Nature neuroscience最新文献_第8页

Maintaining and updating accurate internal representations of continuous variables with a handful of neurons 用少量神经元维护和更新连续变量的精确内部表征

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-10-03 DOI: 10.1038/s41593-024-01766-5

Marcella Noorman, Brad K. Hulse, Vivek Jayaraman, Sandro Romani, Ann M. Hermundstad

{"title":"Maintaining and updating accurate internal representations of continuous variables with a handful of neurons","authors":"Marcella Noorman, Brad K. Hulse, Vivek Jayaraman, Sandro Romani, Ann M. Hermundstad","doi":"10.1038/s41593-024-01766-5","DOIUrl":"10.1038/s41593-024-01766-5","url":null,"abstract":"Many animals rely on persistent internal representations of continuous variables for working memory, navigation, and motor control. Existing theories typically assume that large networks of neurons are required to maintain such representations accurately; networks with few neurons are thought to generate discrete representations. However, analysis of two-photon calcium imaging data from tethered flies walking in darkness suggests that their small head-direction system can maintain a surprisingly continuous and accurate representation. We thus ask whether it is possible for a small network to generate a continuous, rather than discrete, representation of such a variable. We show analytically that even very small networks can be tuned to maintain continuous internal representations, but this comes at the cost of sensitivity to noise and variations in tuning. This work expands the computational repertoire of small networks, and raises the possibility that larger networks could represent more and higher-dimensional variables than previously thought. Many animals rely on internal representations of continuous variables such as head direction to guide behavior. Noorman et al. show how such representations can be accurately maintained in small neural networks, countering decades of theoretical intuition.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 11","pages":"2207-2217"},"PeriodicalIF":21.2,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01766-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142368783","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}

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Proinflammatory immune cells disrupt angiogenesis and promote germinal matrix hemorrhage in prenatal human brain 前炎症性免疫细胞破坏血管生成并促进产前人脑胚芽基质出血

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-09-30 DOI: 10.1038/s41593-024-01769-2

Jiapei Chen, Elizabeth E. Crouch, Miriam E. Zawadzki, Kyle A. Jacobs, Lakyn N. Mayo, Jennifer Ja-Yoon Choi, Pin-Yeh Lin, Saba Shaikh, Jessica Tsui, Susana Gonzalez-Granero, Shamari Waller, Avani Kelekar, Gugene Kang, Edward J. Valenzuela, Janeth Ochoa Birrueta, Loukas N. Diafos, Kaylee Wedderburn-Pugh, Barbara Di Marco, Wenlong Xia, Claudia Z. Han, Nicole G. Coufal, Christopher K. Glass, Stephen P. J. Fancy, Julieta Alfonso, Arnold R. Kriegstein, Michael C. Oldham, Jose Manuel Garcia-Verdugo, Matthew L. Kutys, Maria K. Lehtinen, Alexis J. Combes, Eric J. Huang

{"title":"Proinflammatory immune cells disrupt angiogenesis and promote germinal matrix hemorrhage in prenatal human brain","authors":"Jiapei Chen, Elizabeth E. Crouch, Miriam E. Zawadzki, Kyle A. Jacobs, Lakyn N. Mayo, Jennifer Ja-Yoon Choi, Pin-Yeh Lin, Saba Shaikh, Jessica Tsui, Susana Gonzalez-Granero, Shamari Waller, Avani Kelekar, Gugene Kang, Edward J. Valenzuela, Janeth Ochoa Birrueta, Loukas N. Diafos, Kaylee Wedderburn-Pugh, Barbara Di Marco, Wenlong Xia, Claudia Z. Han, Nicole G. Coufal, Christopher K. Glass, Stephen P. J. Fancy, Julieta Alfonso, Arnold R. Kriegstein, Michael C. Oldham, Jose Manuel Garcia-Verdugo, Matthew L. Kutys, Maria K. Lehtinen, Alexis J. Combes, Eric J. Huang","doi":"10.1038/s41593-024-01769-2","DOIUrl":"10.1038/s41593-024-01769-2","url":null,"abstract":"Germinal matrix hemorrhage (GMH) is a devastating neurodevelopmental condition affecting preterm infants, but why blood vessels in this brain region are vulnerable to rupture remains unknown. Here we show that microglia in prenatal mouse and human brain interact with nascent vasculature in an age-dependent manner and that ablation of these cells in mice reduces angiogenesis in the ganglionic eminences, which correspond to the human germinal matrix. Consistent with these findings, single-cell transcriptomics and flow cytometry show that distinct subsets of CD45+ cells from control preterm infants employ diverse signaling mechanisms to promote vascular network formation. In contrast, CD45+ cells from infants with GMH harbor activated neutrophils and monocytes that produce proinflammatory factors, including azurocidin 1, elastase and CXCL16, to disrupt vascular integrity and cause hemorrhage in ganglionic eminences. These results underscore the brain’s innate immune cells in region-specific angiogenesis and how aberrant activation of these immune cells promotes GMH in preterm infants. Chen et al. show that subtypes of immune cells in prenatal human brain promote angiogenesis in the germinal matrix. Conversely, in preterm infants, proinflammatory immune cells disrupt angiogenesis and promote germinal matrix hemorrhage.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 11","pages":"2115-2129"},"PeriodicalIF":21.2,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01769-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329711","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}

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Stimulating Wnt signaling reveals context-dependent genetic effects on gene regulation in primary human neural progenitors 刺激 Wnt 信号揭示了人类原代神经祖细胞基因调控的环境依赖性遗传效应

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-09-30 DOI: 10.1038/s41593-024-01773-6

Nana Matoba, Brandon D. Le, Jordan M. Valone, Justin M. Wolter, Jessica T. Mory, Dan Liang, Nil Aygün, K. Alaine Broadaway, Marielle L. Bond, Karen L. Mohlke, Mark J. Zylka, Michael I. Love, Jason L. Stein

{"title":"Stimulating Wnt signaling reveals context-dependent genetic effects on gene regulation in primary human neural progenitors","authors":"Nana Matoba, Brandon D. Le, Jordan M. Valone, Justin M. Wolter, Jessica T. Mory, Dan Liang, Nil Aygün, K. Alaine Broadaway, Marielle L. Bond, Karen L. Mohlke, Mark J. Zylka, Michael I. Love, Jason L. Stein","doi":"10.1038/s41593-024-01773-6","DOIUrl":"10.1038/s41593-024-01773-6","url":null,"abstract":"Gene regulatory effects have been difficult to detect at many non-coding loci associated with brain-related traits, likely because some genetic variants have distinct functions in specific contexts. To explore context-dependent gene regulation, we measured chromatin accessibility and gene expression after activation of the canonical Wnt pathway in primary human neural progenitors (n = 82 donors). We found that TCF/LEF motifs and brain-structure-associated and neuropsychiatric-disorder-associated variants were enriched within Wnt-responsive regulatory elements. Genetically influenced regulatory elements were enriched in genomic regions under positive selection along the human lineage. Wnt pathway stimulation increased detection of genetically influenced regulatory elements/genes by 66%/53% and enabled identification of 397 regulatory elements primed to regulate gene expression. Stimulation also increased identification of shared genetic effects on molecular and complex brain traits by up to 70%, suggesting that genetic variant function during neurodevelopmental patterning can lead to differences in adult brain and behavioral traits. Matoba, Le, Valone et al. characterized context-dependent genetic effects on gene regulatory activity during Wnt stimulation, finding that genetic variant function during neurodevelopment patterning can lead to differences in adult brain traits.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 12","pages":"2430-2442"},"PeriodicalIF":21.2,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329714","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}

引用次数: 0

Advances and controversies in meningeal biology 脑膜生物学的进展与争议

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-09-27 DOI: 10.1038/s41593-024-01701-8

Christer Betsholtz, Britta Engelhardt, Gou Young Koh, Donald M. McDonald, Steven T. Proulx, Julie Siegenthaler

{"title":"Advances and controversies in meningeal biology","authors":"Christer Betsholtz, Britta Engelhardt, Gou Young Koh, Donald M. McDonald, Steven T. Proulx, Julie Siegenthaler","doi":"10.1038/s41593-024-01701-8","DOIUrl":"10.1038/s41593-024-01701-8","url":null,"abstract":"The dura, arachnoid and pia mater, as the constituent layers of the meninges, along with cerebrospinal fluid in the subarachnoid space and ventricles, are essential protectors of the brain and spinal cord. Complemented by immune cells, blood vessels, lymphatic vessels and nerves, these connective tissue layers have held many secrets that have only recently begun to be revealed. Each meningeal layer is now known to have molecularly distinct types of fibroblasts. Cerebrospinal fluid clearance through peripheral lymphatics and lymph nodes is well documented, but its routes and flow dynamics are debated. Advances made in meningeal immune functions are also debated. This Review considers the cellular and molecular structure and function of the dura, arachnoid and pia mater in the context of conventional views, recent progress, and what is uncertain or unknown. The hallmarks of meningeal pathophysiology are identified toward developing a more complete understanding of the meninges in health and disease. The authors review current knowledge of the molecular identity and functions of the dura, arachnoid and pial layers of meninges and controversial aspects of meningeal biology that deserve further study to resolve ongoing debates in the field.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 11","pages":"2056-2072"},"PeriodicalIF":21.2,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321970","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}

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Dopamine-mediated formation of a memory module in the nucleus accumbens for goal-directed navigation 多巴胺介导的目标定向导航核记忆模块的形成

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-09-27 DOI: 10.1038/s41593-024-01770-9

Kanghoon Jung, Sarah Krüssel, Sooyeon Yoo, Myungmo An, Benjamin Burke, Nicholas Schappaugh, Youngjin Choi, Zirong Gu, Seth Blackshaw, Rui M. Costa, Hyung-Bae Kwon

{"title":"Dopamine-mediated formation of a memory module in the nucleus accumbens for goal-directed navigation","authors":"Kanghoon Jung, Sarah Krüssel, Sooyeon Yoo, Myungmo An, Benjamin Burke, Nicholas Schappaugh, Youngjin Choi, Zirong Gu, Seth Blackshaw, Rui M. Costa, Hyung-Bae Kwon","doi":"10.1038/s41593-024-01770-9","DOIUrl":"10.1038/s41593-024-01770-9","url":null,"abstract":"Spatial memories guide navigation efficiently toward desired destinations. However, the neuronal and circuit mechanisms underlying the encoding of goal locations and its translation into goal-directed navigation remain unclear. Here we demonstrate that mice rapidly form a spatial memory of a shelter during shelter experiences, guiding escape behavior toward the goal location—a shelter—when under threat. Dopaminergic neurons in the ventral tegmental area and their projection to the nucleus accumbens (NAc) encode safety signals associated with the shelter. Optogenetically induced phasic dopamine signals are sufficient to create a place memory that directs escape navigation. Converging dopaminergic and hippocampal glutamatergic inputs to the NAc mediate the formation of a goal-related memory within a subpopulation of NAc neurons during shelter experiences. Artificial co-activation of this goal-related NAc ensemble with neurons in the dorsal periaqueductal gray was sufficient to trigger memory-guided, rather than random, escape behavior. These findings provide causal evidence of cognitive circuit modules linking memory with goal-directed action. Jung et al. show that shelter experience boosts dopamine release in the nucleus accumbens, generating a goal-location memory. Reactivating a neuronal ensemble developed from shelter experience enables memory-guided navigation to the goal during escape.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 11","pages":"2178-2192"},"PeriodicalIF":21.2,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01770-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321975","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}

引用次数: 0

A potential target for noninvasive neuromodulation of PTSD symptoms derived from focal brain lesions in veterans 对退伍军人因局灶性脑损伤引起的创伤后应激障碍症状进行无创神经调节的潜在目标

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-09-24 DOI: 10.1038/s41593-024-01772-7

Shan H. Siddiqi, Noah S. Philip, Stephan T. Palm, David M. Carreon, Amanda R. Arulpragasam, Jennifer Barredo, Heather Bouchard, Michael A. Ferguson, Jordan H. Grafman, Rajendra A. Morey, Michael D. Fox

{"title":"A potential target for noninvasive neuromodulation of PTSD symptoms derived from focal brain lesions in veterans","authors":"Shan H. Siddiqi, Noah S. Philip, Stephan T. Palm, David M. Carreon, Amanda R. Arulpragasam, Jennifer Barredo, Heather Bouchard, Michael A. Ferguson, Jordan H. Grafman, Rajendra A. Morey, Michael D. Fox","doi":"10.1038/s41593-024-01772-7","DOIUrl":"10.1038/s41593-024-01772-7","url":null,"abstract":"Neuromodulation trials for the treatment of posttraumatic stress disorder (PTSD) have yielded mixed results, and the optimal neuroanatomical target remains unclear. Here we analyzed three datasets to study brain circuitry causally linked to PTSD in military veterans. In veterans with penetrating traumatic brain injury, lesion locations that reduced probability of PTSD were preferentially connected to a circuit including the medial prefrontal cortex, amygdala and anterolateral temporal lobe. In veterans without lesions, PTSD was specifically associated with increased connectivity within this circuit. Reduced functional connectivity within this circuit after transcranial magnetic stimulation correlated with symptom reduction, even though the circuit was not directly targeted. This lesion-based ‘PTSD circuit’ may serve as a target for clinical trials of neuromodulation in veterans with PTSD. Siddiqi et al. identified lesion locations that reduced probability of PTSD. These were connected to a brain circuit in which increased connectivity was associated with PTSD, thus revealing a PTSD target circuit for therapeutic brain stimulation.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 11","pages":"2231-2239"},"PeriodicalIF":21.2,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142313717","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}

引用次数: 0

Publisher Correction: DOR activation in mature oligodendrocytes regulates α-ketoglutarate metabolism leading to enhanced remyelination in aged mice 出版商更正：成熟少突胶质细胞中的DOR激活可调节α-酮戊二酸代谢，从而增强老龄小鼠的髓鞘再形成

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-09-24 DOI: 10.1038/s41593-024-01785-2

Guojiao Huang, Zhidan Li, Xuezhao Liu, Menglong Guan, Songlin Zhou, Xiaowen Zhong, Tao Zheng, Dazhuan Xin, Xiaosong Gu, Dezhi Mu, Yingkun Guo, Lin Zhang, Liguo Zhang, Q. Richard Lu, Xuelian He

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Single-cell m6A profiling in the mouse brain uncovers cell type-specific RNA methylomes and age-dependent differential methylation 小鼠大脑单细胞 m6A 图谱揭示细胞类型特异性 RNA 甲基组和年龄依赖性差异甲基化

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-09-24 DOI: 10.1038/s41593-024-01768-3

Matthew Tegowski, Anna K. Prater, Christopher L. Holley, Kate D. Meyer

{"title":"Single-cell m6A profiling in the mouse brain uncovers cell type-specific RNA methylomes and age-dependent differential methylation","authors":"Matthew Tegowski, Anna K. Prater, Christopher L. Holley, Kate D. Meyer","doi":"10.1038/s41593-024-01768-3","DOIUrl":"10.1038/s41593-024-01768-3","url":null,"abstract":"N6-methyladenosine (m6A) is an abundant mRNA modification in the brain that has important roles in neurodevelopment and brain function. However, because of technical limitations, global profiling of m6A sites within the individual cell types that make up the brain has not been possible. Here, we develop a mouse model that enables transcriptome-wide m6A detection in any tissue of interest at single-cell resolution. We use these mice to map m6A across different brain regions and within single cells of the mouse cortex and discover a high degree of shared methylation across brain regions and cell types. However, we also identify a small number of differentially methylated mRNAs in neurons that encode important regulators of neuronal signaling, and we discover that microglia have lower levels of m6A than other cell types. Finally, we perform single-cell m6A mapping in aged mice and identify many transcripts with age-dependent changes in m6A. The authors perform the first single-cell profiling of m6A in the mouse brain. They uncover relative hypomethylation of microglial mRNA compared to other cell types, and they identify hundreds of RNAs that undergo differential methylation with age.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 12","pages":"2512-2520"},"PeriodicalIF":21.2,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142313754","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}

引用次数: 0

Primate superior colliculus is causally engaged in abstract higher-order cognition 灵长类动物的上丘参与抽象的高阶认知。

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-09-19 DOI: 10.1038/s41593-024-01744-x

Barbara Peysakhovich, Ou Zhu, Stephanie M. Tetrick, Vinay Shirhatti, Alessandra A. Silva, Sihai Li, Guilhem Ibos, Matthew C. Rosen, W. Jeffrey Johnston, David J. Freedman

{"title":"Primate superior colliculus is causally engaged in abstract higher-order cognition","authors":"Barbara Peysakhovich, Ou Zhu, Stephanie M. Tetrick, Vinay Shirhatti, Alessandra A. Silva, Sihai Li, Guilhem Ibos, Matthew C. Rosen, W. Jeffrey Johnston, David J. Freedman","doi":"10.1038/s41593-024-01744-x","DOIUrl":"10.1038/s41593-024-01744-x","url":null,"abstract":"The superior colliculus is an evolutionarily conserved midbrain region that is thought to mediate spatial orienting, including saccadic eye movements and covert spatial attention. Here, we reveal a role for the superior colliculus in higher-order cognition, independent of its role in spatial orienting. We trained rhesus macaques to perform an abstract visual categorization task that involved neither instructed eye movements nor differences in covert attention. We compared neural activity in the superior colliculus and the posterior parietal cortex, a region previously shown to causally contribute to abstract category decisions. The superior colliculus exhibits robust encoding of learned visual categories, which is stronger than in the posterior parietal cortex and arises at a similar latency in the two areas. Moreover, inactivation of the superior colliculus markedly impaired animals’ category decisions. These results demonstrate that the primate superior colliculus mediates abstract, higher-order cognitive processes that have traditionally been attributed to the neocortex. Neuronal recordings show that primate superior colliculus encodes learned abstract visual categories. The authors demonstrate that it plays a causal role in categorization behavior, independent of its role in spatial orienting.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 10","pages":"1999-2008"},"PeriodicalIF":21.2,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273487","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}

引用次数: 0

Inhibiting Ca2+ channels in Alzheimer’s disease model mice relaxes pericytes, improves cerebral blood flow and reduces immune cell stalling and hypoxia 抑制阿尔茨海默病模型小鼠的 Ca2+ 通道可松弛周细胞、改善脑血流并减少免疫细胞停滞和缺氧现象

IF 21.2 1区医学

Nature neuroscience Pub Date : 2024-09-18 DOI: 10.1038/s41593-024-01753-w

Nils Korte, Anna Barkaway, Jack Wells, Felipe Freitas, Huma Sethi, Stephen P. Andrews, John Skidmore, Beth Stevens, David Attwell

{"title":"Inhibiting Ca2+ channels in Alzheimer’s disease model mice relaxes pericytes, improves cerebral blood flow and reduces immune cell stalling and hypoxia","authors":"Nils Korte, Anna Barkaway, Jack Wells, Felipe Freitas, Huma Sethi, Stephen P. Andrews, John Skidmore, Beth Stevens, David Attwell","doi":"10.1038/s41593-024-01753-w","DOIUrl":"10.1038/s41593-024-01753-w","url":null,"abstract":"Early in Alzheimer’s disease (AD), pericytes constrict capillaries, increasing their hydraulic resistance and trapping of immune cells and, thus, decreasing cerebral blood flow (CBF). Therapeutic approaches to attenuate pericyte-mediated constriction in AD are lacking. Here, using in vivo two-photon imaging with laser Doppler and speckle flowmetry and magnetic resonance imaging, we show that Ca2+ entry via L-type voltage-gated calcium channels (CaVs) controls the contractile tone of pericytes. In AD model mice, we identifed pericytes throughout the capillary bed as key drivers of an immune reactive oxygen species (ROS)-evoked and pericyte intracellular calcium concentration ([Ca2+]i)-mediated decrease in microvascular flow. Blocking CaVs with nimodipine early in disease progression improved CBF, reduced leukocyte stalling at pericyte somata and attenuated brain hypoxia. Amyloid β (Aβ)-evoked pericyte contraction in human cortical tissue was also greatly reduced by CaV block. Lowering pericyte [Ca2+]i early in AD may, thus, offer a therapeutic strategy to enhance brain energy supply and possibly cognitive function in AD. Early in Alzheimer’s disease (AD), brain blood flow is reduced by pericytes constricting capillaries. Korte et al. show that oral nimodipine can reverse this and decrease brain hypoxia. Blocking capillary constriction is a potential add-on therapy in AD.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"27 11","pages":"2086-2100"},"PeriodicalIF":21.2,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41593-024-01753-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236288","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}

引用次数: 0