resolution. Using multi-unit recordings, we studied howface, head, arm, and leg movements are represented in the hand knob area ofpremotor cortex (precentral gyrus) in people with tetraplegia. Contrary totraditional expectations, we found strong representation of all movements and apartially "compositional" neural code that linked together all fourlimbs. The code consisted of (1) a limb-coding component representing the limbto be moved and (2) a movement-coding component where analogous movements fromeach limb (e.g., hand grasp and toe curl) were represented similarly.Compositional coding might facilitate skill transfer across limbs, and itprovides a useful framework for thinking about how the motor system constructsmovement. Finally, we leveraged these results to create a whole-bodyintracortical brain-computer interface that spreads targets across all limbs.

参考文献：Hand KnobArea of Premotor Cortex Represents the Whole Body in a Compositional Way. Cell.2020 Apr 16;181(2):396-409.e26.

23. Cell—近乎完美的工作！！海马齿状回两个不同的印记细胞亚群分别调控恐惧记忆的归纳和辨别

摘要

Memoriesare believed to be encoded by sparse ensembles of neurons in the brain.However, it remains unclear whether there is functional heterogeneity withinindividual memory engrams, i.e., if separate neuronal subpopulations encodedistinct aspects of the memory and drive memory expression differently. Here,we show that contextual fear memory engrams in the mouse dentate gyrus containfunctionally distinct neuronal ensembles, genetically defined by the Fos- orNpas4-dependent transcriptional pathways. The Fos-dependent ensemble promotesmemory generalization and receives enhanced excitatory synaptic inputs from themedial entorhinal cortex, which we find itself also mediates generalization.The Npas4-dependent ensemble promotes memory discrimination and receivesenhanced inhibitory drive from local cholecystokinin-expressing interneurons,the activity of which is required for discrimination. Our study provides causalevidence for functional heterogeneity within the memory engram and revealssynaptic and circuit mechanisms used by each ensemble to regulate the memorydiscrimination-generalization balance.

参考文献：FunctionallyDistinct Neuronal Ensembles within the Memory Engram. Cell. 2020 Apr16;181(2):410-423.e17.

24. 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

摘要

Thearousal state of the brain covaries with the motor state of the animal. How thesestate changes are coordinated remains unclear. We discovered that sleep-wakebrain states and motor behaviors are coregulated by shared neurons in thesubstantia nigra pars reticulata (SNr). Analysis of mouse home-cage behavioridentified four states with different levels of brain arousal and motoractivity: locomotion, nonlocomotor movement, quiet wakefulness, and sleep;transitions occurred not randomly but primarily between neighboring states. Theglutamic acid decarboxylase 2 but not the parvalbumin subset of SNrγ-aminobutyric acid (GABA)-releasing (GABAergic) neurons was preferentiallyactive in states of low motor activity and arousal. Their activation orinactivation biased the direction of natural behavioral transitions andpromoted or suppressed sleep, respectively. These GABAergic neurons integratewide-ranging inputs and innervate multiple arousal-promoting and motor-controlcircuits through extensive collateral projections.

参考文献：A commonhub for sleep and motor control in the substantia nigra. Science. 2020 Jan24;367(6476):440-445.

25. Science—改写医学教科书的重磅突破！！脑梗死脑水肿是由脑脊液的渗入引起的，而非来自血管渗入

摘要

Strokeaffects millions each year. Poststroke brain edema predicts the severity ofeventual stroke damage, yet our concept of how edema develops is incomplete andtreatment options remain limited. In early stages, fluid accumulation occursowing to a net gain of ions, widely thought to enter from the vascularcompartment. Here, we used magnetic resonance imaging, radiolabeled tracers,and multiphoton imaging in rodents to show instead that cerebrospinal fluidsurrounding the brain enters the tissue within minutes of an ischemic insultalong perivascular flow channels. This process was initiated by ischemicspreading depolarizations along with subsequent vasoconstriction, which in turnenlarged the perivascular spaces and doubled glymphatic inflow speeds. Thus,our understanding of poststroke edema needs to be revised, and these findingscould provide a conceptual basis for development of alternative treatmentstrategies.

参考文献：Cerebrospinalfluid influx drives acute ischemic tissue swelling. Science. 2020 Mar13;367(6483):eaax7171.

26. Nature—你猜小鼠对糖的偏好是决定于舌头，还是胃？研究发现小鼠肠-脑轴介导了糖偏好

摘要

The tasteof sugar is one of the most basic sensory percepts for humans and otheranimals. Animals can develop a strong preference for sugar even if they lacksweet taste receptors, indicating a mechanism independent of taste1-3. Here weexamined the neural basis for sugar preference and demonstrate that apopulation of neurons in the vagal ganglia and brainstem are activated via thegut-brain axis to create preference for sugar. These neurons are stimulated inresponse to sugar but not artificial sweeteners, and are activated by directdelivery of sugar to the gut. Using functional imaging we monitored activity ofthe gut-brain axis, and identified the vagal neurons activated by intestinaldelivery of glucose. Next, we engineered mice in which synaptic activity inthis gut-to-brain circuit was genetically silenced, and prevented thedevelopment of behavioural preference for sugar. Moreover, we show thatco-opting this circuit by chemogenetic activation can create preferences tootherwise less-preferred stimuli. Together, these findings reveal agut-to-brain post-ingestive sugar-sensing pathway critical for the developmentof sugar preference. In addition, they explain the neural basis for differencesin the behavioural effects of sweeteners versus sugar, and uncover an essentialcircuit underlying the highly appetitive effects of sugar.

参考文献：Thegut-brain axis mediates sugar preference. Nature. 2020 Apr;580(7804):511-516.

27.  Science—4千万盲人的希望！！科学家通过多通道神经假体刺激猴视觉皮层可实现形状感知

摘要

Blindnessaffects 40 million people across the world. A neuroprosthesis could one dayrestore functional vision in the blind. We implanted a 1024-channel prosthesisin areas V1 and V4 of the visual cortex of monkeys and used electricalstimulation to elicit percepts of dots of light (called phosphenes) on hundredsof electrodes, the locations of which matched the receptive fields of thestimulated neurons. Activity in area V4 predicted phosphene percepts that wereelicited in V1. We simultaneously stimulated multiple electrodes to impose visiblepatterns composed of a number of phosphenes. The monkeys immediately recognizedthem as simple shapes, motions, or letters. These results demonstrate thepotential of electrical stimulation to restore functional, life-enhancingvision in the blind.

参考文献：Shapeperception via a high-channel-count neuroprosthesis in monkey visual cortex. Science.2020 Dec 4;370(6521):1191-1196.

28. Nature—哈佛大学研究团队揭示脊髓中存在调控“情感性”触觉和痛觉的平行上行通路

摘要

Theanterolateral pathway consists of ascending spinal tracts that convey pain,temperature and touch information from the spinal cord to the brain1-4.Projection neurons of the anterolateral pathway are attractive therapeutictargets for pain treatment because nociceptive signals emanating from theperiphery are channelled through these spinal projection neurons en route tothe brain. However, the organizational logic of the anterolateral pathwayremains poorly understood. Here we show that two populations of projectionneurons that express the structurally related G-protein-coupled receptors(GPCRs) TACR1 and GPR83 form parallel ascending circuit modules that cooperateto convey thermal, tactile and noxious cutaneous signals from the spinal cordto the lateral parabrachial nucleus of the pons. Within this nucleus, axons ofspinoparabrachial (SPB) neurons that express Tacr1 or Gpr83 innervate distinctsets of subnuclei, and strong optogenetic stimulation of the axon terminalsinduces distinct escape behaviours and autonomic responses. Moreover, SPBneurons that express Gpr83 are highly sensitive to cutaneous mechanical stimuliand receive strong synaptic inputs from both high- and low-threshold primarymechanosensory neurons. Notably, the valence associated with activation of SPBneurons that express Gpr83 can be either positive or negative, depending onstimulus intensity. These findings reveal anatomically, physiologically andfunctionally distinct subdivisions of the SPB tract that underlie affectiveaspects of touch and pain.

参考文献：Parallelascending spinal pathways for affective touch and pain. Nature. 2020Nov;587(7833):258-263.

29. Nature—重磅！！研究发现caveolae是介导神经血管偶联的关键小动脉内皮细胞结构

摘要

Properbrain function depends on neurovascular coupling: neural activity rapidlyincreases local blood flow to meet moment-to-moment changes in regional brainenergy demand1. Neurovascular coupling is the basis for functional brainimaging2, and impaired neurovascular coupling is implicated inneurodegeneration1. The underlying molecular and cellular mechanisms ofneurovascular coupling remain poorly understood. The conventional view is thatneurons or astrocytes release vasodilatory factors that act directly on smoothmuscle cells (SMCs) to induce arterial dilation and increase local blood flow1.Here, using two-photon microscopy to image neural activity and vasculardynamics simultaneously in the barrel cortex of awake mice under whiskerstimulation, we found that arteriolar endothelial cells (aECs) have an activerole in mediating neurovascular coupling. We found that aECs, unlike othervascular segments of endothelial cells in the central nervous system, haveabundant caveolae. Acute genetic perturbations that eliminated caveolae inaECs, but not in neighbouring SMCs, impaired neurovascular coupling. Notably,caveolae function in aECs is independent of the endothelial NO synthase(eNOS)-mediated NO pathway. Ablation of both caveolae and eNOS completely abolishedneurovascular coupling, whereas the single mutants exhibited partialimpairment, revealing that the caveolae-mediated pathway in aECs is a majorcontributor to neurovascular coupling. Our findings indicate that vasodilationis largely mediated by endothelial cells that actively relay signals from thecentral nervous system to SMCs via a caveolae-dependent pathway.

参考文献：Caveolaein CNS arterioles mediate neurovascular coupling. Nature. 2020Mar;579(7797):106-110.

30. 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

摘要

Microgliaare the main immune cells in the brain and have 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 have a 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. Braininjury-induced changes at somatic junctions triggered P2Y12 receptor-dependent microglialneuroprotection, regulating neuronal calcium load and functional connectivity.Thus, microglial processes at these junctions could potentially monitor andprotect neuronal functions.

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

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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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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。

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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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