【Cell】2025年6-7月刊论文导读
期刊介绍：
《Cell》（细胞）是生命科学领域最具影响力和声望的顶级期刊之一，由Cell Press（爱思唯尔旗下）出版。该期刊创刊于1974年，致力于发表生命科学所有领域内具有突破性意义和广泛影响力的原创性研究。Cell 以其严格的同行评审和高标准著称，涵盖了分子生物学、细胞生物学、遗传学、发育生物学、神经科学、免疫学、癌症研究、系统生物学等多个方向。除了研究论文（Article）外，Cell 也刊发评论（Commentary）、综述（Review）、前瞻（Preview）等类型的文章。因其在生命科学领域的核心地位，《Cell》是科学家们展示重大发现和推动学科发展的首选平台之一。最新影响因子为42.5。
Volume 188 Issue 12, June 2025
在2025年6月，Science共发表17篇文章，其中包括Reviews 2篇， Articles 12篇, Resources 3篇。主要内容涉及蛇毒防护、肠道免疫耐受、应激反应机制、增强子设计、药物递送、免疫治疗认知影响、价值决策神经机制、脑淋巴发育等。
1.Snake venom protection by a cocktail of varespladib and broadly neutralizing human antibodies
伐瑞昔布与广谱中和人类抗体的混合制剂对蛇毒的防护作用
Centivax 公司
Snake envenomation is a neglected tropical disease, with 600 species causing over 100,000 deaths and 300,000 permanent disabilities in humans annually. Broadly neutralizing antibodies and broad chemical inhibitors have been proposed as solutions, but how to develop a therapeutically effective cocktail and the number of required components have been unclear. To address this gap, we iteratively recovered two broadly neutralizing antivenom antibodies from the memory B cells of a hyperimmune human donor with extensive snake venom exposure. The antibodies recognized conserved neutralizing epitopes on prevalent long and short snake neurotoxins, with crystal structures revealing antibody mimicry of the interfaces between these neurotoxins and their host target, the nicotinic acetylcholine receptor. We combined and tested these antibodies and the phospholipase inhibitor varespladib. A 3-component cocktail rescued animals from whole-venom challenge of all species in a 19-member WHO Category 1 and Category 2 elapid diversity set, with complete protection against most snakes observed.
蛇咬伤中毒是一种被忽视的热带疾病，每年有600种蛇类导致超过10万人死亡，30万人永久残疾。广泛中和抗体和广谱化学抑制剂被提议作为解决方案，但如何开发一种治疗有效的鸡尾酒疗法以及所需成分的数量尚不清楚。为了填补这一空白，研究者从一位有大量蛇毒接触史的高免疫人类供体的记忆B细胞中，反复筛选出两种广泛中和的抗蛇毒抗体。这些抗体能够识别常见的长链和短链蛇神经毒素上的保守中和表位，晶体结构显示，抗体模拟了这些神经毒素与其宿主靶标烟碱型乙酰胆碱受体之间的界面。研究者将这些抗体与磷脂酶抑制剂伐瑞昔布（varespladib）进行组合并测试。一种由三种成分组成的鸡尾酒疗法，能够使动物在受到世界卫生组织19种1类和2类眼镜蛇科蛇类全毒液攻击后存活，并且对大多数蛇类具有完全的保护作用。
2.A type 1 immune-stromal cell network mediates disease tolerance against intestinal infection
1型免疫-基质细胞网络介导对肠道感染的疾病耐受
麦吉尔大学健康中心研究所
Type 1 immunity mediates host defense through pathogen elimination, but whether this pathway also impacts tissue function is unknown. Here, we demonstrate that rapid induction of interferon γ (IFNγ) signaling coordinates a multicellular response that is critical to limit tissue damage and maintain gut motility following infection of mice with a tissue-invasive helminth. IFNγ production is initiated by antigen-independent activation of lamina propria CD8+ T cells following MyD88-dependent recognition of the microbiota during helminth-induced barrier invasion. IFNγ acted directly on intestinal stromal cells to recruit neutrophils that limited parasite-induced tissue injury. IFNγ sensing also limited the expansion of smooth muscle actin-expressing cells to prevent pathological gut dysmotility. Importantly, this tissue-protective response did not impact parasite burden, indicating that IFNγ supports a disease tolerance defense strategy. Our results have important implications for managing the pathophysiological sequelae of post-infectious gut dysfunction and chronic inflammatory diseases associated with stromal remodeling.
1型免疫通过清除病原体介导宿主防御，但该途径是否也会影响组织功能尚不清楚。在此，研究者证明在小鼠感染组织侵袭性蠕虫后，快速诱导的干扰素γ（IFNγ）信号传导可协调多细胞反应，这对于限制组织损伤和维持肠道蠕动至关重要。在蠕虫诱导的屏障入侵过程中，MyD88依赖性识别肠道菌群后，固有层CD8+ T细胞的抗原非依赖性激活引发IFNγ的产生。IFNγ直接作用于肠道基质细胞，招募中性粒细胞，限制寄生虫诱导的组织损伤。IFNγ感知还限制了表达平滑肌肌动蛋白的细胞扩张，以防止病理性肠道运动障碍。重要的是，这种组织保护反应不影响寄生虫负荷，这表明IFNγ支持一种疾病耐受防御策略。该结果对于管理感染后肠道功能障碍的病理生理后遗症以及与基质重塑相关的慢性炎症性疾病具有重要意义。
3.Integrator loss leads to dsRNA formation that triggers the integrated stress response
整合器缺失导致双链RNA形成并触发整合应激反应
哈佛医学院
Integrator (INT) is a metazoan-specific complex that targets promoter-proximally paused RNA polymerase II (RNAPII) for termination, preventing immature RNAPII from entering gene bodies and functionally attenuating transcription of stress-responsive genes. Mutations in INT subunits are associated with many human diseases, including cancer, ciliopathies, and neurodevelopmental disorders, but how reduced INT activity contributes to disease is unknown. Here, we demonstrate that the loss of INT-mediated termination in human cells triggers the integrated stress response (ISR). INT depletion causes upregulation of short genes such as the ISR transcription factor activating transcription factor 3 (ATF3). Further, immature RNAPII that escapes into genes upon INT depletion is prone to premature termination, generating incomplete pre-mRNAs with retained introns. Retroelements within retained introns form double-stranded RNA (dsRNA) that is recognized by protein kinase R (PKR), which drives ATF4 activation and prolonged ISR. Critically, patient cells with INT mutations exhibit dsRNA accumulation and ISR activation, thereby implicating chronic ISR in diseases caused by INT deficiency.
整合器（INT）是一种后生动物特有的复合物，其作用是使启动子近端暂停的RNA聚合酶II（RNAPII）终止转录，防止未成熟的RNAPII进入基因体，并在功能上减弱应激反应基因的转录。INT亚基的突变与许多人类疾病相关，包括癌症、纤毛病和神经发育障碍，但INT活性降低如何导致疾病尚不清楚。在这里，研究者证明人类细胞中INT介导的终止作用的丧失会触发整合应激反应（ISR）。INT缺失会导致短基因（如ISR转录因子激活转录因子3（ATF3））的上调。此外，INT缺失后逃逸进入基因的未成熟RNAPII容易提前终止，产生含有保留内含子的不完整前体mRNA。保留内含子中的逆转录元件形成双链RNA（dsRNA），可被蛋白激酶R（PKR）识别，从而驱动ATF4激活和持续的ISR。至关重要的是，携带INT突变的患者细胞表现出dsRNA积累和ISR激活，这表明慢性ISR与INT缺乏引起的疾病有关。
4.Design principles of cell-state-specific enhancers in hematopoiesis造血过程中细胞状态特异性增强子的设计原则
巴塞罗那科学技术研究所
During cellular differentiation, enhancers transform overlapping gradients of transcription factors (TFs) to highly specific gene expression patterns. However, the vast complexity of regulatory DNA impedes the identification of the underlying cis-regulatory rules. Here, we characterized 64,400 fully synthetic DNA sequences to bottom-up dissect design principles of cell-state-specific enhancers in the context of the differentiation of blood stem cells to seven myeloid lineages. Focusing on binding sites for 38 TFs and their pairwise interactions, we found that identical sites displayed both repressive and activating function as a consequence of cell state, site combinatorics, or simply predicted occupancy of a TF on an enhancer. Surprisingly, combinations of activating sites frequently neutralized one another or gained repressive function. These negative synergies convert quantitative imbalances in TF expression into binary activity patterns. We exploit this principle to automatically create enhancers with specificity to user-defined combinations of hematopoietic progenitor cell states from scratch.
在细胞分化过程中，增强子将转录因子（TFs）的重叠梯度转化为高度特异性的基因表达模式。然而，调控DNA的巨大复杂性阻碍了对潜在顺式调控规则的识别。在这里，研究者对64,400个完全合成的DNA序列进行了表征，从下而上剖析了造血干细胞向七种髓系谱系分化过程中细胞状态特异性增强子的设计原则。聚焦于38种转录因子的结合位点及其两两相互作用，研究者发现相同的位点会因细胞状态、位点组合，或仅仅是转录因子在增强子上的预测占有率，而表现出抑制和激活两种功能。令人惊讶的是，激活位点的组合常常相互抵消或获得抑制功能。这些负协同作用将转录因子表达的定量失衡转化为二元活性模式。研究者利用这一原理，从零开始自动创建对用户定义的造血祖细胞状态组合具有特异性的增强子。
5.CD36-mediated endocytosis of proteolysis-targeting chimeras
CD36介导的蛋白降解靶向嵌合体的内吞作用
德克萨斯大学健康科学中心
Passive diffusion does not explain why many drugs are too large and/or too polar for rule-breaking membrane penetration, such as proteolysis-targeting chimeras (PROTACs, generally of a molecular weight > 800 Da). Here, using biotinylated chemical-probe-based target fishing and genetic knockdown/knockin approaches, we discovered that the membrane cluster of differentiation 36 (CD36) binds to and facilitates the uptake and efficacy of diverse PROTACs (e.g., SIM1-Me, MZ1, and clinical ARV-110) and large and/or polar small-molecule drugs (e.g., rapalink-1, rapamycin, navitoclax, birinapant, tubacin, and doxorubicin) via the CD36-mediated early endosome antigen 1 (EEA1)/Ras-related protein 5A (Rab5) endosomal cascade in vitro and/or in vivo. We then devised a novel chemical endocytic medicinal chemistry strategy to improve binding of PROTACs to CD36 using structural modifications via the prodrug approach, markedly enhancing PROTAC anti-tumor efficacy through spontaneously augmenting permeability and solubility.
被动扩散无法解释为什么许多药物因太大和/或极性太强而难以穿透细胞膜，比如蛋白降解靶向嵌合体（PROTACs，通常分子量大于800Da）。在此，利用基于生物素化化学探针的靶标捕获以及基因敲低/敲入方法，研究者发现细胞膜分化簇 36（CD36）可结合并促进多种PROTACs（如SIM1-Me、MZ1及临床药物 ARV-110）及大分子量/极性小分子药物（如rapalink-1、雷帕霉素、navitoclax、birinapant、tubacin 和阿霉素）的细胞摄取和药效，这一过程是通过体外和/或体内的CD36介导的早期内体抗原1（EEA1）/Ras相关蛋白5A（Rab5）内体级联反应实现的。研究者设计了一种新颖的化学内吞药物化学策略，通过前药方法进行结构修饰，改善PROTACs与CD36的结合，通过自发提高渗透性和溶解性，显著增强了PROTACs的抗肿瘤功效。
6.Immunotherapy-related cognitive impairment after CAR T cell therapy in mice
小鼠CAR-T细胞治疗后的免疫治疗相关认知障碍
斯坦福大学医学院神经病学和神经科学系
Immunotherapies have revolutionized cancer care for many tumor types, but their potential long-term cognitive impacts are incompletely understood. Here, we demonstrated in mouse models that chimeric antigen receptor (CAR) T cell therapy for both central nervous system (CNS) and non-CNS cancers impaired cognitive function and induced a persistent CNS immune response characterized by white matter microglial reactivity, microglial chemokine expression, and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis were disrupted. Single-nucleus sequencing studies of human frontal lobe from patients with or without previous CAR T cell therapy for brainstem tumors confirmed reactive states of microglia and oligodendrocytes following treatment. In mice, transient microglial depletion or CCR3 chemokine receptor blockade rescued oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function following CAR T cell therapy. Taken together, these findings illustrate targetable neural-immune mechanisms underlying immunotherapy-related cognitive impairment.
免疫疗法已经彻底改变了多种肿瘤类型的癌症治疗方式，但其潜在的长期认知影响尚未完全明确。研究者在小鼠模型中证明，针对中枢神经系统（CNS）和非中枢神经系统癌症的嵌合抗原受体（CAR）T细胞疗法会损害认知功能，并诱导持续性的中枢神经系统免疫反应，其特征为白质小胶质细胞反应性增强、小胶质细胞趋化因子表达增加，以及脑脊液（CSF）细胞因子和趋化因子水平升高。这进而破坏了少突胶质细胞的稳态和海马神经发生。对接受或未接受过针对脑干肿瘤的CAR T细胞疗法的患者的人类额叶进行单核测序研究，证实了治疗后小胶质细胞和少突胶质细胞的反应状态。在小鼠中，在CAR T细胞治疗后的注意力和短期记忆功能行为测试中，短暂的小胶质细胞耗竭或CCR3趋化因子受体阻断挽救了少突胶质细胞缺陷并改善了认知表现。这些发现揭示了免疫疗法相关认知障碍背后的可靶向神经免疫机制。
7.Neural-activity-regulated and glia-mediated control of brain lymphatic development
神经活动调节和胶质细胞介导的脑淋巴发育控制
中国科学院脑科学与智能技术卓越创新中心
The nervous system regulates peripheral immune responses under physiological and pathological conditions, but the brain's impact on immune system development remains unknown. Meningeal mural lymphatic endothelial cells (muLECs), embedded in the leptomeninges, form an immune niche surrounding the brain that contributes to brain immunosurveillance. Here, we report that the brain controls the development of muLECs via a specialized glial subpopulation, slc6a11b+ radial astrocytes (RAs), a process modulated by neural activity in zebrafish. slc6a11b+ RAs, with processes extending to the meninges, govern muLEC formation by expressing vascular endothelial growth factor C (vegfc). Moreover, neural activity regulates muLEC development, and this regulation requires Vegfc in slc6a11b+ RAs. Intriguingly, slc6a11b+ RAs cooperate with calcium-binding EGF domain 1 (ccbe1)+ fibroblasts to restrict muLEC growth on the brain surface via controlling mature Vegfc distribution. Thus, our study uncovers a glia-mediated and neural-activity-regulated control of brain lymphatic development and highlights the importance of inter-tissue cellular cooperation in development.
神经系统在生理和病理状态下会调节外周免疫反应，但大脑对免疫系统发育的影响尚不明确。脑膜壁层淋巴内皮细胞（muLECs）存在于软脑膜中，形成一个环绕大脑的免疫微环境，对大脑免疫监视起到重要作用。在斑马鱼中，研究者发现大脑通过一种特殊的神经胶质亚群——slc6a11b+放射状星形胶质细胞（RAs）来控制muLECs的发育，而这一过程会受到神经活动的调节。slc6a11b+ RAs的突起延伸至脑膜，通过表达血管内皮生长因子C（vegfc）调控muLEC的形成。此外，神经活动会调节muLEC的发育，而这种调节依赖于slc6a11b+ RAs中的Vegfc。有趣的是，slc6a11b+ RAs与钙结合EGF结构域 1（ccbe1）+ 成纤维细胞协同作用，通过调控成熟Vegfc的分布来限制脑表面muLECs的生长。该研究揭示了一种由神经胶质介导且受神经活动调节的脑淋巴发育调控机制，并强调了组织间细胞协作在发育过程中的重要性。
Volume 188 Issue 13, June 2025
在2025年7月，Science共发表17篇文章，其中包括Preview 1篇，Commentary 1篇, Resources 2篇，Correction 1篇，Research articles 12篇。主要内容包括HIV预防药物的全球健康影响评估、病毒进化边界研究、胆固醇代谢通路、癌症免疫疗法工程化改造、转基因动物技术等内容。
1.Extrachromosomal DNA replication and maintenance couple with DNA damage pathway in tumors
肿瘤中染色体外DNA的复制和维持与DNA损伤途径相关
中国科学院深圳先进技术研究院
Extrachromosomal DNA (ecDNA) drives the evolution of cancer cells. However, the functional significance of ecDNA and the molecular components involved in its replication and maintenance remain largely unknown. Here, using CRISPR-C technology, we generated ecDNA-carrying (ecDNA+) cell models. By leveraging these models alongside other well-established systems, we demonstrated that ecDNA can replicate and be maintained in ecDNA+ cells. The replication of ecDNA activates the ataxia telangiectasia mutated (ATM)-mediated DNA damage response (DDR) pathway. Topoisomerases, such as TOP1 and TOP2B, play a role in ecDNA replication-induced DNA double-strand breaks (DSBs). A subset of these elevated DSBs persists into the mitotic phase and is primarily repaired by the alternative non-homologous end joining (alt-NHEJ) pathway, which involves POLθ and LIG3. Correspondingly, ecDNA maintenance requires DDR, and inhibiting DDR impairs the circularization of ecDNA. In summary, we demonstrate reciprocal interactions between ecDNA maintenance and DDR, providing new insights into the detection and treatment of ecDNA+ tumors.
染色体外DNA（ecDNA）驱动癌细胞的进化。然而，ecDNA的功能意义以及参与其复制和维持的分子成分在很大程度上仍不清楚。研究者使用CRISPR-C技术生成了携带ecDNA（ecDNA+）的细胞模型。通过利用这些模型以及其他成熟的系统，证明了ecDNA可以在ecDNA+细胞中复制并维持。ecDNA的复制激活了共济失调毛细血管扩张突变（ATM）介导的DNA损伤反应（DDR）途径。拓扑异构酶，如TOP1和TOP2B，在ecDNA复制诱导的DNA双链断裂（DSB）中起作用。这些增加的DSB中有一部分会持续到有丝分裂期，主要由涉及POLθ和LIG3的替代非同源末端连接（alt-NHEJ）途径修复。相应地，ecDNA的维持需要DDR，抑制DDR会损害ecDNA的环化。该研究证明了ecDNA维持和DDR之间的相互作用，为ecDNA+肿瘤的检测和治疗提供了新的见解。
2.SLC7A11 is an unconventional H+ transporter in lysosomes
SLC7A11是溶酶体中一种非传统的H+转运体
浙江大学
Lysosomes maintain an acidic pH of 4.5–5.0, optimal for macromolecular degradation. Whereas proton influx is produced by a V-type H+ ATPase, proton efflux is mediated by a fast H+ leak through TMEM175 channels, as well as an unidentified slow pathway. A candidate screen on an orphan lysosome membrane protein (OLMP) library enabled us to discover that SLC7A11, the protein target of the ferroptosis-inducing compound erastin, mediates a slow lysosomal H+ leak through downward flux of cystine and glutamate, two H+ equivalents with uniquely large but opposite concentration gradients across lysosomal membranes. SLC7A11 deficiency or inhibition caused lysosomal over-acidification, reduced degradation, accumulation of storage materials, and ferroptosis, as well as facilitated α-synuclein aggregation in neurons. Correction of abnormal lysosomal acidity restored lysosome homeostasis and prevented ferroptosis. These studies have revealed an unconventional H+ transport conduit that is integral to lysosomal flux of protonatable metabolites to regulate lysosome function, ferroptosis, and Parkinson’s disease (PD) pathology.
溶酶体维持4.5- 5.0的酸性pH值，这是大分子降解的最佳条件。虽然质子流入是由V型H+ ATP酶产生的，但质子流出是由通过TMEM175通道的快速H+泄漏以及一种未确定的缓慢途径介导的。通过对孤儿溶酶体膜蛋白（OLMP）文库的候选筛选，研究者发现SLC7A11，即诱导铁死亡的化合物erastin的蛋白靶点，通过胱氨酸和谷氨酸（两种在溶酶体膜上具有独特大且相反浓度梯度的H+等价物）的下行通量介导溶酶体的缓慢H+泄漏。SLC7A11的缺失或抑制导致溶酶体过度酸化、降解减少、储存物质积累和铁死亡，以及促进神经元中α-突触核蛋白的聚集。纠正异常的溶酶体酸度可恢复溶酶体稳态并预防铁死亡。该研究揭示了一种非传统的H+转运途径，它是溶酶体中可质子化代谢物通量的组成部分，以调节溶酶体功能、铁死亡和帕金森病（PD）病理。
3.Selective requirement of glycosphingolipid synthesis for natural killer and cytotoxic T cells
自然杀伤细胞和细胞毒性T细胞对糖鞘脂合成的选择性需求
美国国立卫生研究院
Cell identity genes that exhibit complex regulation are marked by super-enhancer (SE) architecture. Assessment of SEs in natural killer (NK) cells identified Ugcg, encoding the enzyme responsible for glycosphingolipid (GSL) synthesis. Conditional deletion of Ugcg in early hematopoiesis abrogated NK cell generation while sparing other lineages. Pharmacological inhibition of UGCG disrupted cytotoxic granules and cytotoxicity, reduced expansion after viral infection, and promoted apoptosis. B4galt5 transcribes an enzyme downstream of UGCG and possesses SE structure. Addition of its product, lactosylceramide (LacCer), reversed apoptosis due to UGCG inhibition. By contrast, complex GSLs, such as asialo-GM1, were not required for NK cell viability and granule integrity. Ugcg and B4galt5 were upregulated in CD8+ T cells during viral infection, correlating with the acquisition of cytotoxic machinery. Antigen-specific CD8+ T cells lacking Ugcg failed to expand during infection. Our study reveals a selective and essential role of GSL metabolism in NK and CD8+ T cell biology.
自然杀伤（NK）细胞中具有复杂调控的细胞身份基因往往由超级增强子（SE）结构标记。对NK细胞SE的分析发现Ugcg基因，其编码的酶负责糖鞘脂（GSL）合成。在早期造血阶段条件性敲除Ugcg会阻断NK细胞的产生，但对其他造血谱系细胞无影响。药理学抑制UGCG会破坏细胞毒性颗粒及其功能，降低病毒感染后的扩增能力，并诱导细胞凋亡。B4galt5转录的酶位于UGCG下游，并具有SE结构。补充其产物乳糖神经酰胺（LacCer）可逆转由UGCG抑制引起的凋亡。相比之下，复杂型GSL（如去唾液酸GM1）对NK细胞的存活和颗粒完整性并非必需。在病毒感染期间，Ugcg和B4galt5在CD8⁺ T细胞中上调，与细胞毒性机制的获得相关。缺乏Ugcg的抗原特异性CD8⁺ T细胞在感染时无法扩增。该研究揭示了GSL代谢在NK和CD8⁺ T细胞生物学中的选择性和关键作用。
4.Transcriptional regulation by PHGDH drives amyloid pathology in Alzheimer’s disease
PHGDH的转录调控驱动阿尔茨海默病的淀粉样变性
加利福尼亚大学圣地亚哥分校
Virtually all individuals aged 65 or older develop at least early pathology of Alzheimer’s disease (AD), yet most lack disease-causing mutations in APP, PSEN, or MAPT, and many do not carry the APOE4 risk allele. This raises questions about AD development in the general population. Although transcriptional dysregulation has not traditionally been a hallmark of AD, recent studies reveal significant epigenomic changes in late-onset AD (LOAD) patients. We show that altered expression of the LOAD biomarker phosphoglycerate dehydrogenase (PHGDH) modulates AD pathology in mice and human brain organoids independent of its enzymatic activity. PHGDH has an uncharacterized role in transcriptional regulation, promoting the transcription of inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKa) and high-mobility group box 1 (HMGB1) in astrocytes, which suppress autophagy and accelerate amyloid pathology. A blood-brain-barrier-permeable small-molecule inhibitor targeting PHGDH’s transcriptional function reduces amyloid pathology and improves AD-related behavioral deficits. These findings highlight transcriptional regulation in LOAD and suggest therapeutic strategies beyond targeting familial mutations.
几乎所有65岁及以上的个体都会至少出现早期阿尔茨海默病（AD）的病理变化，但大多数人在APP、PSEN或MAPT基因中没有致病突变，许多人也不携带APOE4风险等位基因。这就引发了关于普通人群中AD发展的疑问。虽然转录失调传统上并非AD的标志，但最近的研究揭示了晚发性AD（LOAD）患者存在显著的表观基因组变化。研究者发现，LOAD生物标志物磷酸甘油酸脱氢酶（PHGDH）的表达改变在小鼠和人脑类器官中调节AD病理，且独立于其酶活性。PHGDH在转录调控中具有未被充分认识的作用，它促进星形胶质细胞中核因子κB激酶亚基α（IKKa）和高迁移率族蛋白B1（HMGB1）的转录，抑制自噬并加速淀粉样病变。一种可穿透血脑屏障的小分子抑制剂靶向PHGDH的转录功能，可减少淀粉样病理并改善AD相关的行为缺陷。这些发现突出了LOAD中的转录调控，并提出了超越针对家族性突变的治疗策略。
5.Hypothalamic PNOC/NPY neurons constitute mediators of leptin-controlled energy homeostasis
下丘脑PNOC/NPY神经元是瘦素控制能量稳态的介质
马克斯・普朗克新陈代谢研究所
Leptin acts in the brain to suppress appetite, yet the responsible neurocircuitries underlying leptin’s anorectic effect are incompletely defined. Prepronociceptin (PNOC)-expressing neurons mediate diet-induced hyperphagia and weight gain in mice. Here, we show that leptin regulates appetite and body weight via PNOC neurons, and that loss of leptin receptor (Lepr) expression in PNOC-expressing neurons in the arcuate nucleus of the hypothalamus (ARC) causes hyperphagia and obesity. Restoring Lepr expression in PNOC neurons on a Lepr-null obese background substantially reduces body weight. Lepr inactivation in PNOC neurons increases neuropeptide Y (Npy) expression in a subset of hypothalamic PNOC neurons that do not express agouti-related peptide (Agrp). Selective chemogenetic activation of PNOC/NPY neurons promotes feeding to the same extent as activating all PNOCARC neurons, and overexpression of Npy in PNOCARC neurons promotes hyperphagia and obesity. Thus, we introduce PNOC/NPYARC neurons as an additional critical mediator of leptin action and as a promising target for obesity therapeutics.
瘦素在大脑中发挥抑制食欲的作用，然而，瘦素厌食作用背后的神经回路尚未完全明确。表达前阿片促黑皮质素原（PNOC）的神经元介导小鼠饮食诱导的暴饮暴食和体重增加。研究者表明瘦素通过PNOC神经元调节食欲和体重，并且在下丘脑弓状核（ARC）中表达PNOC的神经元中瘦素受体（Lepr）表达缺失会导致暴饮暴食和肥胖。在Lepr基因敲除的肥胖背景下，恢复PNOC神经元中Lepr的表达可显著降低体重。PNOC神经元中Lepr失活会增加一组不表达刺鼠相关肽（Agrp）的下丘脑PNOC神经元中神经肽Y（Npy）的表达。选择性化学遗传学激活PNOC/NPY神经元促进进食的程度与激活所有ARC中的PNOC神经元相同，并且在ARC中的PNOC神经元中过表达Npy会促进暴饮暴食和肥胖。因此，研究者提出PNOC/NPY^ARC神经元是瘦素作用的另一个关键介质，也是肥胖治疗的有前景的靶点。
6.Regional differences in progenitor metabolism shape brain growth during development
发育过程中祖细胞代谢的区域差异塑造大脑生长
日内瓦大学
Mammals have particularly large forebrains compared with other brain parts, yet the developmental mechanisms underlying this regional expansion remain poorly understood. Here, we provide a single-cell-resolution birthdate atlas of the mouse brain (www.neurobirth.org), which reveals that while hindbrain neurogenesis is transient and restricted to early development, forebrain neurogenesis is temporally sustained through reduced consumptive divisions of ventricular zone progenitors. This atlas additionally reveals region-specific patterns of direct and indirect neurogenesis. Using single-cell RNA sequencing, we identify evolutionarily conserved cell-cycle programs and metabolism-related molecular pathways that control regional temporal windows of proliferation. We identify the late neocortex-enriched mitochondrial protein FAM210B as a key regulator using in vivo gain- and loss-of-function experiments. FAM210B elongates mitochondria and increases lactate production, which promotes progenitor self-replicative divisions and, ultimately, the larger clonal size of their progeny. Together, these findings indicate that spatiotemporal heterogeneity in mitochondrial function regulates regional progenitor cycling behavior and associated clonal neuronal production during brain development.
与大脑其他部分相比，哺乳动物的前脑特别大，然而，这种区域扩张背后的发育机制仍知之甚少。研究者提供了一个小鼠大脑单细胞分辨率的出生日期图谱（www.neurobirth.org），该图谱显示，后脑神经发生是短暂的，且局限于早期发育，而前脑神经发生通过脑室区祖细胞减少消耗性分裂在时间上得以持续。这个图谱还揭示了直接和间接神经发生的区域特异性模式。通过单细胞RNA测序，研究者识别出进化上保守的细胞周期程序和与代谢相关的分子途径，这些途径控制着区域增殖的时间窗口。通过体内的功能获得和功能丧失实验，确定了在新皮层晚期富集的线粒体蛋白FAM210B是一个关键调节因子。FAM210B延长线粒体并增加乳酸产生，这促进了祖细胞的自我复制分裂，并最终增加了其后代的克隆大小。这些发现表明线粒体功能的时空异质性调节着大脑发育过程中区域祖细胞的循环行为和相关的克隆神经元产生。
Volume 188 Issue 14, June 2025
在2025年7月，Science共发表21篇文章，其中包括Previews 2篇，Perspective 2篇，Commentary 1篇，Resources 2篇，Correction 1篇， Research articles 13篇。主要内容涉及活体蛋白激活、tRNA修饰调控mRNA降解、m⁶A作用机制、细菌免疫、胚外发育模型、AD神经元功能障碍、学习多巴胺机制、抗肿瘤免疫新靶点、致癌融合凝聚物、屏状核图谱等。
Machine-learning-assisted universal protein activation in living mice
机器学习辅助的活体小鼠通用蛋白质激活
北京大学
A universal strategy to precisely control protein activation in living animals is crucial for gain-of-function study of proteins under in vivo settings. We herein report CAGE-Proxvivo, a computer-aided proximal decaging strategy for on-demand protein activation as well as protein-protein interaction modulations in living mice. Through machine-learning-assisted evolution of desired aminoacyl-tRNA synthetases (aaRSs), we successfully incorporated chemically caged amino acids into rationally designed “decaging sites” to transiently block target proteins’ function, which can be restored in situ via a small-molecule-triggered bioorthogonal cleavage reaction. This method demonstrates broad applicability ranging from activating proteins of interest to cell-type-specific modulation of distinct phenotypes in living systems. Beyond the active-pocket decaging, CAGE-Proxvivo also enables precise control of protein-protein interactions, as exemplified by a “gated” anti-CD3 antibody that permits chemically regulated T cell recruitment and activation at tumor sites. Overall, CAGE-Proxvivo offers a universal platform for time-resolved biological studies and on-demand therapeutic interventions under living conditions.
在活体动物中精确控制蛋白质激活的通用策略对于在体内环境下研究蛋白质的功能获得至关重要。研究者报告了CAGE-Proxvivo——一种计算机辅助的近端脱笼策略，可在活体小鼠中实现按需蛋白质激活及蛋白质-蛋白质相互作用调节。通过机器学习辅助的所需氨酰-tRNA合成酶（aaRSs）进化，成功地将化学笼状氨基酸整合到合理设计的“脱笼位点”中，暂时阻断靶蛋白的功能，然后可以通过小分子触发的生物正交裂解反应在原位恢复其功能。该方法具有广泛的适用性，从激活感兴趣的蛋白质到在生命系统中对不同表型进行细胞类型特异性调节。除了活性口袋脱笼之外，CAGE-Proxvivo还能够精确控制蛋白质-蛋白质相互作用，例如“门控”抗CD3抗体，它可以在肿瘤部位实现化学调节的T细胞募集和激活。CAGE-Proxvivo为在活体条件下进行时间分辨的生物学研究和按需治疗干预提供了一个通用平台。
tRNA modifications tune m6A-dependent mRNA decay
tRNA修饰调控m⁶A依赖的mRNA降解
伯尔尼大学
Chemically modified nucleotides in mRNA are critical regulators of gene expression, primarily through interactions with reader proteins that bind to these modifications. Here, we present a mechanism by which the epitranscriptomic mark N6-methyladenosine (m6A) is read by tRNAs during translation. Codons that are modified with m6A are decoded inefficiently by the ribosome, rendering them “non-optimal” and inducing ribosome collisions on cellular transcripts. This couples mRNA translation to decay. 5-Methoxycarbonylmethyl-2-thiouridine (mcm5s2U) in the tRNA anticodon loop counteracts this effect. This unanticipated link between the mRNA and tRNA epitranscriptomes enables the coordinated decay of mRNA regulons, including those encoding oncogenic signaling pathways. In cancer, dysregulation of the m6A and mcm5s2U biogenesis pathways—marked by a shift toward more mcm5s2U—is associated with more aggressive tumors and poor prognosis. Overall, this pan-epitranscriptomic interaction represents a novel mechanism of post-transcriptional gene regulation with implications for human health.
mRNA中的化学修饰核苷酸是基因表达的关键调节因子，主要通过与识别这些修饰的读取蛋白相互作用来实现调节。研究者提出了一种机制，即表观转录组标记N6-甲基腺苷（m6A）在翻译过程中被tRNA识别。被m6A修饰的密码子在核糖体上的解码效率较低，使其成为“非最优”密码子，并导致核糖体在细胞转录本上发生碰撞。这将mRNA翻译与降解联系起来。tRNA反密码子环中的5-甲氧基羰基甲基-2-硫尿苷（mcm5s2U）可以抵消这种影响。mRNA和tRNA转录组之间这种未被发现的关联，可实现mRNA调节子（包括编码致癌信号通路的调节子）的协同降解。在癌症中，m6A和mcm5s2U生物合成途径的失调（表现为mcm5s2U水平升高）与更具侵袭性的肿瘤和不良预后相关。这种泛转录组相互作用代表了一种新的转录后基因调控机制，对人类健康具有重要意义。
m6A alters ribosome dynamics to initiate mRNA degradation
m⁶A通过改变核糖体动态来启动mRNA降解
康奈尔大学
Degradation of mRNA containing N6-methyladenosine (m6A) is essential for cell growth, differentiation, and stress responses. Here, we show that m6A markedly alters ribosome dynamics and that these alterations mediate the degradation effect of m6A on mRNA. We find that m6A is a potent inducer of ribosome stalling, and these stalls lead to ribosome collisions that form a unique conformation unlike those seen in other contexts. We find that the degree of ribosome stalling correlates with m6A-mediated mRNA degradation, and increasing the persistence of collided ribosomes correlates with enhanced m6A-mediated mRNA degradation. Ribosome stalling and collision at m6A is followed by recruitment of YTHDF m6A reader proteins to promote mRNA degradation. We show that mechanisms that reduce ribosome stalling and collisions, such as translation suppression during stress, stabilize m6A-mRNAs and increase their abundance, enabling stress responses. Overall, our study reveals the ribosome as the initial m6A sensor for beginning m6A-mRNA degradation.
含有N6-甲基腺苷（m6A）的mRNA的降解对于细胞生长、分化和应激反应至关重要。研究者表明m6A显著改变核糖体动力学，并且这些改变介导了m6A对mRNA的降解作用。m6A是核糖体停滞的强效诱导剂，这些停滞会导致核糖体碰撞，形成一种与其他情况不同的独特构象。核糖体停滞的程度与m6A介导的mRNA降解相关，并且增加碰撞核糖体的持续时间与增强的m6A介导的mRNA降解相关。m6A处的核糖体停滞和碰撞之后，会招募YTHDF m6A读取蛋白来促进mRNA降解。减少核糖体停滞和碰撞的机制，如应激期间的翻译抑制，会稳定m6A-mRNA并增加其丰度，从而实现应激反应。该研究揭示了核糖体是启动m6A-mRNA降解的初始m6A传感器。
Cyclic-dinucleotide-induced filamentous assembly of phospholipases governs broad CBASS immunity
环二核苷酸诱导的磷脂酶丝状组装调控广泛的CBASS免疫
北京理工大学
Cyclic-oligonucleotide-based antiphage signaling systems (CBASS), a widespread antiviral bacterial immune system homologous to the mammalian cGAS-STING pathway, synthesizes cyclic nucleotide signals and triggers effector proteins to induce cell death and prevent viral propagation. Among various CBASS effectors, phospholipase effectors are the first to be discovered and are one of the most widespread families that sense cyclic dinucleotides to degrade cell membrane phospholipids. Here, we report that CBASS phospholipases assemble from a dimeric inactive state into active higher-order filamentous oligomers upon sensing cyclic dinucleotides. Using a combined approach of cryo-electron microscopy and X-ray crystallography, we have determined the structures of CBASS phospholipase in the inactive dimeric state, the cyclic-dinucleotide-bound active higher-order state, and the substrate-analog-bound catalytic mimicry state, thereby visualizing the complete conformational reorganization process. Complemented by functional assays of intermolecular binding, phospholipase enzymatic activity, in vitro membrane disruption, and in vivo antiphage efficiency, our work elucidates the mechanisms of assembly and activation of CBASS phospholipases.
基于环寡核苷酸的抗噬菌体信号系统（CBASS）是一种广泛存在的抗病毒细菌免疫系统，与哺乳动物的cGAS-STING途径同源，它能合成环核苷酸信号并触发效应蛋白诱导细胞死亡，从而阻止病毒传播。在各种CBASS效应蛋白中，磷脂酶效应蛋白是最早被发现的，也是最广泛存在的家族之一，它们能够感知环二核苷酸并降解细胞膜磷脂。研究者报告称，CBASS磷脂酶在感知环二核苷酸后，会从二聚体非活性状态组装成活性的高阶丝状寡聚体。结合冷冻电镜和X射线晶体学技术，确定了CBASS磷脂酶在非活性二聚体状态、结合环二核苷酸的活性高阶状态以及结合底物类似物的催化模拟状态下的结构，从而直观地展示了完整的构象重组过程。通过分子间结合、磷脂酶酶活性、体外膜破坏和体内抗噬菌体效率等功能分析，该研究阐明了CBASS磷脂酶的组装和激活机制。
Post-gastrulation amnioids as a stem cell-derived model of human extra-embryonic development
原肠胚形成后类羊膜囊作为干细胞衍生的人类胚外发育模型
弗朗西斯・克里克研究所
The amnion, an extra-embryonic tissue in mammalian embryos, is thought to provide crucial signaling, structural, and nutritional support during pregnancy. Despite its pivotal importance, studying human amnion formation and function has been hampered by the lack of accurate in vitro models. Here, we present an embryonic stem cell-derived 3D model of the post-gastrulation amnion, post-gastrulation amnioids (PGAs), that faithfully recapitulates extra-embryonic development up to 4 weeks post-fertilization, closely mimicking the functional traits of the human amniotic sac. PGAs self-organize, forming the amnion and the yolk sac, and are surrounded by the extra-embryonic mesoderm. Using PGAs, we show that GATA3 is required and sufficient for amniogenesis and that an autoregulatory feedback loop governs amnion formation, whereby extra-embryonic signals promote amnion specification. The reproducibility and scalability of the PGA system, with its precise cellular, structural, and functional integrity, opens avenues for investigating embryo-amnion interactions beyond gastrulation and offers an ideal platform for large-scale pharmacological and clinical studies.
羊膜是哺乳动物胚胎中的一种胚胎外组织，被认为在怀孕期间提供关键的信号、结构和营养支持。尽管其至关重要，但由于缺乏准确的体外模型，研究人类羊膜的形成和功能一直受到阻碍。研究者提出了一种由胚胎干细胞衍生的后原肠胚羊膜的3D模型——原肠胚形成后类羊膜囊（PGAs），可忠实地重现受精后长达4周的胚胎外发育过程，紧密模拟人类羊膜囊的功能特征。PGAs能够自我组织，形成羊膜和卵黄囊，并被胚胎外中胚层所包围。通过使用PGAs，发现GATA3对于羊膜形成既是必需的也是充分的，并且存在一个自调节反馈回路来控制羊膜形成，即胚胎外信号促进羊膜的特化。PGA系统具有可重复性和可扩展性，具有精确的细胞、结构和功能完整性，为研究原肠胚形成后胚胎与羊膜的相互作用开辟了途径，并为大规模药理学和临床研究提供了一个理想的平台。
Alzheimer’s disease patient-derived high-molecular-weight tau impairs bursting in hippocampal neurons
阿尔茨海默病患者来源的高分子量tau蛋白损害海马神经元的爆发式放电
伦敦大学学院
tau蛋白积累与阿尔茨海默病（AD）的认知症状密切相关。然而，tau蛋白导致记忆相关认知能力下降的细胞驱动因素仍然不清楚。研究者在小鼠模型中采用体内Neuropixels和膜片钳记录技术，证明tau蛋白，独立于β-淀粉样蛋白，选择性地削弱了CA1海马神经元的复杂棘波爆发，这是学习和记忆的基本细胞机制。爆发受损与改变的海马网络活动有关，这些活动与爆发放电模式（即theta节律和高频涟漪）相关，并且与CaV2.3钙通道的神经元表达减少同时发生，而CaV2.3钙通道对于体内爆发放电至关重要。研究者从人类AD大脑中分离出可溶性高分子量（HMW）tau蛋白，并确定其为抑制爆发放电的tau蛋白种类。这些数据为AD中tau蛋白相关的认知能力下降提供了一种细胞机制，并表明细胞内HMW tau这种罕见的蛋白种类是一个治疗靶点。
Dopamine encodes deep network teaching signals for individual learning trajectories
多巴胺为个体学习轨迹编码深度网络教学信号
西北大学; 多伦多大学
Striatal dopamine plays fundamental roles in fine-tuning learned decisions. However, when learning from naive to expert, individuals often exhibit diverse learning trajectories, defying understanding of its underlying dopaminergic mechanisms. Here, we longitudinally measure and manipulate dorsal striatal dopamine signals in mice learning a decision task from naive to expert. Mice learning trajectories transitioned through sequences of strategies, showing substantial individual diversity. Remarkably, the transitions were systematic; each mouse’s early strategy determined its strategy weeks later. Dopamine signals reflected strategies each animal transitioned through, encoding a subset of stimulus-choice associations. Optogenetic manipulations selectively updated these associations, leading to learning effects distinct from that of reward. A deep neural network using heterogeneous teaching signals, each updating a subset of network association weights, captured our results. Analyzing the model’s fixed points explained learning diversity and systematicity. Altogether, this work provides insights into the biological and mathematical principles underlying individual long-term learning trajectories.
纹状体多巴胺在微调习得决策中起着基础性作用。然而，从新手到专家的学习过程中，个体往往表现出多样的学习轨迹，这使得人们难以理解其潜在的多巴胺能机制。研究者对学习决策任务的小鼠从新手到专家的过程中，纵向测量并操控其背侧纹状体多巴胺信号。小鼠的学习轨迹通过一系列策略转变，表现出显著的个体差异。这些转变是有系统性的；每只小鼠早期的策略决定了其几周后的策略。多巴胺信号反映了每只动物所经历的策略转变，编码了一部分刺激-选择关联。光遗传学操作选择性地更新了这些关联，产生了与奖励不同的学习效果。一个使用异质教学信号（每个信号更新网络关联权重的一个子集）的深度神经网络能够解释该结果。对模型固定点的分析解释了学习的多样性和系统性。该工作为理解个体长期学习轨迹背后的生物学和数学原理提供了见解。
Serotonin transporter inhibits antitumor immunity through regulating the intratumoral serotonin axis
血清素转运体通过调节肿瘤内血清素轴抑制抗肿瘤免疫
加利福尼亚大学圣地亚哥分校
Identifying additional immune checkpoints hindering antitumor T cell responses is key to the development of next-generation cancer immunotherapies. Here, we report the induction of serotonin transporter (SERT), a regulator of serotonin levels and physiological functions in the brain and peripheral tissues, in tumor-infiltrating CD8 T cells. Inhibition of SERT using selective serotonin reuptake inhibitors (SSRIs), the most widely prescribed antidepressants, significantly suppressed tumor growth and enhanced T cell antitumor immunity in various mouse syngeneic and human xenograft tumor models. Importantly, SSRI treatment exhibited significant therapeutic synergy with programmed cell death protein 1 (PD-1) blockade, and clinical data correlation studies negatively associated intratumoral SERT expression with patient survival in a range of cancers. Mechanistically, SERT functions as a negative-feedback regulator inhibiting CD8 T cell reactivities by depleting intratumoral T cell-autocrine serotonin. These findings highlight the significance of the intratumoral serotonin axis and identify SERT as an immune checkpoint, positioning SSRIs as promising candidates for cancer immunotherapy.
识别阻碍抗肿瘤T细胞反应的其他免疫检查点是开发下一代癌症免疫疗法的关键。研究者报告了血清素转运体（SERT）在肿瘤浸润性CD8 T细胞中的诱导情况，SERT是大脑和外周组织中血清素水平和生理功能的调节因子。使用选择性血清素再摄取抑制剂（SSRIs，最广泛使用的抗抑郁药）抑制SERT，在多种小鼠同基因和人异种移植肿瘤模型中显著抑制了肿瘤生长并增强了T细胞的抗肿瘤免疫。SSRI治疗与程序性细胞死亡蛋白1（PD-1）阻断剂表现出显著的治疗协同作用，并且临床数据相关性研究表明，在一系列癌症中，肿瘤内SERT的表达与患者生存率呈负相关。从机制上讲，SERT作为一种负反馈调节因子，通过消耗肿瘤内T细胞自分泌的血清素来抑制CD8 T细胞的反应性。这些发现凸显了肿瘤内血清素轴的重要性，并将SERT确定为一种免疫检查点，使SSRIs成为有前景的癌症免疫治疗候选药物。
RNA polymerase II partitioning is a shared feature of diverse oncofusion condensates
RNA聚合酶II的分区是多种致癌融合凝聚物的共同特征
纪念斯隆-凯特琳癌症中心
Condensates regulate transcription by selectively compartmentalizing biomolecules, yet the rules of specificity and their relationship to function remain enigmatic. To identify rules linked to function, we leverage the genetic selection bias of condensate-promoting oncofusions. Focusing on the three most frequent oncofusions driving translocation renal cell carcinoma, we find that they promote the formation of condensates that activate transcription by gain-of-function RNA polymerase II partitioning through a shared signature of elevated π and π-interacting residues and depletion of aliphatic residues. This signature is shared among a broad set of DNA-binding oncofusions associated with diverse cancers. We find that this signature is necessary and sufficient for RNA polymerase II partitioning, gene activation, and cancer cell phenotypes. Our results reveal that dysregulated condensate specificity is a shared molecular mechanism of diverse oncofusions, highlighting the functional role of condensate composition and the power of disease genetics in investigating relationships between condensate specificity and function.
凝聚物通过选择性地分隔生物分子来调节转录，然而特异性的规则及其与功能的关系仍不明确。为了确定与功能相关的规则，研究者利用了促进凝聚物形成的致癌融合的遗传选择偏向性。聚焦于驱动易位性肾细胞癌的三种最常见的致癌融合，发现它们促进凝聚物的形成，这些凝聚物通过RNA聚合酶II的分区（一种功能获得机制）来激活转录，其特征是具有升高的π和π相互作用残基以及脂肪族残基的缺失。这一特征在与多种癌症相关的广泛的DNA结合致癌融合中是共有的。该特征对于RNA聚合酶II的分区、基因激活和癌细胞表型既是必要的也是充分的。该结果揭示了失调的凝聚物特异性是多种致癌融合的共同分子机制，突出了凝聚物组成的功能作用以及疾病遗传学在研究凝聚物特异性与功能关系方面的作用。
Single-cell spatial transcriptome atlas and whole-brain connectivity of the macaque claustrum
猕猴屏状核的单细胞空间转录组图谱和全脑连接性
中国科学院脑科学与智能技术卓越创新中心
Claustrum orchestrates brain functions via its connections with numerous brain regions, but its molecular and cellular organization remains unresolved. Single-nucleus RNA sequencing of 227,750 macaque claustral cells identified 48 transcriptome-defined cell types, with most glutamatergic neurons similar to deep-layer insular neurons. Comparison of macaque, marmoset, and mouse transcriptomes revealed macaque-specific cell types. Retrograde tracer injections at 67 cortical and 7 subcortical regions defined four distinct distribution zones of retrogradely labeled claustral neurons. Joint analysis of whole-brain connectivity and single-cell spatial transcriptome showed that these four zones containing distinct compositions of glutamatergic (but not GABAergic) cell types preferentially connected to specific brain regions with a strong ipsilateral bias. Several macaque-specific glutamatergic cell types in ventral vs. dorsal claustral zones selectively co-projected to two functionally related areas—entorhinal cortex and hippocampus vs. motor cortex and putamen, respectively. These data provide the basis for elucidating the neuronal organization underlying diverse claustral functions.
屏状核通过与众多脑区的连接来协调大脑功能，但其分子和细胞组织仍未得到解决。对227,750个猕猴屏状核细胞进行单核RNA测序，鉴定出48种由转录组定义的细胞类型，其中大多数谷氨酸能神经元与岛叶深层神经元相似。对猕猴、狨猴和小鼠转录组的比较揭示了猕猴特有的细胞类型。在67个皮质和7个皮质下区域注射逆行示踪剂，定义了逆行标记的屏状核神经元的四个不同分布区域。全脑连接性和单细胞空间转录组的联合分析表明，这四个区域包含不同组成的谷氨酸能（而非GABA能）细胞类型，它们优先与特定的脑区相连，且具有很强的同侧偏向性。猕猴腹侧与背侧屏状核区域的几种特有的谷氨酸能细胞类型分别选择性地共同投射到两个功能相关的区域——内嗅皮层和海马体，以及运动皮层和壳核。这些数据为阐明灵长类动物大脑中屏状核多样功能背后的神经元组织提供了基础。
汇报人：谢尔杰
导师：唐玥玓
审核：张宇阳、任建君
