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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 Q1 NEUROSCIENCES 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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引用次数: 0
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 25 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-09-24 DOI: 10.1038/s41593-024-01768-3
Matthew Tegowski, Anna K. Prater, Christopher L. Holley, Kate D. Meyer

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.

N6-甲基腺苷(m6A)是大脑中一种丰富的mRNA修饰,在神经发育和大脑功能中具有重要作用。然而,由于技术限制,目前还无法对构成大脑的各个细胞类型中的 m6A 位点进行全面分析。在这里,我们开发了一种小鼠模型,可以在任何感兴趣的组织中以单细胞分辨率进行全转录组 m6A 检测。我们利用这些小鼠绘制了不同脑区和小鼠皮层单细胞内的 m6A 图谱,并发现了不同脑区和细胞类型之间高度共享的甲基化。不过,我们也在神经元中发现了少量不同甲基化的 mRNA,这些 mRNA 编码神经元信号传导的重要调控因子,我们还发现小胶质细胞的 m6A 水平低于其他细胞类型。最后,我们在老龄小鼠体内进行了单细胞 m6A 图谱绘制,发现了许多 m6A 变化随年龄变化的转录本。
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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 Q1 NEUROSCIENCES 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
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.
上丘是一个进化保守的中脑区域,它被认为介导空间定向,包括眼球回旋运动和隐蔽的空间注意。在这里,我们揭示了上丘在高阶认知中的作用,与其在空间定向中的作用无关。我们训练猕猴完成一项抽象的视觉分类任务,该任务既不涉及指示性眼球运动,也不涉及隐蔽注意力的差异。我们比较了上丘和后顶叶皮层的神经活动,后顶叶皮层以前曾被证明对抽象分类决策有因果关系。上丘表现出对已学视觉类别的稳健编码,这种编码比后顶叶皮层更强,而且在这两个区域中产生的潜伏期相似。此外,上丘的失活会明显影响动物的分类决策。这些结果表明,灵长类动物的上丘介导了抽象的、高阶的认知过程,而这些过程历来被认为是由新皮层介导的。
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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 Q1 NEUROSCIENCES 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
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.
阿尔茨海默病(AD)早期,周细胞会收缩毛细血管,增加毛细血管的水阻力并困住免疫细胞,从而降低脑血流量(CBF)。目前还缺乏治疗方法来减弱包膜细胞介导的AD收缩。在这里,我们利用体内双光子成像激光多普勒和斑点血流测量以及磁共振成像技术,证明了通过 L 型电压门控钙通道(CaVs)进入的 Ca2+ 控制着周细胞的收缩张力。在AD模型小鼠中,我们发现整个毛细血管床的周细胞是免疫活性氧(ROS)诱发和周细胞胞内钙浓度([Ca2+]i)介导的微血管流量下降的主要驱动因素。在疾病进展早期用尼莫地平阻断钙离子通道可改善CBF,减少白细胞在周细胞体节的滞留,并减轻脑缺氧。淀粉样β(Aβ)诱发的人皮质组织周细胞收缩也因 CaV 阻断而大大减少。因此,在注意力缺失症早期降低周细胞[Ca2+]i可能是提高大脑能量供应和认知功能的一种治疗策略。
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引用次数: 0
A cell-autonomous role for border-associated macrophages in ApoE4 neurovascular dysfunction and susceptibility to white matter injury 边界相关巨噬细胞在载脂蛋白E4神经血管功能障碍和白质损伤易感性中的细胞自主作用
IF 21.2 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-09-18 DOI: 10.1038/s41593-024-01757-6
Antoine Anfray, Samantha Schaeffer, Yorito Hattori, Monica M. Santisteban, Nicole Casey, Gang Wang, Michael Strickland, Ping Zhou, David M. Holtzman, Josef Anrather, Laibaik Park, Costantino Iadecola
Apolipoprotein E4 (ApoE4), the strongest genetic risk factor for sporadic Alzheimer’s disease, is also a risk factor for microvascular pathologies leading to cognitive impairment, particularly subcortical white matter injury. These effects have been attributed to alterations in the regulation of the brain blood supply, but the cellular source of ApoE4 and the underlying mechanisms remain unclear. In mice expressing human ApoE3 or ApoE4, we report that border-associated macrophages (BAMs), myeloid cells closely apposed to neocortical microvessels, are both sources and effectors of ApoE4 mediating the neurovascular dysfunction through reactive oxygen species. ApoE4 in BAMs is solely responsible for the increased susceptibility to oligemic white matter damage in ApoE4 mice and is sufficient to enhance damage in ApoE3 mice. The data unveil a new aspect of BAM pathobiology and highlight a previously unrecognized cell-autonomous role of BAM in the neurovascular dysfunction of ApoE4 with potential therapeutic implications. ApoE4 is a risk factor for Alzheimer’s disease and vascular dementia. We report that in ApoE4 mice perivascular macrophages are the sole source and effectors of the ApoE4 mediating the neurovascular dysfunction, enhanced white matter damage and cognitive impairment.
载脂蛋白 E4(ApoE4)是散发性阿尔茨海默病的最强遗传风险因素,也是导致认知障碍的微血管病变的风险因素,尤其是皮层下白质损伤。这些影响被归因于大脑供血调节的改变,但载脂蛋白E4的细胞来源和内在机制仍不清楚。在表达人类载脂蛋白E3或载脂蛋白E4的小鼠中,我们发现边界相关巨噬细胞(BAMs)--与新皮质微血管紧密相连的髓细胞--既是载脂蛋白E4的来源,也是载脂蛋白E4的效应器,通过活性氧介导神经血管功能障碍。BAMs 中的载脂蛋白 E4 是导致载脂蛋白 E4 小鼠白质少血症损伤易感性增加的唯一原因,也足以加重载脂蛋白 E3 小鼠的损伤。这些数据揭示了 BAM 病理生物学的一个新方面,并强调了 BAM 在载脂蛋白 E4 神经血管功能障碍中的一个以前未被认识到的细胞自主作用,具有潜在的治疗意义。
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引用次数: 0
Synergistic association of Aβ and tau pathology with cortical neurophysiology and cognitive decline in asymptomatic older adults 无症状老年人的 Aβ 和 tau 病理学与皮层神经生理学和认知能力下降之间的协同关系
IF 21.2 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-09-18 DOI: 10.1038/s41593-024-01763-8
Jonathan Gallego-Rudolf, Alex I. Wiesman, Alexa Pichet Binette, Sylvia Villeneuve, Sylvain Baillet, PREVENT-AD Research Group
Animal and computational models of Alzheimer’s disease (AD) indicate that early amyloid-β (Aβ) deposits drive neurons into a hyperactive regime, and that subsequent tau depositions manifest an opposite, suppressive effect as behavioral deficits emerge. Here we report analogous changes in macroscopic oscillatory neurophysiology in the human brain. We used positron emission tomography and task-free magnetoencephalography to test the effects of Aβ and tau deposition on cortical neurophysiology in 104 cognitively unimpaired older adults with a family history of sporadic AD. In these asymptomatic individuals, we found that Aβ depositions colocalize with accelerated neurophysiological activity. In those also presenting medial–temporal tau pathology, linear mixed effects of Aβ and tau depositions indicate a shift toward slower neurophysiological activity, which was also linked to cognitive decline. We conclude that early Aβ and tau depositions relate synergistically to human cortical neurophysiology and subsequent cognitive decline. Our findings provide insight into the multifaceted neurophysiological mechanisms engaged in the preclinical phases of AD. Gallego-Rudolf et al. report accelerated brain activity with initial amyloid-β deposition in asymptomatic individuals. In those where tau also starts accumulating, brain activity decelerates, correlating with subsequent cognitive decline.
阿尔茨海默病(AD)的动物模型和计算模型表明,早期淀粉样蛋白-β(Aβ)沉积会促使神经元进入亢奋状态,而随后的tau沉积则会随着行为障碍的出现而产生相反的抑制作用。在这里,我们报告了人脑中宏观振荡神经生理学的类似变化。我们使用正电子发射断层扫描和无任务脑磁图来测试 Aβ 和 tau 沉积对 104 名有散发性老年痴呆症家族史、认知功能未受损的老年人大脑皮层神经生理学的影响。我们发现,在这些无症状的人中,Aβ沉积与神经电生理活动的加速有共同之处。在那些同时出现内颞侧 tau 病理学的患者中,Aβ 和 tau 沉积的线性混合效应表明神经生理活动转向缓慢,这也与认知能力下降有关。我们的结论是,早期 Aβ 和 tau 沉积与人类大脑皮层神经生理学和随后的认知能力下降有协同关系。我们的研究结果让我们深入了解了多发性硬化症临床前期所涉及的多方面神经生理学机制。
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引用次数: 0
Semi-orthogonal subspaces for value mediate a binding and generalization trade-off 价值的半正交子空间介导约束与泛化之间的权衡
IF 21.2 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-09-17 DOI: 10.1038/s41593-024-01758-5
W. Jeffrey Johnston, Justin M. Fine, Seng Bum Michael Yoo, R. Becket Ebitz, Benjamin Y. Hayden
When choosing between options, we must associate their values with the actions needed to select them. We hypothesize that the brain solves this binding problem through neural population subspaces. Here, in macaques performing a choice task, we show that neural populations in five reward-sensitive regions encode the values of offers presented on the left and right in distinct subspaces. This encoding is sufficient to bind offer values to their locations while preserving abstract value information. After offer presentation, all areas encode the value of the first and second offers in orthogonal subspaces; this orthogonalization also affords binding. Our binding-by-subspace hypothesis makes two new predictions confirmed by the data. First, behavioral errors should correlate with spatial, but not temporal, neural misbinding. Second, behavioral errors should increase when offers have low or high values, compared to medium values, even when controlling for value difference. Together, these results support the idea that the brain uses semi-orthogonal subspaces to bind features. This study shows that the brain can link action to value through neural population subspaces, balancing reliable binding of action to value and generalization to novel stimuli.
在选项之间做出选择时,我们必须将它们的价值与选择这些选项所需的行动联系起来。我们假设大脑是通过神经群子空间来解决这一关联问题的。在这里,我们在猕猴执行选择任务时发现,五个奖赏敏感区域的神经群会在不同的子空间中对左右两侧出现的提议值进行编码。这种编码足以在保留抽象价值信息的同时将要约价值与其位置联系起来。要约呈现后,所有区域都会在正交子空间中对第一个和第二个要约的价值进行编码;这种正交化也能实现绑定。我们的子空间绑定假设提出了两个新的预测,并得到了数据的证实。首先,行为错误应该与空间神经错误绑定相关,而不是与时间神经错误绑定相关。其次,与中等价值相比,当提议的价值较低或较高时,即使控制了价值差异,行为错误也会增加。这些结果共同支持了大脑使用半正交子空间来绑定特征的观点。
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引用次数: 0
Author Correction: Oligodendroglial fatty acid metabolism as a central nervous system energy reserve 作者更正:作为中枢神经系统能量储备的少突胶质细胞脂肪酸代谢
IF 21.2 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-09-17 DOI: 10.1038/s41593-024-01776-3
Ebrahim Asadollahi, Andrea Trevisiol, Aiman S. Saab, Zoe J. Looser, Payam Dibaj, Reyhane Ebrahimi, Kathrin Kusch, Torben Ruhwedel, Wiebke Möbius, Olaf Jahn, Jun Yup Lee, Anthony S. Don, Michelle-Amirah Khalil, Karsten Hiller, Myriam Baes, Bruno Weber, E. Dale Abel, Andrea Ballabio, Brian Popko, Celia M. Kassmann, Hannelore Ehrenreich, Johannes Hirrlinger, Klaus-Armin Nave
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引用次数: 0
Tonic and burst-like locus coeruleus stimulation distinctly shift network activity across the cortical hierarchy 节律性和猝发样刺激可明显改变整个大脑皮层的网络活动
IF 21.2 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-09-16 DOI: 10.1038/s41593-024-01755-8
Christina Grimm, Sian N. Duss, Mattia Privitera, Brandon R. Munn, Nikolaos Karalis, Stefan Frässle, Maria Wilhelm, Tommaso Patriarchi, Daniel Razansky, Nicole Wenderoth, James M. Shine, Johannes Bohacek, Valerio Zerbi
Noradrenaline (NA) release from the locus coeruleus (LC) changes activity and connectivity in neuronal networks across the brain, modulating multiple behavioral states. NA release is mediated by both tonic and burst-like LC activity. However, it is unknown whether the functional changes in target areas depend on these firing patterns. Using optogenetics, photometry, electrophysiology and functional magnetic resonance imaging in mice, we show that tonic and burst-like LC firing patterns elicit brain responses that hinge on their distinct NA release dynamics. During moderate tonic LC activation, NA release engages regions associated with associative processing, while burst-like stimulation biases the brain toward sensory processing. These activation patterns locally couple with increased astrocytic and inhibitory activity and change the brain’s topological configuration in line with the hierarchical organization of the cerebral cortex. Together, these findings reveal how the LC–NA system achieves a nuanced regulation of global circuit operations. Tonic and burst-like locus coeruleus firing distinctly tune brain topology toward associative and sensory regions, recruiting both astrocytic and neuronal inhibitory activity.
去甲肾上腺素(NA)从脑小叶位置(LC)释放,会改变整个大脑神经元网络的活动和连接,从而调节多种行为状态。NA的释放是由LC的强直性和爆发性活动介导的。然而,目标区域的功能变化是否取决于这些发射模式尚不得而知。通过在小鼠体内使用光遗传学、光度计、电生理学和功能磁共振成像技术,我们发现强直性和爆发样 LC 发射模式会引起大脑反应,而这些反应取决于它们不同的 NA 释放动态。在适度的强直性 LC 激活过程中,NA 的释放涉及与联想处理相关的区域,而爆发式刺激则使大脑偏向于感觉处理。这些激活模式在局部与增加的星形胶质细胞和抑制性活动相结合,改变了大脑的拓扑结构,使其与大脑皮层的分层组织相一致。这些发现共同揭示了 LC-NA 系统如何实现对全局电路运行的细微调节。
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引用次数: 0
Neuroanatomical changes observed over the course of a human pregnancy 在人类怀孕期间观察到的神经解剖学变化
IF 21.2 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-09-16 DOI: 10.1038/s41593-024-01741-0
Laura Pritschet, Caitlin M. Taylor, Daniela Cossio, Joshua Faskowitz, Tyler Santander, Daniel A. Handwerker, Hannah Grotzinger, Evan Layher, Elizabeth R. Chrastil, Emily G. Jacobs
Pregnancy is a period of profound hormonal and physiological changes experienced by millions of women annually, yet the neural changes unfolding in the maternal brain throughout gestation are not well studied in humans. Leveraging precision imaging, we mapped neuroanatomical changes in an individual from preconception through 2 years postpartum. Pronounced decreases in gray matter volume and cortical thickness were evident across the brain, standing in contrast to increases in white matter microstructural integrity, ventricle volume and cerebrospinal fluid, with few regions untouched by the transition to motherhood. This dataset serves as a comprehensive map of the human brain across gestation, providing an open-access resource for the brain imaging community to further explore and understand the maternal brain. Neural changes in pregnancy are not well understood. Here Pritschet et al. present an open-access precision brain imaging resource, mapping neuroanatomical change in an individual from preconception through postpartum.
每年都有数百万妇女在怀孕期间经历深刻的荷尔蒙和生理变化,但人类对整个妊娠期母体大脑神经变化的研究还不够深入。利用精确成像技术,我们绘制了一个人从怀孕前到产后两年的神经解剖变化图。整个大脑的灰质体积和皮质厚度明显减少,与之形成鲜明对比的是白质微结构完整性、脑室体积和脑脊液的增加,很少有区域在向母亲过渡时没有受到影响。该数据集是整个妊娠期人类大脑的综合地图,为大脑成像界进一步探索和了解孕产妇大脑提供了一个开放访问的资源。
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引用次数: 0
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Nature neuroscience
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