Adult neurogenesis persists after birth in the subventricular zone, with new neurons migrating to the granule cell layer and glomerular layers of the olfactory bulb, where they integrate into existing circuitry as inh...Adult neurogenesis persists after birth in the subventricular zone, with new neurons migrating to the granule cell layer and glomerular layers of the olfactory bulb, where they integrate into existing circuitry as inhibitory interneurons. The generation of these new neurons in the olfactory bulb supports both structural and functional plasticity, aiding in circuit remodeling triggered by memory and learning processes. However, the presence of these neurons, coupled with the cellular diversity within the olfactory bulb, presents an ongoing challenge in understanding its network organization and function. Moreover,the continuous integration of new neurons in the olfactory bulb plays a pivotal role in regulating olfactory information processing. This adaptive process responds to changes in epithelial composition and contributes to the formation of olfactory memories by modulating cellular connectivity within the olfactory bulb and interacting intricately with higher-order brain regions. The role of adult neurogenesis in olfactory bulb functions remains a topic of debate. Nevertheless, the functionality of the olfactory bulb is intricately linked to the organization of granule cells around mitral and tufted cells. This organizational pattern significantly impacts output, network behavior, and synaptic plasticity, which are crucial for olfactory perception and memory. Additionally, this organization is further shaped by axon terminals originating from cortical and subcortical regions. Despite the crucial role of olfactory bulb in brain functions and behaviors related to olfaction, these complex and highly interconnected processes have not been comprehensively studied as a whole. Therefore, this manuscript aims to discuss our current understanding and explore how neural plasticity and olfactory neurogenesis contribute to enhancing the adaptability of the olfactory system. These mechanisms are thought to support olfactory learning and memory, potentially through increased complexity and restructuring of neural network structures, as well as the addition of new granule granule cells that aid in olfactory adaptation. Additionally, the manuscript underscores the importance of employing precise methodologies to elucidate the specific roles of adult neurogenesis amidst conflicting data and varying experimental paradigms. Understanding these processes is essential for gaining insights into the complexities of olfactory function and behavior.展开更多
Elucidating the complex dynamic cellular organization in the hypothalamus is critical for understanding its role in coordinating fundamental body functions. Over the past decade, single-cell and spatial omics technolo...Elucidating the complex dynamic cellular organization in the hypothalamus is critical for understanding its role in coordinating fundamental body functions. Over the past decade, single-cell and spatial omics technologies have significantly evolved, overcoming initial technical challenges in capturing and analyzing individual cells. These high-throughput omics technologies now offer a remarkable opportunity to comprehend the complex spatiotemporal patterns of transcriptional diversity and cell-type characteristics across the entire hypothalamus. Current single-cell and single-nucleus RNA sequencing methods comprehensively quantify gene expression by exploring distinct phenotypes across various subregions of the hypothalamus. However, single-cell/single-nucleus RNA sequencing requires isolating the cell/nuclei from the tissue, potentially resulting in the loss of spatial information concerning neuronal networks. Spatial transcriptomics methods, by bypassing the cell dissociation, can elucidate the intricate spatial organization of neural networks through their imaging and sequencing technologies. In this review, we highlight the applicative value of single-cell and spatial transcriptomics in exploring the complex molecular-genetic diversity of hypothalamic cell types, driven by recent high-throughput achievements.展开更多
Rab5 is a GTPase protein that is involved in intracellular membrane trafficking. It functions by binding to various effector proteins and regulating cellular responses, including the formation of transport vesicles an...Rab5 is a GTPase protein that is involved in intracellular membrane trafficking. It functions by binding to various effector proteins and regulating cellular responses, including the formation of transport vesicles and their fusion with the cellular membrane. Rab5 has been reported to play an important role in the development of the zebrafish embryo;however, its role in axonal regeneration in the central nervous system remains unclear. In this study, we established a zebrafish Mauthner cell model of axonal injury using single-cell electroporation and two-photon axotomy techniques. We found that overexpression of Rab5 in single Mauthner cells promoted marked axonal regeneration and increased the number of intra-axonal transport vesicles. In contrast, treatment of zebrafish larvae with the Rab kinase inhibitor CID-1067700markedly inhibited axonal regeneration in Mauthner cells. We also found that Rab5 activated phosphatidylinositol 3-kinase(PI3K) during axonal repair of Mauthner cells and promoted the recovery of zebrafish locomotor function. Additionally, rapamycin, an inhibitor of the mechanistic target of rapamycin downstream of PI3K, markedly hindered axonal regeneration. These findings suggest that Rab5 promotes the axonal regeneration of injured zebrafish Mauthner cells by activating the PI3K signaling pathway.展开更多
In eukaryotic cells,organelles in the secretory,lysosomal,and endocytic pathways actively exchange biological materials with each other through intracellular membrane trafficking,which is the process of transporting t...In eukaryotic cells,organelles in the secretory,lysosomal,and endocytic pathways actively exchange biological materials with each other through intracellular membrane trafficking,which is the process of transporting the cargo of proteins,lipids,and other molecules to appropriate compartments via transport vesicles or intermediates.These processes are strictly regulated by various small GTPases such as the RAS-like in rat brain(RAB)protein family,which is the largest subfamily of the RAS superfamily.Dysfunction of membrane trafficking affects tissue homeostasis and leads to a wide range of diseases,including neurological disorders and neurodegenerative diseases.Therefore,it is important to understand the physiological and pathological roles of RAB proteins in brain function.RAB35,a member of the RAB family,is an evolutionarily conserved protein in metazoans.A wide range of studies using cultured mammalian cells and model organisms have revealed that RAB35 mediates various processes such as cytokinesis,endocytic recycling,actin bundling,and cell migration.RAB35 is also involved in neurite outgrowth and turnover of synaptic vesicles.We generated brain-specific Rab35 knockout mice to study the physiological roles of RAB35 in brain development and function.These mice exhibited defects in anxiety-related behaviors and spatial memory.Strikingly,RAB35 is required for the precise positioning of pyramidal neurons during hippocampal development,and thereby for normal hippocampal lamination.In contrast,layer formation in the cerebral cortex occurred superficially,even in the absence of RAB35,suggesting a predominant role for RAB35 in hippocampal development rather than in cerebral cortex development.Recent studies have suggested an association between RAB35 and neurodegenerative diseases,including Parkinson's disease and Alzheimer's disease.In this review,we provide an overview of the current understanding of subcellular functions of RAB35.We also provide insights into the physiological role of RAB35 in mammalian brain development and function,and discuss the involvement of RAB35 dysfunction in neurodegenerative diseases.展开更多
Multilayered control of myelination:Quick,saltatory conduction of action potentials along nerve fibers requires the electrical insulation of axons by myelinating glia.In the central nervous system,this role is taken u...Multilayered control of myelination:Quick,saltatory conduction of action potentials along nerve fibers requires the electrical insulation of axons by myelinating glia.In the central nervous system,this role is taken up by oligodendrocytes.Oligodendrocytes are marked by the expression of the lineage determinants Sox10 and Olig2 and arise from oligodendrocyte precursor cells(OPCs)during embryonal stages.While the majority of OPCs differentiate into mature oligodendrocytes when nearby axonal segments require myelination,a small subpopulation of OPCs persist as a progenitor pool.Therefore,the timing of myelination and maintenance of the OPC pool both need to be precisely regulated.Different transcription factors either positively or negatively affect oligodendrocyte differentiation and maintenance of the OPC pool as components of a complex gene regulatory network(reviewed in Sock and Wegner,2021).Network activity is additionally influenced by extracellular signaling molecules that bind to receptors on the oligodendroglial cell surface and activate intracellular signaling pathways.How the receptors are linked to the network is poorly understood so far,but pivotal to understanding the overall regulation of central nervous system(CNS)myelination in response to environmental cues.Relevant insights were recently gained for Gpr37(Schmidt et al.,2024),a G-protein coupled receptor(GPCR)with known relevance in differentiating oligodendrocytes(Yang et al,2016).展开更多
Spatial memory is crucial for survival within external surroundings and wild environments.The hippocampus,a critical hub for spatial learning and memory formation,has received extensive investigations on how neuromodu...Spatial memory is crucial for survival within external surroundings and wild environments.The hippocampus,a critical hub for spatial learning and memory formation,has received extensive investigations on how neuromodulators shape its functions(Teixeira et al.,2018;Zhang et al.,2024).However,the landscape of neuromodulations in the hippocampal system remains poorly understood because most studies focus on classical monoamine neuromodulators,such as acetylcholine,serotonin,dopamine,and noradrenaline.The neuropeptides,comprising the most abundant neuromodulators in the central nervous system,play a pivotal role in neural information processing in the hippocampal system.Cholecystokinin(CCK),one of the most abundant neuropeptides,has been implicated in regulating various physiological and neurobiological statuses(Chen et al.,2019).CCK-A receptor(CCK-AR)and CCK-B receptors(CCK-BR)are two key receptors mediating the biological functions of CCK,both of which belong to class-A sevenfold transmembrane G protein-coupled receptors(Nishimura et al.,2015).CCK-AR preferentially reacts to sulfated CCK,whereas CCK-BR binds both CCK and gastrin with similar affinities(Ding et al.,2022).The expression patterns of CCK-AR and CCK-BR are distinct,implying that CCK has various functions in target regions.For instance,CCK-AR is widely expressed in the GI and brain subregions and is hence implicated in the control of digestive function and satiety regulation.Conversely,CCK-BR is abundantly and widely distributed in the central nervous system,which majorly regulates anxiety,learning,and memory(Ding et al.,2022).However,the roles of endogenous CCK and CCK receptors in regulating hippocampal function at electrophysiological and behavioral levels have received less attention.展开更多
Brain plasticity-A universal tool with many variations:The study of brain plasticity has been gaining interest since almost a century and has now reached a huge amount of information(>80,000 results in PubMed).Over...Brain plasticity-A universal tool with many variations:The study of brain plasticity has been gaining interest since almost a century and has now reached a huge amount of information(>80,000 results in PubMed).Overall,different types of plasticity,including stem cell-driven genesis of new neurons(adult neurogenesis),cells in arrested maturation(dormant neurons),neuro-glial and synaptic plasticity,can coexist and contribute to grant plastic changes in the brain,from a cellular to system level(Benedetti and Couillard-Despres,2022;Bonfanti et al.,2023).展开更多
Cells,tissues,and organs are constantly subjected to the action of mechanical forces from the extracellular environment-and the nervous system is no exception.Cell-intrinsic properties such as membrane lipid compositi...Cells,tissues,and organs are constantly subjected to the action of mechanical forces from the extracellular environment-and the nervous system is no exception.Cell-intrinsic properties such as membrane lipid composition,abundance of mechanosensors,and cytoskeletal dynamics make cells more or less likely to sense these forces.Intrinsic and extrinsic cues are integrated by cells and this combined information determines the rate and dynamics of membrane protrusion growth or retraction(Yamada and Sixt,2019).Cell protrusions are extensions of the plasma membrane that play crucial roles in diverse contexts such as cell migration and neuronal synapse formation.In the nervous system,neurons are highly dynamic cells that can change the size and number of their pre-and postsynaptic elements(called synaptic boutons and dendritic spines,respectively),in response to changes in the levels of synaptic activity through a process called plasticity.Synaptic plasticity is a hallmark of the nervous system and is present throughout our lives,being required for functions like memory formation or the learning of new motor skills(Minegishi et al.,2023;Pillai and Franze,2024).展开更多
The brain's extracellular matrix(ECM),which is comprised of protein and glycosaminoglycan(GAG)scaffolds,constitutes 20%-40% of the human brain and is considered one of the largest influencers on brain cell functio...The brain's extracellular matrix(ECM),which is comprised of protein and glycosaminoglycan(GAG)scaffolds,constitutes 20%-40% of the human brain and is considered one of the largest influencers on brain cell functioning(Soles et al.,2023).Synthesized by neural and glial cells,the brain's ECM regulates a myriad of homeostatic cellular processes,including neuronal plasticity and firing(Miyata et al.,2012),cation buffering(Moraws ki et al.,2015),and glia-neuron interactions(Anderson et al.,2016).Considering the diversity of functions,dynamic remodeling of the brain's ECM indicates that this understudied medium is an active participant in both normal physiology and neurological diseases.展开更多
The cerebellum is receiving increasing attention for its cognitive,emotional,and social functions,as well as its unique metabolic profiles.Cerebellar microglia exhibit specialized and highly immunogenic phenotypes und...The cerebellum is receiving increasing attention for its cognitive,emotional,and social functions,as well as its unique metabolic profiles.Cerebellar microglia exhibit specialized and highly immunogenic phenotypes under both physiological and pathological conditions.These immune cells communicate with intrinsic and systemic factors and contribute to the structural and functional compartmentalization of the cerebellum.In this review,we discuss the roles of microglia in the cerebellar microenvironment,neuroinflammation,cerebellar adaptation,and neuronal activity,the associated molecular and cellular mechanisms,and potential therapeutic strategies targeting cerebellar microglia in the context of neuroinflammation.Future directions and unresolved questions in this field are further highlighted,particularly regarding therapeutic interventions targeting cerebellar microglia,functional mechanisms and activities of microglia in the cerebellar circuitry,neuronal connectivity,and neurofunctional outcomes of their activity.Cerebellar morphology and neuronal performance are influenced by both intrinsic and systemic factors that are actively monitored by microglia in both healthy and diseased states.Under pathological conditions,local subsets of microglia exhibit diverse responses to the altered microenvironment that contribute to the structural and functional compartmentalization of the cerebellum.Microglia in the cerebellum undergo early maturation during the embryonic stage and display specialized,highly immunogenic phenotypes.In summary,cerebellar microglia have the capacity to serve as regulatory tools that influence outcomes across a wide range of neurological and systemic conditions,including neurodevelopmental,neurodegenerative,metabolic,and stress-related disorders.展开更多
Feeding behavior is regulated by a complex network of endogenous neuropeptides.In chordates,this role is suggested to be under the control of diverse factors including thyrotropin-releasing hormone(TRH).However,whethe...Feeding behavior is regulated by a complex network of endogenous neuropeptides.In chordates,this role is suggested to be under the control of diverse factors including thyrotropin-releasing hormone(TRH).However,whether this regulatory activity of TRH is functionally conserved in non-chordate metazoans,and to what extent this process is underpinned by interactions of TRH with other neuropeptides such as cholecystokinin(CCK,known as a satiety signal),remain unclear.This study investigated the TRH signaling system in the echinoderm Apostichopus japonicus.Bioinformatic analyses and ligand-binding assays identified a functional TRH receptor(AjTRHR)that activated signaling via the MAPK/ERK1/2pathways.Experimental administration of TRH significantly reduced feeding activity,while up-regulating CCK expression.RNA interference(RNAi)experiments confirmed that both CCK and TRH are essential components of satiety signaling,working synergistically to mediate feeding inhibition.Evolutionary analysis of TRHtype peptides revealed greater conservation of the short isoform of TRH compared to the long isoform,probably driven by strong selection acting on the functional redundancy.These findings provide compelling evidence of a TRH-mediated signaling system in non-chordate deuterostomes,expandingourunderstandingof neuropeptide-regulated feeding mechanisms in marine invertebrates.展开更多
The suprachiasmatic nucleus in the hypothalamus is the master circadian clock in mammals,coordinating physiological processes with the 24-hour day–night cycle.Comprising various cell types,the suprachiasmatic nucleus...The suprachiasmatic nucleus in the hypothalamus is the master circadian clock in mammals,coordinating physiological processes with the 24-hour day–night cycle.Comprising various cell types,the suprachiasmatic nucleus(SCN)integrates environmental signals to maintain complex and robust circadian rhythms.Understanding the complexity and synchrony within SCN neurons is essential for effective circadian clock function.Synchrony involves coordinated neuronal firing for robust rhythms,while complexity reflects diverse activity patterns and interactions,indicating adaptability.Interestingly,the SCN retains circadian rhythms in vitro,demonstrating intrinsic rhythmicity.This study introduces the multiscale structural complexity method to analyze changes in SCN neuronal activity and complexity at macro and micro levels,based on Bagrov et al.’s approach.By examining structural complexity and local complexities across scales,we aim to understand how tetrodotoxin,a neurotoxin that inhibits action potentials,affects SCN neurons.Our method captures critical scales in neuronal interactions that traditional methods may overlook.Validation with the Goodwin model confirms the reliability of our observations.By integrating experimental data with theoretical models,this study provides new insights into the effects of tetrodotoxin(TTX)on neuronal complexities,contributing to the understanding of circadian rhythms.展开更多
All vertebrates have a definitive thyroid gland,or thyroid for short.As a critical organ for growth,development and metabolism,its origin and evolution have long received attention.On the basis of anatomical position,...All vertebrates have a definitive thyroid gland,or thyroid for short.As a critical organ for growth,development and metabolism,its origin and evolution have long received attention.On the basis of anatomical position,endodermal origination and histological features,the endostyle of amphioxus has been proposed as a homologue to the thyroid of vertebrates.This homology is further supported by the findings that the amphioxus endostyle abounds in thyroid hormones,possesses several thyroid-specific proteins such as thyroperoxidase,nicotinamide adenine dinucleotide phosphate(NADPH)oxidase and thyroglobulin,and expresses the thyroid-related transcription factors involved in the regulation of development of the vertebrate thyroid,including Nkx2.1,FoxE4 and Pax2/5/8.Importantly,our study on functionality,together with others,indicates significant similarities between the amphioxus endostyle and the vertebrate thyroid gland.Moreover,we show that the production of thyroid hormones by the amphioxus endostyle is mediated in a fashion similar to that of the vertebrate thyroid.These provide solid evidences that the amphioxus endostyle is the homologue of the vertebrate thyroid.From a phylogenetic viewpoint,we propose that the hypobranchial ridge,or endostyle-like structure,of hemichordates is the most primitive forerunner of the thyroid,from which the vertebrate thyroid is formed through the transformation of non-follicular endostyle of amphioxus to follicular endocrine organ of vertebrates.We also raise a couple of questions that demand further study.展开更多
文摘Adult neurogenesis persists after birth in the subventricular zone, with new neurons migrating to the granule cell layer and glomerular layers of the olfactory bulb, where they integrate into existing circuitry as inhibitory interneurons. The generation of these new neurons in the olfactory bulb supports both structural and functional plasticity, aiding in circuit remodeling triggered by memory and learning processes. However, the presence of these neurons, coupled with the cellular diversity within the olfactory bulb, presents an ongoing challenge in understanding its network organization and function. Moreover,the continuous integration of new neurons in the olfactory bulb plays a pivotal role in regulating olfactory information processing. This adaptive process responds to changes in epithelial composition and contributes to the formation of olfactory memories by modulating cellular connectivity within the olfactory bulb and interacting intricately with higher-order brain regions. The role of adult neurogenesis in olfactory bulb functions remains a topic of debate. Nevertheless, the functionality of the olfactory bulb is intricately linked to the organization of granule cells around mitral and tufted cells. This organizational pattern significantly impacts output, network behavior, and synaptic plasticity, which are crucial for olfactory perception and memory. Additionally, this organization is further shaped by axon terminals originating from cortical and subcortical regions. Despite the crucial role of olfactory bulb in brain functions and behaviors related to olfaction, these complex and highly interconnected processes have not been comprehensively studied as a whole. Therefore, this manuscript aims to discuss our current understanding and explore how neural plasticity and olfactory neurogenesis contribute to enhancing the adaptability of the olfactory system. These mechanisms are thought to support olfactory learning and memory, potentially through increased complexity and restructuring of neural network structures, as well as the addition of new granule granule cells that aid in olfactory adaptation. Additionally, the manuscript underscores the importance of employing precise methodologies to elucidate the specific roles of adult neurogenesis amidst conflicting data and varying experimental paradigms. Understanding these processes is essential for gaining insights into the complexities of olfactory function and behavior.
基金supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI)the Ministry of Health&Welfare,Republic of Korea (HR22C1734)+2 种基金the National Research Foundation (NRF) of Korea (2020R1A6A1A03043539,2020M3A9D8037604,2022R1C1C1004756)(to SBL)the NRF of Korea (2022R1C1C1005741 and RS-2023-00217595)the new faculty research fund of Ajou University School of Medicine (to EJL)。
文摘Elucidating the complex dynamic cellular organization in the hypothalamus is critical for understanding its role in coordinating fundamental body functions. Over the past decade, single-cell and spatial omics technologies have significantly evolved, overcoming initial technical challenges in capturing and analyzing individual cells. These high-throughput omics technologies now offer a remarkable opportunity to comprehend the complex spatiotemporal patterns of transcriptional diversity and cell-type characteristics across the entire hypothalamus. Current single-cell and single-nucleus RNA sequencing methods comprehensively quantify gene expression by exploring distinct phenotypes across various subregions of the hypothalamus. However, single-cell/single-nucleus RNA sequencing requires isolating the cell/nuclei from the tissue, potentially resulting in the loss of spatial information concerning neuronal networks. Spatial transcriptomics methods, by bypassing the cell dissociation, can elucidate the intricate spatial organization of neural networks through their imaging and sequencing technologies. In this review, we highlight the applicative value of single-cell and spatial transcriptomics in exploring the complex molecular-genetic diversity of hypothalamic cell types, driven by recent high-throughput achievements.
基金supported by the Research Funds of the Center for Advanced Interdisciplinary Science and Biomedicine of IHM,No.QYZD20220002the National Natural Science Foundation of China,No.82071357a grant from the Ministry of Science and Technology of China,No.2019YFA0405600 (all to BH)。
文摘Rab5 is a GTPase protein that is involved in intracellular membrane trafficking. It functions by binding to various effector proteins and regulating cellular responses, including the formation of transport vesicles and their fusion with the cellular membrane. Rab5 has been reported to play an important role in the development of the zebrafish embryo;however, its role in axonal regeneration in the central nervous system remains unclear. In this study, we established a zebrafish Mauthner cell model of axonal injury using single-cell electroporation and two-photon axotomy techniques. We found that overexpression of Rab5 in single Mauthner cells promoted marked axonal regeneration and increased the number of intra-axonal transport vesicles. In contrast, treatment of zebrafish larvae with the Rab kinase inhibitor CID-1067700markedly inhibited axonal regeneration in Mauthner cells. We also found that Rab5 activated phosphatidylinositol 3-kinase(PI3K) during axonal repair of Mauthner cells and promoted the recovery of zebrafish locomotor function. Additionally, rapamycin, an inhibitor of the mechanistic target of rapamycin downstream of PI3K, markedly hindered axonal regeneration. These findings suggest that Rab5 promotes the axonal regeneration of injured zebrafish Mauthner cells by activating the PI3K signaling pathway.
基金supported by the Japan Society for the Promotion of Science KAKENHI(grant Nos.23K05678 to IM,19H05711 and 20H00466 to KS)the Joint Research Program of Institute for Molecular and Cellular Regulation,Gunma University(to KS)。
文摘In eukaryotic cells,organelles in the secretory,lysosomal,and endocytic pathways actively exchange biological materials with each other through intracellular membrane trafficking,which is the process of transporting the cargo of proteins,lipids,and other molecules to appropriate compartments via transport vesicles or intermediates.These processes are strictly regulated by various small GTPases such as the RAS-like in rat brain(RAB)protein family,which is the largest subfamily of the RAS superfamily.Dysfunction of membrane trafficking affects tissue homeostasis and leads to a wide range of diseases,including neurological disorders and neurodegenerative diseases.Therefore,it is important to understand the physiological and pathological roles of RAB proteins in brain function.RAB35,a member of the RAB family,is an evolutionarily conserved protein in metazoans.A wide range of studies using cultured mammalian cells and model organisms have revealed that RAB35 mediates various processes such as cytokinesis,endocytic recycling,actin bundling,and cell migration.RAB35 is also involved in neurite outgrowth and turnover of synaptic vesicles.We generated brain-specific Rab35 knockout mice to study the physiological roles of RAB35 in brain development and function.These mice exhibited defects in anxiety-related behaviors and spatial memory.Strikingly,RAB35 is required for the precise positioning of pyramidal neurons during hippocampal development,and thereby for normal hippocampal lamination.In contrast,layer formation in the cerebral cortex occurred superficially,even in the absence of RAB35,suggesting a predominant role for RAB35 in hippocampal development rather than in cerebral cortex development.Recent studies have suggested an association between RAB35 and neurodegenerative diseases,including Parkinson's disease and Alzheimer's disease.In this review,we provide an overview of the current understanding of subcellular functions of RAB35.We also provide insights into the physiological role of RAB35 in mammalian brain development and function,and discuss the involvement of RAB35 dysfunction in neurodegenerative diseases.
基金supported by grants from the Deutsche Forschungsgemeinschaft to MW。
文摘Multilayered control of myelination:Quick,saltatory conduction of action potentials along nerve fibers requires the electrical insulation of axons by myelinating glia.In the central nervous system,this role is taken up by oligodendrocytes.Oligodendrocytes are marked by the expression of the lineage determinants Sox10 and Olig2 and arise from oligodendrocyte precursor cells(OPCs)during embryonal stages.While the majority of OPCs differentiate into mature oligodendrocytes when nearby axonal segments require myelination,a small subpopulation of OPCs persist as a progenitor pool.Therefore,the timing of myelination and maintenance of the OPC pool both need to be precisely regulated.Different transcription factors either positively or negatively affect oligodendrocyte differentiation and maintenance of the OPC pool as components of a complex gene regulatory network(reviewed in Sock and Wegner,2021).Network activity is additionally influenced by extracellular signaling molecules that bind to receptors on the oligodendroglial cell surface and activate intracellular signaling pathways.How the receptors are linked to the network is poorly understood so far,but pivotal to understanding the overall regulation of central nervous system(CNS)myelination in response to environmental cues.Relevant insights were recently gained for Gpr37(Schmidt et al.,2024),a G-protein coupled receptor(GPCR)with known relevance in differentiating oligodendrocytes(Yang et al,2016).
文摘Spatial memory is crucial for survival within external surroundings and wild environments.The hippocampus,a critical hub for spatial learning and memory formation,has received extensive investigations on how neuromodulators shape its functions(Teixeira et al.,2018;Zhang et al.,2024).However,the landscape of neuromodulations in the hippocampal system remains poorly understood because most studies focus on classical monoamine neuromodulators,such as acetylcholine,serotonin,dopamine,and noradrenaline.The neuropeptides,comprising the most abundant neuromodulators in the central nervous system,play a pivotal role in neural information processing in the hippocampal system.Cholecystokinin(CCK),one of the most abundant neuropeptides,has been implicated in regulating various physiological and neurobiological statuses(Chen et al.,2019).CCK-A receptor(CCK-AR)and CCK-B receptors(CCK-BR)are two key receptors mediating the biological functions of CCK,both of which belong to class-A sevenfold transmembrane G protein-coupled receptors(Nishimura et al.,2015).CCK-AR preferentially reacts to sulfated CCK,whereas CCK-BR binds both CCK and gastrin with similar affinities(Ding et al.,2022).The expression patterns of CCK-AR and CCK-BR are distinct,implying that CCK has various functions in target regions.For instance,CCK-AR is widely expressed in the GI and brain subregions and is hence implicated in the control of digestive function and satiety regulation.Conversely,CCK-BR is abundantly and widely distributed in the central nervous system,which majorly regulates anxiety,learning,and memory(Ding et al.,2022).However,the roles of endogenous CCK and CCK receptors in regulating hippocampal function at electrophysiological and behavioral levels have received less attention.
基金supported by Progetto Trapezio,Compagnia di San Paolo(67935-2021.2174)to LB,Fondazione CRT(Cassa di Risparmio di Torino,RF=2022.0618)to LB。
文摘Brain plasticity-A universal tool with many variations:The study of brain plasticity has been gaining interest since almost a century and has now reached a huge amount of information(>80,000 results in PubMed).Overall,different types of plasticity,including stem cell-driven genesis of new neurons(adult neurogenesis),cells in arrested maturation(dormant neurons),neuro-glial and synaptic plasticity,can coexist and contribute to grant plastic changes in the brain,from a cellular to system level(Benedetti and Couillard-Despres,2022;Bonfanti et al.,2023).
基金supported by PTDC-01778/2022-NeuroDev3D,iNOVA4Health(UIDB/04462/2020 and UIDP/04462/2020)LS4FUTURE(LA/P/0087/2020)。
文摘Cells,tissues,and organs are constantly subjected to the action of mechanical forces from the extracellular environment-and the nervous system is no exception.Cell-intrinsic properties such as membrane lipid composition,abundance of mechanosensors,and cytoskeletal dynamics make cells more or less likely to sense these forces.Intrinsic and extrinsic cues are integrated by cells and this combined information determines the rate and dynamics of membrane protrusion growth or retraction(Yamada and Sixt,2019).Cell protrusions are extensions of the plasma membrane that play crucial roles in diverse contexts such as cell migration and neuronal synapse formation.In the nervous system,neurons are highly dynamic cells that can change the size and number of their pre-and postsynaptic elements(called synaptic boutons and dendritic spines,respectively),in response to changes in the levels of synaptic activity through a process called plasticity.Synaptic plasticity is a hallmark of the nervous system and is present throughout our lives,being required for functions like memory formation or the learning of new motor skills(Minegishi et al.,2023;Pillai and Franze,2024).
基金supported by National Institute on Aging(NIH-NIA)R21 AG074152(to KMA)National Institute of Allergy and Infectious Diseases(NIAID)grant DP2 AI171150(to KMA)Department of Defense(DoD)grant AZ210089(to KMA)。
文摘The brain's extracellular matrix(ECM),which is comprised of protein and glycosaminoglycan(GAG)scaffolds,constitutes 20%-40% of the human brain and is considered one of the largest influencers on brain cell functioning(Soles et al.,2023).Synthesized by neural and glial cells,the brain's ECM regulates a myriad of homeostatic cellular processes,including neuronal plasticity and firing(Miyata et al.,2012),cation buffering(Moraws ki et al.,2015),and glia-neuron interactions(Anderson et al.,2016).Considering the diversity of functions,dynamic remodeling of the brain's ECM indicates that this understudied medium is an active participant in both normal physiology and neurological diseases.
基金supported by grants from STI2030-Major Projects,No.2021ZD0204000(to YS)Key Strategic Science and Technology Cooperation Project of the Ministry of Science and Technology of China,No.SQ2023YFE0201430(to YS)+1 种基金the National Natural Science Foundation of China,Nos.31820103005(to YS),32200620(to LW)the Natural Science Foundation of Zhejiang Province of China,No.LZ24C090003(to YS)。
文摘The cerebellum is receiving increasing attention for its cognitive,emotional,and social functions,as well as its unique metabolic profiles.Cerebellar microglia exhibit specialized and highly immunogenic phenotypes under both physiological and pathological conditions.These immune cells communicate with intrinsic and systemic factors and contribute to the structural and functional compartmentalization of the cerebellum.In this review,we discuss the roles of microglia in the cerebellar microenvironment,neuroinflammation,cerebellar adaptation,and neuronal activity,the associated molecular and cellular mechanisms,and potential therapeutic strategies targeting cerebellar microglia in the context of neuroinflammation.Future directions and unresolved questions in this field are further highlighted,particularly regarding therapeutic interventions targeting cerebellar microglia,functional mechanisms and activities of microglia in the cerebellar circuitry,neuronal connectivity,and neurofunctional outcomes of their activity.Cerebellar morphology and neuronal performance are influenced by both intrinsic and systemic factors that are actively monitored by microglia in both healthy and diseased states.Under pathological conditions,local subsets of microglia exhibit diverse responses to the altered microenvironment that contribute to the structural and functional compartmentalization of the cerebellum.Microglia in the cerebellum undergo early maturation during the embryonic stage and display specialized,highly immunogenic phenotypes.In summary,cerebellar microglia have the capacity to serve as regulatory tools that influence outcomes across a wide range of neurological and systemic conditions,including neurodevelopmental,neurodegenerative,metabolic,and stress-related disorders.
基金supported by the National Natural Science Foundation of China (42276103)。
文摘Feeding behavior is regulated by a complex network of endogenous neuropeptides.In chordates,this role is suggested to be under the control of diverse factors including thyrotropin-releasing hormone(TRH).However,whether this regulatory activity of TRH is functionally conserved in non-chordate metazoans,and to what extent this process is underpinned by interactions of TRH with other neuropeptides such as cholecystokinin(CCK,known as a satiety signal),remain unclear.This study investigated the TRH signaling system in the echinoderm Apostichopus japonicus.Bioinformatic analyses and ligand-binding assays identified a functional TRH receptor(AjTRHR)that activated signaling via the MAPK/ERK1/2pathways.Experimental administration of TRH significantly reduced feeding activity,while up-regulating CCK expression.RNA interference(RNAi)experiments confirmed that both CCK and TRH are essential components of satiety signaling,working synergistically to mediate feeding inhibition.Evolutionary analysis of TRHtype peptides revealed greater conservation of the short isoform of TRH compared to the long isoform,probably driven by strong selection acting on the functional redundancy.These findings provide compelling evidence of a TRH-mediated signaling system in non-chordate deuterostomes,expandingourunderstandingof neuropeptide-regulated feeding mechanisms in marine invertebrates.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.12275179,11875042,and 12150410309)the Natural Science Foundation of Shanghai(Grant No.21ZR1443900).
文摘The suprachiasmatic nucleus in the hypothalamus is the master circadian clock in mammals,coordinating physiological processes with the 24-hour day–night cycle.Comprising various cell types,the suprachiasmatic nucleus(SCN)integrates environmental signals to maintain complex and robust circadian rhythms.Understanding the complexity and synchrony within SCN neurons is essential for effective circadian clock function.Synchrony involves coordinated neuronal firing for robust rhythms,while complexity reflects diverse activity patterns and interactions,indicating adaptability.Interestingly,the SCN retains circadian rhythms in vitro,demonstrating intrinsic rhythmicity.This study introduces the multiscale structural complexity method to analyze changes in SCN neuronal activity and complexity at macro and micro levels,based on Bagrov et al.’s approach.By examining structural complexity and local complexities across scales,we aim to understand how tetrodotoxin,a neurotoxin that inhibits action potentials,affects SCN neurons.Our method captures critical scales in neuronal interactions that traditional methods may overlook.Validation with the Goodwin model confirms the reliability of our observations.By integrating experimental data with theoretical models,this study provides new insights into the effects of tetrodotoxin(TTX)on neuronal complexities,contributing to the understanding of circadian rhythms.
基金The National Natural Science Foundation of China under contact No.32270434.
文摘All vertebrates have a definitive thyroid gland,or thyroid for short.As a critical organ for growth,development and metabolism,its origin and evolution have long received attention.On the basis of anatomical position,endodermal origination and histological features,the endostyle of amphioxus has been proposed as a homologue to the thyroid of vertebrates.This homology is further supported by the findings that the amphioxus endostyle abounds in thyroid hormones,possesses several thyroid-specific proteins such as thyroperoxidase,nicotinamide adenine dinucleotide phosphate(NADPH)oxidase and thyroglobulin,and expresses the thyroid-related transcription factors involved in the regulation of development of the vertebrate thyroid,including Nkx2.1,FoxE4 and Pax2/5/8.Importantly,our study on functionality,together with others,indicates significant similarities between the amphioxus endostyle and the vertebrate thyroid gland.Moreover,we show that the production of thyroid hormones by the amphioxus endostyle is mediated in a fashion similar to that of the vertebrate thyroid.These provide solid evidences that the amphioxus endostyle is the homologue of the vertebrate thyroid.From a phylogenetic viewpoint,we propose that the hypobranchial ridge,or endostyle-like structure,of hemichordates is the most primitive forerunner of the thyroid,from which the vertebrate thyroid is formed through the transformation of non-follicular endostyle of amphioxus to follicular endocrine organ of vertebrates.We also raise a couple of questions that demand further study.
