Pub Date : 2024-09-05DOI: 10.1038/s41593-024-01760-x
Luis A. Mejia
{"title":"Changing dynamics in real time","authors":"Luis A. Mejia","doi":"10.1038/s41593-024-01760-x","DOIUrl":"10.1038/s41593-024-01760-x","url":null,"abstract":"","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 9","pages":"1638-1638"},"PeriodicalIF":21.2,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-04DOI: 10.1038/s41593-024-01756-7
Éric Martineau, Antoine Malescot, Nouha Elmkinssi, Ravi L. Rungta
Neurovascular coupling links brain activity to local changes in blood flow, forming the basis for non-invasive brain mapping. Using multiscale imaging, we investigated how vascular activity spatially relates to neuronal activity elicited by single whiskers across different columns and layers of mouse cortex. Here we show that mesoscopic hemodynamic signals quantitatively reflect neuronal activity across space but are composed of a highly heterogeneous pattern of responses across individual vessel segments that is poorly predicted by local neuronal activity. Rather, this heterogeneity is dependent on vessel directionality, specifically in thalamocortical input layer 4, where capillaries respond preferentially to neuronal activity patterns along their downstream perfusion domain. Thus, capillaries fine-tune blood flow based on distant activity and encode laminar-specific activity patterns. These findings imply that vascular anatomy sets a resolution limit on functional imaging signals, where individual blood vessels inaccurately report neuronal activity in their immediate vicinity but, instead, integrate activity patterns along the vascular arbor. The spatial relationship between neuronal and vascular activity remains highly debated. In this study, the authors used multiscale optical imaging to show how vascular architecture limits the spatial specificity of neurovascular coupling.
{"title":"Distal activity patterns shape the spatial specificity of neurovascular coupling","authors":"Éric Martineau, Antoine Malescot, Nouha Elmkinssi, Ravi L. Rungta","doi":"10.1038/s41593-024-01756-7","DOIUrl":"10.1038/s41593-024-01756-7","url":null,"abstract":"Neurovascular coupling links brain activity to local changes in blood flow, forming the basis for non-invasive brain mapping. Using multiscale imaging, we investigated how vascular activity spatially relates to neuronal activity elicited by single whiskers across different columns and layers of mouse cortex. Here we show that mesoscopic hemodynamic signals quantitatively reflect neuronal activity across space but are composed of a highly heterogeneous pattern of responses across individual vessel segments that is poorly predicted by local neuronal activity. Rather, this heterogeneity is dependent on vessel directionality, specifically in thalamocortical input layer 4, where capillaries respond preferentially to neuronal activity patterns along their downstream perfusion domain. Thus, capillaries fine-tune blood flow based on distant activity and encode laminar-specific activity patterns. These findings imply that vascular anatomy sets a resolution limit on functional imaging signals, where individual blood vessels inaccurately report neuronal activity in their immediate vicinity but, instead, integrate activity patterns along the vascular arbor. The spatial relationship between neuronal and vascular activity remains highly debated. In this study, the authors used multiscale optical imaging to show how vascular architecture limits the spatial specificity of neurovascular coupling.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 11","pages":"2101-2114"},"PeriodicalIF":21.2,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142130751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1038/s41593-024-01745-w
Zhenrui Liao, Satoshi Terada, Ivan Georgiev Raikov, Darian Hadjiabadi, Miklos Szoboszlay, Ivan Soltesz, Attila Losonczy
Memory consolidation assimilates recent experiences into long-term memory. This process requires the replay of learned sequences, although the content of these sequences remains controversial. Recent work has shown that the statistics of replay deviate from those of experience: stimuli that are experientially salient may be either recruited or suppressed from sharp-wave ripples. In this study, we found that this phenomenon can be explained parsimoniously and biologically plausibly by a Hebbian spike-time-dependent plasticity rule at inhibitory synapses. Using models at three levels of abstraction—leaky integrate-and-fire, biophysically detailed and abstract binary—we show that this rule enables efficient generalization, and we make specific predictions about the consequences of intact and perturbed inhibitory dynamics for network dynamics and cognition. Finally, we use optogenetics to artificially implant non-generalizable representations into the network in awake behaving mice, and we find that these representations also accumulate inhibition during sharp-wave ripples, experimentally validating a major prediction of our model. Our work outlines a potential direct link between the synaptic and cognitive levels of memory consolidation, with implications for both normal learning and neurological disease. The study of neural plasticity has focused on excitatory neural connections, but inhibitory connections can also change. Learning at inhibitory synapses may support high-level cognitive phenomena, such as selecting information for memory storage.
{"title":"Inhibitory plasticity supports replay generalization in the hippocampus","authors":"Zhenrui Liao, Satoshi Terada, Ivan Georgiev Raikov, Darian Hadjiabadi, Miklos Szoboszlay, Ivan Soltesz, Attila Losonczy","doi":"10.1038/s41593-024-01745-w","DOIUrl":"10.1038/s41593-024-01745-w","url":null,"abstract":"Memory consolidation assimilates recent experiences into long-term memory. This process requires the replay of learned sequences, although the content of these sequences remains controversial. Recent work has shown that the statistics of replay deviate from those of experience: stimuli that are experientially salient may be either recruited or suppressed from sharp-wave ripples. In this study, we found that this phenomenon can be explained parsimoniously and biologically plausibly by a Hebbian spike-time-dependent plasticity rule at inhibitory synapses. Using models at three levels of abstraction—leaky integrate-and-fire, biophysically detailed and abstract binary—we show that this rule enables efficient generalization, and we make specific predictions about the consequences of intact and perturbed inhibitory dynamics for network dynamics and cognition. Finally, we use optogenetics to artificially implant non-generalizable representations into the network in awake behaving mice, and we find that these representations also accumulate inhibition during sharp-wave ripples, experimentally validating a major prediction of our model. Our work outlines a potential direct link between the synaptic and cognitive levels of memory consolidation, with implications for both normal learning and neurological disease. The study of neural plasticity has focused on excitatory neural connections, but inhibitory connections can also change. Learning at inhibitory synapses may support high-level cognitive phenomena, such as selecting information for memory storage.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 10","pages":"1987-1998"},"PeriodicalIF":21.2,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1038/s41593-024-01742-z
Anna S. Fröhlich, Nathalie Gerstner, Miriam Gagliardi, Maik Ködel, Natan Yusupov, Natalie Matosin, Darina Czamara, Susann Sauer, Simone Roeh, Vanessa Murek, Chris Chatzinakos, Nikolaos P. Daskalakis, Janine Knauer-Arloth, Michael J. Ziller, Elisabeth B. Binder
Aging is a complex biological process and represents the largest risk factor for neurodegenerative disorders. The risk for neurodegenerative disorders is also increased in individuals with psychiatric disorders. Here, we characterized age-related transcriptomic changes in the brain by profiling ~800,000 nuclei from the orbitofrontal cortex from 87 individuals with and without psychiatric diagnoses and replicated findings in an independent cohort with 32 individuals. Aging affects all cell types, with LAMP5+LHX6+ interneurons, a cell-type abundant in primates, by far the most affected. Disrupted synaptic transmission emerged as a convergently affected pathway in aged tissue. Age-related transcriptomic changes overlapped with changes observed in Alzheimer’s disease across multiple cell types. We find evidence for accelerated transcriptomic aging in individuals with psychiatric disorders and demonstrate a converging signature of aging and psychopathology across multiple cell types. Our findings shed light on cell-type-specific effects and biological pathways underlying age-related changes and their convergence with effects driven by psychiatric diagnosis. Single-cell profiling in the human cortex reveals aging-associated transcriptomic changes across all brain cell types, which overlap with effects with Alzheimer’s disease and show a convergent signature with psychopathology across multiple cell types.
{"title":"Single-nucleus transcriptomic profiling of human orbitofrontal cortex reveals convergent effects of aging and psychiatric disease","authors":"Anna S. Fröhlich, Nathalie Gerstner, Miriam Gagliardi, Maik Ködel, Natan Yusupov, Natalie Matosin, Darina Czamara, Susann Sauer, Simone Roeh, Vanessa Murek, Chris Chatzinakos, Nikolaos P. Daskalakis, Janine Knauer-Arloth, Michael J. Ziller, Elisabeth B. Binder","doi":"10.1038/s41593-024-01742-z","DOIUrl":"10.1038/s41593-024-01742-z","url":null,"abstract":"Aging is a complex biological process and represents the largest risk factor for neurodegenerative disorders. The risk for neurodegenerative disorders is also increased in individuals with psychiatric disorders. Here, we characterized age-related transcriptomic changes in the brain by profiling ~800,000 nuclei from the orbitofrontal cortex from 87 individuals with and without psychiatric diagnoses and replicated findings in an independent cohort with 32 individuals. Aging affects all cell types, with LAMP5+LHX6+ interneurons, a cell-type abundant in primates, by far the most affected. Disrupted synaptic transmission emerged as a convergently affected pathway in aged tissue. Age-related transcriptomic changes overlapped with changes observed in Alzheimer’s disease across multiple cell types. We find evidence for accelerated transcriptomic aging in individuals with psychiatric disorders and demonstrate a converging signature of aging and psychopathology across multiple cell types. Our findings shed light on cell-type-specific effects and biological pathways underlying age-related changes and their convergence with effects driven by psychiatric diagnosis. Single-cell profiling in the human cortex reveals aging-associated transcriptomic changes across all brain cell types, which overlap with effects with Alzheimer’s disease and show a convergent signature with psychopathology across multiple cell types.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 10","pages":"2021-2032"},"PeriodicalIF":21.2,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01742-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1038/s41593-024-01739-8
Sumin Jang, Elias Gumnit, Hynek Wichterle
Neurogenesis lasts ~10 times longer in developing humans compared to mice, resulting in a >1,000-fold increase in the number of neurons in the CNS. To identify molecular and cellular mechanisms contributing to this difference, we studied human and mouse motor neurogenesis using a stem cell differentiation system that recapitulates species-specific scales of development. Comparison of human and mouse single-cell gene expression data identified human-specific progenitors characterized by coexpression of NKX2-2 and OLIG2 that give rise to spinal motor neurons. Unlike classical OLIG2+ motor neuron progenitors that give rise to two motor neurons each, OLIG2+/NKX2-2+ ventral motor neuron progenitors remain cycling longer, yielding ~5 times more motor neurons that are biased toward later-born, FOXP1-expressing subtypes. Knockout of NKX2-2 converts ventral motor neuron progenitors into classical motor neuron progenitors. Such new progenitors may contribute to the increased production of human motor neurons required for the generation of larger, more complex nervous systems. The authors find a newly evolved progenitor domain extends and expands spinal motor neurogenesis in humans.
{"title":"A human-specific progenitor sub-domain extends neurogenesis and increases motor neuron production","authors":"Sumin Jang, Elias Gumnit, Hynek Wichterle","doi":"10.1038/s41593-024-01739-8","DOIUrl":"10.1038/s41593-024-01739-8","url":null,"abstract":"Neurogenesis lasts ~10 times longer in developing humans compared to mice, resulting in a >1,000-fold increase in the number of neurons in the CNS. To identify molecular and cellular mechanisms contributing to this difference, we studied human and mouse motor neurogenesis using a stem cell differentiation system that recapitulates species-specific scales of development. Comparison of human and mouse single-cell gene expression data identified human-specific progenitors characterized by coexpression of NKX2-2 and OLIG2 that give rise to spinal motor neurons. Unlike classical OLIG2+ motor neuron progenitors that give rise to two motor neurons each, OLIG2+/NKX2-2+ ventral motor neuron progenitors remain cycling longer, yielding ~5 times more motor neurons that are biased toward later-born, FOXP1-expressing subtypes. Knockout of NKX2-2 converts ventral motor neuron progenitors into classical motor neuron progenitors. Such new progenitors may contribute to the increased production of human motor neurons required for the generation of larger, more complex nervous systems. The authors find a newly evolved progenitor domain extends and expands spinal motor neurogenesis in humans.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 10","pages":"1945-1953"},"PeriodicalIF":21.2,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1038/s41593-024-01743-y
Sarah J. Pfau, Urs H. Langen, Theodore M. Fisher, Indumathi Prakash, Faheem Nagpurwala, Ricardo A. Lozoya, Wei-Chung Allen Lee, Zhuhao Wu, Chenghua Gu
The blood–brain barrier (BBB) protects the brain and maintains neuronal homeostasis. BBB properties can vary between brain regions to support regional functions, yet how BBB heterogeneity occurs is poorly understood. Here, we used single-cell and spatial transcriptomics to compare the mouse median eminence, one of the circumventricular organs that has naturally leaky blood vessels, with the cortex. We identified hundreds of molecular differences in endothelial cells (ECs) and perivascular cells, including astrocytes, pericytes and fibroblasts. Using electron microscopy and an aqueous-based tissue-clearing method, we revealed distinct anatomical specializations and interaction patterns of ECs and perivascular cells in these regions. Finally, we identified candidate regionally enriched EC–perivascular cell ligand–receptor pairs. Our results indicate that both molecular specializations in ECs and unique EC–perivascular cell interactions contribute to BBB functional heterogeneity. This platform can be used to investigate BBB heterogeneity in other regions and may facilitate the development of central nervous system region-specific therapeutics. Comprehensive profiling of a circumventricular organ with leaky blood vessels, and comparison to cortex vasculature reveal that blood–brain barrier heterogeneity reflects differences in endothelial cells and their interactions with perivascular cells.
{"title":"Characteristics of blood–brain barrier heterogeneity between brain regions revealed by profiling vascular and perivascular cells","authors":"Sarah J. Pfau, Urs H. Langen, Theodore M. Fisher, Indumathi Prakash, Faheem Nagpurwala, Ricardo A. Lozoya, Wei-Chung Allen Lee, Zhuhao Wu, Chenghua Gu","doi":"10.1038/s41593-024-01743-y","DOIUrl":"10.1038/s41593-024-01743-y","url":null,"abstract":"The blood–brain barrier (BBB) protects the brain and maintains neuronal homeostasis. BBB properties can vary between brain regions to support regional functions, yet how BBB heterogeneity occurs is poorly understood. Here, we used single-cell and spatial transcriptomics to compare the mouse median eminence, one of the circumventricular organs that has naturally leaky blood vessels, with the cortex. We identified hundreds of molecular differences in endothelial cells (ECs) and perivascular cells, including astrocytes, pericytes and fibroblasts. Using electron microscopy and an aqueous-based tissue-clearing method, we revealed distinct anatomical specializations and interaction patterns of ECs and perivascular cells in these regions. Finally, we identified candidate regionally enriched EC–perivascular cell ligand–receptor pairs. Our results indicate that both molecular specializations in ECs and unique EC–perivascular cell interactions contribute to BBB functional heterogeneity. This platform can be used to investigate BBB heterogeneity in other regions and may facilitate the development of central nervous system region-specific therapeutics. Comprehensive profiling of a circumventricular organ with leaky blood vessels, and comparison to cortex vasculature reveal that blood–brain barrier heterogeneity reflects differences in endothelial cells and their interactions with perivascular cells.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 10","pages":"1892-1903"},"PeriodicalIF":21.2,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01743-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1038/s41593-024-01738-9
Hiroshi M. Shiozaki, Kaiyu Wang, Joshua L. Lillvis, Min Xu, Barry J. Dickson, David L. Stern
Motor systems implement diverse motor programs to pattern behavioral sequences, yet how different motor actions are controlled on a moment-by-moment basis remains unclear. Here, we investigated the neural circuit mechanisms underlying the control of distinct courtship songs in Drosophila. Courting males rapidly alternate between two types of song: pulse and sine. By recording calcium signals in the ventral nerve cord in singing flies, we found that one neural population is active during both songs, whereas an expanded neural population, which includes neurons from the first population, is active during pulse song. Brain recordings showed that this nested activation pattern is present in two descending pathways required for singing. Connectomic analysis reveals that these two descending pathways provide structured input to ventral nerve cord neurons in a manner consistent with their activation patterns. These results suggest that nested premotor circuit activity, directed by distinct descending signals, enables rapid switching between motor actions. Activation of nested, but not discrete, neural circuits drives alternative courtship songs in male Drosophila melanogaster, providing further insight into how the nervous system can drive the same motor systems to rapidly switch between different actions.
{"title":"Activity of nested neural circuits drives different courtship songs in Drosophila","authors":"Hiroshi M. Shiozaki, Kaiyu Wang, Joshua L. Lillvis, Min Xu, Barry J. Dickson, David L. Stern","doi":"10.1038/s41593-024-01738-9","DOIUrl":"10.1038/s41593-024-01738-9","url":null,"abstract":"Motor systems implement diverse motor programs to pattern behavioral sequences, yet how different motor actions are controlled on a moment-by-moment basis remains unclear. Here, we investigated the neural circuit mechanisms underlying the control of distinct courtship songs in Drosophila. Courting males rapidly alternate between two types of song: pulse and sine. By recording calcium signals in the ventral nerve cord in singing flies, we found that one neural population is active during both songs, whereas an expanded neural population, which includes neurons from the first population, is active during pulse song. Brain recordings showed that this nested activation pattern is present in two descending pathways required for singing. Connectomic analysis reveals that these two descending pathways provide structured input to ventral nerve cord neurons in a manner consistent with their activation patterns. These results suggest that nested premotor circuit activity, directed by distinct descending signals, enables rapid switching between motor actions. Activation of nested, but not discrete, neural circuits drives alternative courtship songs in male Drosophila melanogaster, providing further insight into how the nervous system can drive the same motor systems to rapidly switch between different actions.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 10","pages":"1954-1965"},"PeriodicalIF":21.2,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01738-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1038/s41593-024-01740-1
Lindsey D. Goodman, Isha Ralhan, Xin Li, Shenzhao Lu, Matthew J. Moulton, Ye-Jin Park, Pinghan Zhao, Oguz Kanca, Ziyaneh S. Ghaderpour Taleghani, Julie Jacquemyn, Joshua M. Shulman, Kanae Ando, Kai Sun, Maria S. Ioannou, Hugo J. Bellen
The accumulation of reactive oxygen species (ROS) is a common feature of tauopathies, defined by Tau accumulations in neurons and glia. High ROS in neurons causes lipid production and the export of toxic peroxidated lipids (LPOs). Glia uptake these LPOs and incorporate them into lipid droplets (LDs) for storage and catabolism. We found that overexpressing Tau in glia disrupts LDs in flies and rat neuron–astrocyte co-cultures, sensitizing the glia to toxic, neuronal LPOs. Using a new fly tau loss-of-function allele and RNA-mediated interference, we found that endogenous Tau is required for glial LD formation and protection against neuronal LPOs. Similarly, endogenous Tau is required in rat astrocytes and human oligodendrocyte-like cells for LD formation and the breakdown of LPOs. Behaviorally, flies lacking glial Tau have decreased lifespans and motor defects that are rescuable by administering the antioxidant N-acetylcysteine amide. Overall, this work provides insights into the important role that Tau has in glia to mitigate ROS in the brain. Goodman et al. found that Tau is critical for ROS-induced lipid droplet formation in glia from flies and mammals. Too much or too little glial Tau disrupts lipid droplets, leaving the glia susceptible to neuronal ROS-induced damage and causing phenotypes in tau−/− flies.
活性氧（ROS）的积累是神经元和胶质细胞中Tau积累所定义的tau病的一个共同特征。神经元中的高ROS会导致脂质生成和有毒过氧化脂质（LPO）的输出。胶质细胞吸收这些过氧化脂质，并将其纳入脂滴（LDs）进行储存和分解。我们发现，在神经胶质细胞中过表达 Tau 会破坏苍蝇和大鼠神经元-胃细胞共培养物中的 LDs，使神经胶质细胞对有毒的神经元 LPOs 敏感。利用一种新的蝇tau功能缺失等位基因和RNA介导的干扰，我们发现神经胶质细胞LD的形成和对神经元LPO的保护需要内源性Tau。同样，大鼠星形胶质细胞和人类少突胶质细胞也需要内源性 Tau 来形成 LD 和分解 LPO。从行为学角度看，缺乏神经胶质 Tau 的苍蝇寿命缩短，运动机能出现缺陷，但通过服用抗氧化剂 N-乙酰半胱氨酸酰胺可以挽救这些缺陷。总之，这项研究深入揭示了 Tau 在胶质细胞中缓解大脑中 ROS 的重要作用。
{"title":"Tau is required for glial lipid droplet formation and resistance to neuronal oxidative stress","authors":"Lindsey D. Goodman, Isha Ralhan, Xin Li, Shenzhao Lu, Matthew J. Moulton, Ye-Jin Park, Pinghan Zhao, Oguz Kanca, Ziyaneh S. Ghaderpour Taleghani, Julie Jacquemyn, Joshua M. Shulman, Kanae Ando, Kai Sun, Maria S. Ioannou, Hugo J. Bellen","doi":"10.1038/s41593-024-01740-1","DOIUrl":"10.1038/s41593-024-01740-1","url":null,"abstract":"The accumulation of reactive oxygen species (ROS) is a common feature of tauopathies, defined by Tau accumulations in neurons and glia. High ROS in neurons causes lipid production and the export of toxic peroxidated lipids (LPOs). Glia uptake these LPOs and incorporate them into lipid droplets (LDs) for storage and catabolism. We found that overexpressing Tau in glia disrupts LDs in flies and rat neuron–astrocyte co-cultures, sensitizing the glia to toxic, neuronal LPOs. Using a new fly tau loss-of-function allele and RNA-mediated interference, we found that endogenous Tau is required for glial LD formation and protection against neuronal LPOs. Similarly, endogenous Tau is required in rat astrocytes and human oligodendrocyte-like cells for LD formation and the breakdown of LPOs. Behaviorally, flies lacking glial Tau have decreased lifespans and motor defects that are rescuable by administering the antioxidant N-acetylcysteine amide. Overall, this work provides insights into the important role that Tau has in glia to mitigate ROS in the brain. Goodman et al. found that Tau is critical for ROS-induced lipid droplet formation in glia from flies and mammals. Too much or too little glial Tau disrupts lipid droplets, leaving the glia susceptible to neuronal ROS-induced damage and causing phenotypes in tau−/− flies.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 10","pages":"1918-1933"},"PeriodicalIF":21.2,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1038/s41593-024-01737-w
Alexa Pichet Binette, Chris Gaiteri, Malin Wennström, Atul Kumar, Ines Hristovska, Nicola Spotorno, Gemma Salvadó, Olof Strandberg, Hansruedi Mathys, Li-Huei Tsai, Sebastian Palmqvist, Niklas Mattsson-Carlgren, Shorena Janelidze, Erik Stomrud, Jacob W. Vogel, Oskar Hansson
Proteomics can shed light on the dynamic and multifaceted alterations in neurodegenerative disorders like Alzheimer’s disease (AD). Combining radioligands measuring β-amyloid (Aβ) plaques and tau tangles with cerebrospinal fluid proteomics, we uncover molecular events mirroring different stages of AD pathology in living humans. We found 127 differentially abundant proteins (DAPs) across the AD spectrum. The strongest Aβ-related proteins were mainly expressed in glial cells and included SMOC1 and ITGAM. A dozen proteins linked to ATP metabolism and preferentially expressed in neurons were independently associated with tau tangle load and tau accumulation. Only 20% of the DAPs were also altered in other neurodegenerative diseases, underscoring AD’s distinct proteome. Two co-expression modules related, respectively, to protein metabolism and microglial immune response encompassed most DAPs, with opposing, staggered trajectories along the AD continuum. We unveil protein signatures associated with Aβ and tau proteinopathy in vivo, offering insights into complex neural responses and potential biomarkers and therapeutics targeting different disease stages. Using human cerebrospinal fluid proteomics, the authors found that proteins associated with Aβ pathology in Alzheimer disease were mainly expressed in glial cells, whereas those associated with tau tangle were linked to metabolism and mainly expressed in neurons.
蛋白质组学可以揭示阿尔茨海默病（AD）等神经退行性疾病的多方面动态变化。我们将测量β-淀粉样蛋白（Aβ）斑块和tau缠结的放射性配体与脑脊液蛋白质组学相结合，发现了反映活人阿尔茨海默病不同病理阶段的分子事件。我们发现了127种AD谱系中的差异丰度蛋白（DAPs）。最强的Aβ相关蛋白主要在神经胶质细胞中表达，包括SMOC1和ITGAM。十几种与 ATP 代谢有关并优先在神经元中表达的蛋白质与 tau 纠结负荷和 tau 累积有独立关联。只有20%的DAPs在其他神经退行性疾病中也发生了改变，这突显了AD独特的蛋白质组。两个共表达模块分别与蛋白质代谢和小胶质细胞免疫反应有关，涵盖了大多数 DAPs，它们在 AD 连续体中的轨迹相反且交错。我们揭示了与体内 Aβ 和 tau 蛋白病变相关的蛋白质特征，为复杂的神经反应以及针对不同疾病阶段的潜在生物标记物和疗法提供了见解。
{"title":"Proteomic changes in Alzheimer’s disease associated with progressive Aβ plaque and tau tangle pathologies","authors":"Alexa Pichet Binette, Chris Gaiteri, Malin Wennström, Atul Kumar, Ines Hristovska, Nicola Spotorno, Gemma Salvadó, Olof Strandberg, Hansruedi Mathys, Li-Huei Tsai, Sebastian Palmqvist, Niklas Mattsson-Carlgren, Shorena Janelidze, Erik Stomrud, Jacob W. Vogel, Oskar Hansson","doi":"10.1038/s41593-024-01737-w","DOIUrl":"10.1038/s41593-024-01737-w","url":null,"abstract":"Proteomics can shed light on the dynamic and multifaceted alterations in neurodegenerative disorders like Alzheimer’s disease (AD). Combining radioligands measuring β-amyloid (Aβ) plaques and tau tangles with cerebrospinal fluid proteomics, we uncover molecular events mirroring different stages of AD pathology in living humans. We found 127 differentially abundant proteins (DAPs) across the AD spectrum. The strongest Aβ-related proteins were mainly expressed in glial cells and included SMOC1 and ITGAM. A dozen proteins linked to ATP metabolism and preferentially expressed in neurons were independently associated with tau tangle load and tau accumulation. Only 20% of the DAPs were also altered in other neurodegenerative diseases, underscoring AD’s distinct proteome. Two co-expression modules related, respectively, to protein metabolism and microglial immune response encompassed most DAPs, with opposing, staggered trajectories along the AD continuum. We unveil protein signatures associated with Aβ and tau proteinopathy in vivo, offering insights into complex neural responses and potential biomarkers and therapeutics targeting different disease stages. Using human cerebrospinal fluid proteomics, the authors found that proteins associated with Aβ pathology in Alzheimer disease were mainly expressed in glial cells, whereas those associated with tau tangle were linked to metabolism and mainly expressed in neurons.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 10","pages":"1880-1891"},"PeriodicalIF":21.2,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01737-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-23DOI: 10.1038/s41593-024-01736-x
Hao-Ming Dong, Xi-Han Zhang, Loïc Labache, Shaoshi Zhang, Leon Qi Rong Ooi, B. T. Thomas Yeo, Daniel S. Margulies, Avram J. Holmes, Xi-Nian Zuo
The human brain experiences functional changes through childhood and adolescence, shifting from an organizational framework anchored within sensorimotor and visual regions into one that is balanced through interactions with later-maturing aspects of association cortex. Here, we link this profile of functional reorganization to the development of ventral attention network connectivity across independent datasets. We demonstrate that maturational changes in cortical organization link preferentially to within-network connectivity and heightened degree centrality in the ventral attention network, whereas connectivity within network-linked vertices predicts cognitive ability. This connectivity is associated closely with maturational refinement of cortical organization. Children with low ventral attention network connectivity exhibit adolescent-like topographical profiles, suggesting that attentional systems may be relevant in understanding how brain functions are refined across development. These data suggest a role for attention networks in supporting age-dependent shifts in cortical organization and cognition across childhood and adolescence. Understanding brain development and systems linked to behavioral change is a key goal in population neuroscience. The authors show the ventral attention network is key for brain development and cognitive ability in cross-culture longitudinal cohorts.
{"title":"Ventral attention network connectivity is linked to cortical maturation and cognitive ability in childhood","authors":"Hao-Ming Dong, Xi-Han Zhang, Loïc Labache, Shaoshi Zhang, Leon Qi Rong Ooi, B. T. Thomas Yeo, Daniel S. Margulies, Avram J. Holmes, Xi-Nian Zuo","doi":"10.1038/s41593-024-01736-x","DOIUrl":"10.1038/s41593-024-01736-x","url":null,"abstract":"The human brain experiences functional changes through childhood and adolescence, shifting from an organizational framework anchored within sensorimotor and visual regions into one that is balanced through interactions with later-maturing aspects of association cortex. Here, we link this profile of functional reorganization to the development of ventral attention network connectivity across independent datasets. We demonstrate that maturational changes in cortical organization link preferentially to within-network connectivity and heightened degree centrality in the ventral attention network, whereas connectivity within network-linked vertices predicts cognitive ability. This connectivity is associated closely with maturational refinement of cortical organization. Children with low ventral attention network connectivity exhibit adolescent-like topographical profiles, suggesting that attentional systems may be relevant in understanding how brain functions are refined across development. These data suggest a role for attention networks in supporting age-dependent shifts in cortical organization and cognition across childhood and adolescence. Understanding brain development and systems linked to behavioral change is a key goal in population neuroscience. The authors show the ventral attention network is key for brain development and cognitive ability in cross-culture longitudinal cohorts.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 10","pages":"2009-2020"},"PeriodicalIF":21.2,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142042670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：