神经胶质细胞与神经突触的相互作用——从星形胶质细胞到小胶质细胞和少突胶质细胞谱系细胞

哺乳动物的大脑是一个由神经元、神经胶质细胞和超过1×1014个突触组成的复杂的器官。神经元是一组异质的电活性细胞,形成大脑复杂电回路的框架。然而,神经胶质细胞约占哺乳动物中枢神经系统(CNS)所有神经细胞的一半,主要分为星形胶质细胞、小胶质细胞、少突胶质细胞(OL)和少突胶质细胞前体细胞(OPC);神经胶质细胞主要为大脑中的神经元提供营养支持。近二十年来,“三联突触”的概念引起了广泛关注,该概念强调星形胶质细胞是突触的组成部分,并在接受神经元信号后以反馈方式调节神经元活动。自此,神经胶质细胞的突触调节得到了广泛的研究和实质性的修改。本综述总结了关于神经胶质细胞(特别是小胶质细胞和OL谱系细胞)如何影响和重塑大脑突触结构和功能的最新重要发现。我们的综述强调了神经元-神经胶质细胞串扰的细胞和分子方面,并提供了有关神经元和神经胶质细胞之间的异常突触通讯如何导致神经病理学的额外信息。

Lysosomal Exocytosis in Schwann Cells Contributes to Axon Remyelination

髓鞘形成是一个包括协同性的胞吐、内吞、mRNA转运和细胞骨架的动态变化的复杂过程。尽管髓鞘的异常在溶酶体贮积症中很常见,但对溶酶体在髓鞘形成和维持中所扮演的角色仍不清楚。本文发现Schwann细胞中的晚期内涵体/溶酶体包含大量的髓鞘蛋白P0,含量占超过一半的外周神经系统中的致密髓鞘的总蛋白并且在不同的刺激下表现出Ca2+依赖性的胞吐作用。Rab27a(一种将分泌溶酶体运输至细胞膜的小GTP酶)下调,极大地阻碍了Schwann细胞中的溶酶体胞吐作用,减少了再生坐骨神经的髓鞘形成。这些发现强调了Schwann细胞中溶酶体的新角色,提示调节Schwann细胞中的溶酶体胞吐作用在外周神经系统中有很重要的生理和病理意义。

Frontiers and future perspectives of neuroimmunology

Neuroimmunology is an interdisciplinary branch of biomedical science that emerges from the intersection of studies on the nervous system and the immune system.The complex interplay between the two systems has long been recognized.Research efforts directed at the underlying functional interface and associated pathophysiology,however,have garnered attention only in recent decades.In this narrative review,we highlight significant advances in research on neuroimmune interplay and modulation.A particular focus is on early-and middle-career neuroimmunologists in China and their achievements in frontier areas of"neuroimmune interface","neuro-endocrine-immune network and modulation","neuroimmune interactions in diseases","meningeal lymphatic and glymphatic systems in health and disease",and"tools and methodologies in neuroimmunology research".Key scientific questions and future directions for potential breakthroughs in neuroimmunology research are proposed.

Temporal-spatial Generation of Astrocytes in the Developing Diencephalon

tAstrocytes are the largest glial population in the mammalian brain.However,we have a minimal understanding of astrocyte development,especially fate specification in different regions of the brain.Through lineage tracing of the progenitors of the third ventricle(3V)wall via in-utero electroporation in the embryonic mouse brain,we show the fate specification and migration pattern of astrocytes derived from radial glia along the 3V wall.Unexpectedly,radial glia located in different regions along the 3V wall of the diencephalon produce distinct cell types:radial glia in the upper region produce astrocytes and those in the lower region produce neurons in the diencephalon.With genetic fate mapping analysis,we reveal that the first population of astrocytes appears along the zona incerta in the diencephalon.Astrogenesis occurs at an early time point in the dorsal region relative to that in the ventral region of the developing diencephalon.With transcriptomic analysis of the region-specific 3V wall and lateral ventricle(LV)wall,we identified cohorts of differentially-expressed genes in the dorsal 3V wall compared to the ventral 3V wall and LV wall that may regulate astrogenesis in the dorsal diencephalon.Together,these results demonstrate that the generation of astrocytes shows a spatiotemporal pattern in the developing mouse diencephalon.

Immunology reshapes neuroscience,and neuroscience reshapes immunology

As a result of evolution,our body has evolved into a sophisticated system in which various tissues and organs cooperate in a highly orchestrated manner.Few tissues or organs operate in isolation.The brain serves as the command center of our body and is relatively isolated from the peripheral system due to the presence of the blood-brain barrier(BBB).This barrier prevents direct and extensive interaction between blood cells,plasma molecules,and brain cells,contributing to the longstanding perception of the brain as an“immune-privileged”area.Consequently,neuroscientists and immunologists historically conducted separate research with minimal overlap between these two disciplines.However,this perspective has undergone reconsideration over the past few decades.

神经免疫学关键科学问题与展望

近年来,神经—免疫互作与调控成为神经科学和免疫学研究的交叉前沿和共同热点。国家自然科学基金作为资助基础研究的“主渠道”,不断推动神经科学、免疫学等学科的均衡协调发展。基于国家自然科学基金委员会第299期双清论坛“神经—免疫互作与调控”的研讨成果,本文聚焦国内科学家在神经免疫学领域的最新进展,从“神经—免疫互作的途径与机制”“系统生理的神经—内分泌—免疫调控”“神经—免疫互作与疾病”“类淋巴系统的生理与病理功能”和“神经—免疫互作研究的技术手段和方法学”五个方面总结重要成果和凝练关键科学问题。为促进我国神经免疫学研究的进步,科研工作者在凝练科学问题时应坚持“四个面向”特别是“面向世界科技前沿”和“面向人民生命健康”;科研资助机构有必要前瞻性布局神经—免疫互作与调控相关研究的重点领域和发展方向,鼓励基础研究成果向临床应用转化,以助力国家卫生健康事业和生物医药产业的高质量发展。

Novel Insight into Glial Biology and Diseases

In the central nervous system(CNS),there are mainly two types of nerve cells.One is neurons,the other is glial cells.Neurons are electrically excitable,whereas glial cells are not,and this is the fundamental difference between the two types of cells.Glial cells,consisting of astrocytes,oligodendrocyte lineage cells,and microglia,contribute more than half of the total cells in the mammalian CNS.

A Critical Time-Window for the Selective Induction of Hippocampal Memory Consolidation by a Brief Episode of Slow-Wave Sleep

Although extensively studied, the exact role of sleep in learning and memory is still not very clear. Sleep deprivation has been most frequently used to explore the effects of sleep on learning and memory, but the results from such studies are inevitably complicated by concurrent stress and distress. Furthermore, it is not clear whether there is a strict time-window between sleep and memory consolidation. In the present study we were able to induce time-locked slow-wave sleep(SWS) in mice by optogenetically stimulating GABAergic neurons in the parafacial zone(PZ), providing a direct approach to analyze the influences of SWS on learning and memory with precise time-windows. We found that SWS induced by light for 30 min immediately or 15 min after the training phase of the object-in-place task significantly prolonged the memory from 30 min to 6 h. However, induction of SWS 30 min after the training phase did not improve memory, suggesting a critical time-window between the induction of a brief episode of SWS and learning for memory consolidation.Application of a gentle touch to the mice during light stimulation to prevent SWS induction also failed to improve memory, indicating the specific role of SWS,but not the activation of PZ GABAergic neurons itself, in memory consolidation. Similar influences of light-induced SWS on memory consolidation also occurred for Y-maze spatial memory and contextual fear memory, but not for cued fear memory. SWS induction immediately before the test phase had no effect on memory performance, indicating that SWS does not affect memory retrieval. Thus, by induction of a brief-episode SWS we have revealed a critical time window for the consolidation of hippocampusdependent memory.

Standardized Operational Protocol for Human Brain Banking in China

With the progress of society, there is an increasing need to tackle disorders of the central nervous system. Human brain tissue, unlike animal tissues, is an irreplaceable resource for the study of neurological diseases (1)Aimed at scientific research and education, the roles of human brain tissue repositories are to acquire brain tissue from donors, prepare, process, and preserve collected samples,provide tissue to specific eligible facilities, and determine the characteristics of each tissue sample.

Brain-wide Mapping of Mono-synaptic Afferents to Different Cell Types in the Laterodorsal Tegmentum

The laterodorsal tegmentum(LDT) is a brain structure involved in distinct behaviors including arousal,reward, and innate fear. How environmental stimuli and top-down control from high-order sensory and limbic cortical areas converge and coordinate in this region to modulate diverse behavioral outputs remains unclear.Using a modified rabies virus, we applied monosynaptic retrograde tracing to the whole brain to examine the LDT cell type specific upstream nuclei. The LDT received very strong midbrain and hindbrain afferents and moderate cortical and hypothalamic innervation but weak connections to the thalamus. The main projection neurons from cortical areas were restricted to the limbic lobe, including the ventral orbital cortex(VO), prelimbic, and cingulate cortices. Although different cell populations received qualitatively similar inputs, primarily via afferents from the periaqueductal gray area, superior colliculus, and the LDT itself, parvalbumin-positive(PV?) GABAergic cells received preferential projections from local LDT neurons.With regard to the different subtypes of GABAergic cells, aconsiderable number of nuclei, including those of the ventral tegmental area, central amygdaloid nucleus, and VO, made significantly greater inputs to somatostatinpositive cells than to PV?cells. Diverse inputs to the LDT on a system-wide level were revealed.

Trafficking pathway between plasma membrane and mitochondria via clathrin-mediated endocytosis

Endocytosis is a basic cellular process that describes a form of active transport across the plasma membrane into the cell.The endocytic pathway consists of distinct membrane compartments;internalized molecules are delivered to early endosomes,and some of them are recycled back to the surface,whereas other molecules are sent to late endosomes and lysosomes for degradation.However,little is known about how mitochondria are involved in the endocytic pathway.Here,we report that FM dyes, membrane-impermeant fluorescent lipid probes,can traffic to mitochondria directly from the plasma membrane by clathrinmediated endocytosis.FM dye entry into mitochondria uses microtubule-dependent active transport,but the mechanism is different from the classical endocytic pathway.Hence,this study reveals a previously unrealized lipid trafficking pathway from the plasma membrane to mitochondria.

Anxiolytic Effect of Increased NREM Sleep after Acute Social Defeat Stress in Mice

Social defeat stress(SDS)plays a major role in the pathogenesis of psychiatric disorders like anxiety and depression.Sleep is generally considered to involve recovery of the brain from prior experience during wakefulness and is altered after acute SDS.However,the effect of acute SDS on sleep/wake behavior in mice varies between studies.In addition,whether sleep changes in response to stress contribute to anxiety is not well established.Here,we first investigated the effects of acute SDS on sleep/wake states in the active period in mice.Our results showed that total sleep time(time in rapid eyemovement[REM]and non-REM[NREM]sleep)increased in the active period after acute SDS.NREM sleep increased mainly during the first 3 h after SDS,while REM sleep increased at a later time.Then,we demonstrated that the increased NREM sleep had an anxiolytic benefit in acute SDS.Mice deprived of sleep for 1 h or 3 h after acute SDS remained in a highly anxious state,while in mice with ad libitum sleep the anxiety rapidly faded away.Altogether,our findings suggest an anxiolytic effect of NREM sleep,and indicate a potential therapeutic strategy for anxiety.

Lysosomal Hydrolase Cathepsin D Non-proteolytically Modulates Dendritic Morphology in Drosophila

The main lysosomal protease cathepsin D(cathD)is essential for maintaining tissue homeostasis via its degradative function,and its loss leads to ceroid accumulation in the mammalian nervous system,which results in progressive neurodegeneration.Increasing evidence implies non-proteolytic roles of cathD in regulating various biological processes such as apoptosis,cell proliferation,and migration.Along these lines,we here showed that cathD is required for modulating dendritic architecture in the nervous system independent of its traditional degradative function.Upon cathD depletion,class I and class III arborization(da)neurons in Drosophila larvae exhibited aberrant dendritic morphology,including overbranching,aberrant turning,and elongation defects.Reintroduction of wild-type cathD or its proteolyticallyinactive mutant dramatically abolished these morphological defects.Moreover,cathD knockdown also led to dendritic defects in the adult mushroom bodies,suggesting that cathD-mediated processes are required in both the peripheral and central nervous systems.Taken together,our results demonstrate a critical role of cathD in shaping dendritic architecture independent of its proteolytic function.

Pathological Networks Involving Dysmorphic Neurons in Type ⅡFocal Cortical Dysplasia

Focal cortical dysplasia(FCD)is one of the most common causes of drug-resistant epilepsy.Dysmorphic neurons are the major histopathological feature of typeⅡFCD,but their role in seizure genesis in FCD is unclear.Here we performed whole-cell patch-clamp recording and morphological reconstruction of cortical principal neurons in postsurgical brain tissue from drug-resistant epilepsy patients.Quantitative analyses revealed distinct morphological and electrophysiological characteristics of the upper layer dysmorphic neurons in typeⅡFCD,including an enlarged soma,aberrant dendritic arbors,increased current injection for rheobase action potential firing,and reduced action potential firing frequency.Intriguingly,the upper layer dysmorphic neurons received decreased glutamatergic and increased GABAergic synaptic inputs that were coupled with upregulation of the Na^(+)-K^(+)-Cl^(−)cotransporter.In addition,we found a depolarizing shift of the GABA reversal potential in the CamKⅡ-cre::PTENflox/flox mouse model of drug-resistant epilepsy,suggesting that enhanced GABAergic inputs might depolarize dysmorphic neurons.Thus,imbalance of synaptic excitation and inhibition of dysmorphic neurons may contribute to seizure genesis in typeⅡFCD.

Anterograde Trans-Synaptic Tagging Mediated by Adeno-Associated Virus

Trans-neuronal viral tracing is becoming one of the most important methods for mapping neuronal circuit connections,but an anterograde trans-synaptic tracer compatible with functional assays is still lacking.Adeno-associated virus（AAV）is replication-defective,and its production of offspring needs the help of adenovirus（AV）[1]or herpesvirus co-infection[2].The replication deficiency,non-pathogenicity,easy manipulability,

FTO is a transcriptional repressor to auto-regulate its own gene and potentially associated with homeostasis of body weight

Fat mass and obesity-associated (FTO) protein is a ferrous ion (Fe^2+)/2-oxoglutarate (2-OG)-dependent demethylase preferentially catalyzing m^6A sites in RNA. The FTO gene is highly expressed in the hypothalamus with fluctuation in response to various nutritional conditions, which is believed to be involved in the control of whole body metabolism. However, the underlying mechanism in response to different nutritional cues remains poorly understood. Here we show that ketogenic diet-derived ketone body β-hydroxybutyrate (BHB) transiently increases FTO expression in both mouse hypothalamus and cultured cells. Interestingly, the FTO protein represses Fto promoter activity, which can be offset by BHB. We then demonstrate that FTO binds to its own gene promoter, and Fe^2+, but not 2-OG, impedes this binding and increases FTO expression. The BHB-induced occupancy of the promoter by FTO influences the assembly of the basal transcriptional machinery. Importantly, a loss-of-function FTO mutant (I367F), which induces a lean phenotype in FTO^I367F mice, exhibits augmented binding and elevated potency to repress the promoter. Furthermore, FTO fails to bind to its own promoter that promotes FTO expression in the hypothalamus of high-fat diet-induced obese and 48-h fasting mice, suggesting a disruption of the stable expression of this gene. Taken together, this study uncovers a new function of FTO as a Fe^(2+)-sensitive transcriptional repressor dictating its own gene switch to form an auto-regulatory loop that may link with the hypothalamic control of body weight.

cFos-ANAB:A cFos-based Web Tool for Exploring Activated Neurons and Associated Behaviors

cFos is one of the most widely-studied genes in the field of neuroscience.Currently,there is no systematic database focusing on cFos in neuroscience.We developed a curated database-cFos-ANAB-a cFos-based web tool for exploring activated neurons and associated behaviors in rats and mice,comprising 398 brain nuclei and sub-nuclei,and five associated behaviors:pain,fear,feeding,aggression,and sexual behavior.Direct relationships among behaviors and nuclei(even cell types)under specific stimulating conditions were constructed based on cFos expression profiles extracted from original publications.Moreover,overlapping nuclei and sub-nuclei with potentially complex functions among different associated behaviors were emphasized,leading to results serving as important clues to the development of valid hypotheses for exploring as yet unknown circuits.Using the analysis function of cFos-ANAB,multi-layered pictures of networks and their relationships can quickly be explored depending on users’purposes.These features provide a useful tool and good reference for early exploration in neuroscience.The cFos-ANAB database is available at www.cfos-db.net.

Neuroscience Bulletin calls for papers

Neuroscience Bulletin is an international bimonthly journal in neuroscience, and is the official journal of the Chinese Society for Neuroscience. Beginning with the first 2009 issue, Neuroscience Bulletin is included in the Science Citation Index Expanded （SCI-E, available as the Web of Science）,