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Development and transdifferentiation into inner hair cells require Tbx2

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National Science Review 2022年第12期9卷 135-148页

作者： Zhenghong Bi Xiang Li Minhui Ren Yunpeng Gu Tong Zhu Shuting Li Guangqin Wang Suhong Sun Yuwei Sun Zhiyong Liu institute of Neuroscience State Key Laboratory of Neuroscience CAS Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences University of Chinese Academy of Sciences Shanghai Center for brain Science and brain-Inspired intelligence Technology

Atohl is essential for the development of both outer hair cells(OHCs) and inner hair cells(IHCs) in the mammalian co chlea.Whereas Ikzf2 is necessary for OHC development,the key gene re quired for IHC development remains unknown.We found that deletion of Tbx2 in neonatal IHCs led to their transdifferentiation into OHCs by repressing 26.7% of IHC genes and inducing 56.3% of OHC genes,including Ikzf2.More importantly,persistent expression of Tbx2 coupled with transient Atohl expression effe ctively reprogrammed non-sensory supporting cells into new IHCs expressing the functional IHC marker vGlut3.The differentiation status of these new IHCs was considerably more advanced than that previously reported.Thus,Tbx2 is essential for IHC development and co-upregulation of Tbx2 with Atohl in supporting cells represents a new approach for treating deafness related to IHC degeneration.

关键词： Tbx2 cochlea inner hair cell supporting cell Ikzf2 outer hair cell

Programmable deaminase-free base editors for G-to-Y conversion by engineered glycosylase

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National Science Review 2023年第8期10卷 78-87页

作者： Huawei Tong Nana Liu Yinghui Wei Yingsi Zhou Yun Li Danni Wu Ming Jin Shuna Cui Hengbin Li Guoling Li Jingxing Zhou Yuan Yuan Hainan Zhang Linyu Shi Xuan Yao Hui Yang HuidaGene Therapeutics Co. Ltd. Department of Neurology and institute of Neurology of First Affiliated Hospital Institute of Neuroscience and Fujian Key Laboratory of Molecular Neurology Fujian Medical University institute of Neuroscience Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences Shanghai Center for brain Science and brain-Inspired intelligence

Current DNA base editors contain nuclease and DNA deaminase that enables deamination of cytosine(C)or adenine(A), but no method for guanine(G) or thymine(T) editing is available at present. Here we developed a deaminase-free glycosylase-based guanine base editor(gGBE) with G editing ability, by fusing Cas9 nickase with engineered N-methylpurine DNA glycosylase protein(MPG). By several rounds of MPG mutagenesis via unbiased and rational screening using an intron-split EGFP reporter, we demonstrated that gGBE with engineered MPG could increase G editing efficiency by more than 1500 fold.Furthermore, this gGBE exhibited high base editing efficiency(up to 81.2%) and high G-to-T or G-to-C(i.e. G-to-Y) conversion ratio(up to 0.95) in both cultured human cells and mouse embryos. Thus, we have provided a proof-of-concept of a new base editing approach by endowing the engineered DNA glycosylase the capability to selectively excise a new type of substrate.

关键词： glycosylase base excision repair base editor depurination deaminase-free transversion

The brain Connectome for Chinese Reading

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Neuroscience Bulletin 2022年第9期38卷 1097-1113页

作者： Wanwan Guo Shujie Geng Miao Cao Jianfeng Feng institute of Science and Technology for brain-Inspired intelligence Fudan UniversityShanghai200433China Key Laboratory of Computational Neuroscience and brain-Inspired intelligence(Ministry of Education) Fudan UniversityShanghai200433China

Chinese,as a logographic language,fundamentally differs from alphabetic languages like English.Previous neuroimaging studies have mainly focused on alphabetic languages,while the exploration of Chinese reading is still an emerging and fast-growing research field.Recently,a growing number of neuroimaging studies have explored the neural circuit of Chinese reading.Here,we summarize previous research on Chinese reading from a connectomic perspective.Converging evidence indicates that the left middle frontal gyrus is a specialized hub region that connects the ventral with dorsal pathways for Chinese reading.Notably,the orthography-to-phonology and orthography-to-semantics mapping,mainly processed in the ventral pathway,are more specific during Chinese reading.Besides,in addition to the left-lateralized language-related regions,reading pathways in the right hemisphere also play an important role in Chinese reading.Throughout,we comprehensively review prior findings and emphasize several challenging issues to be explored in future work.

关键词： brain connectome Chinese reading Word recognition Reading comprehension Structural connectivity Functional connectivity

Memristive dynamics enabled neuromorphic computing systems

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Science China(Information Sciences) 2023年第10期66卷 5-19页

作者： Bonan YAN Yuchao YANG Ru HUANG Center for brain Inspired Chips Institute for Artificial Intelligence Peking University Beijing Advanced Innovation Center for Integrated Circuits School of Integrated Circuits Peking University School of Electronic and Computer Engineering Peking University Center for brain Inspired intelligence Chinese Institute for Brain Research(CIBR)

The slowing down of transistor scaling and explosive growth for intelligence computing power emerge as the two driving factors for the study of novel devices and materials to pursue highly-efficient computing systems. Memristors, incorporating rich intrinsic dynamics, are a promising candidate for constructing efficient and scalable bio-inspired computing systems. In this progress report, we review the latest advances in novel types of memristors as well as their applications in implementing neuromorphic computing systems. This paper not only covers the memristive dynamics-enabled bionic computing systems but also discusses the memristive sensory systems that integrate sensing and computing. Eventually, device-circuit co-optimization methods are given to emphasize the trend of cross-layer co-design in this fast-evolving field.The innovation in memristor devices mainly focuses on specialized computing hardware and yields superior computing and sensing efficiency. At last, we offer our insight into the trend of state-of-the-art research in memristive materials, devices, circuits, and systems.

关键词： memrsitor memristive dynamics artificial synapse artificial neuron neuromorphic computing

Large language models and brain-inspired general intelligence

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National Science Review 2023年第10期10卷 6-7页

作者： Bo Xu Mu-ming Poo institute of Automation Chinese Academy of Sciences CAS Center for Excellence for brain Science and intelligence Technology

The emergence of large language models(LLMs) such as ChatGPT/GPT-4 and their stunning performance in generative tasks heralds the beginning of a new era of artificial general intelligence(AGI).The LLMs have shown amazing generalization ability in natural language processing,computer vision and other generative tasks [1].These models point to a feasible approach for developing AGI.To a large extent,they have passed the classical Turing test and their capability is still growing without an upper bound identified.

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Influence of Recent Trial History on Interval Timing

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Neuroscience Bulletin 2023年第4期39卷 559-575页

作者： Taorong Xie Can Huang Yijie Zhang Jing Liu Haishan Yao institute of Neuroscience State Key Laboratory of NeuroscienceCAS Center for Excellence in Brain Science and Intelligence TechnologyChinese Academy of SciencesShanghai 200031China University of Chinese Academy of Sciences Beijing 100049China Shanghai Center for brain Science and brain-Inspired intelligence Technology Shanghai 201210China

Interval timing is involved in a variety of cognitive behaviors such as associative learning and decision-making.While it has been shown that time estimation is adaptive to the temporal context,it remains unclear how interval timing behavior is influenced by recent trial history.Here we found that,in mice trained to perform a licking-based interval timing task,a decrease of inter-reinforcement interval in the previous trial rapidly shifted the time of anticipatory licking earlier.Optogenetic inactivation of the anterior lateral motor cortex(ALM),but not the medial prefrontal cortex,for a short time before reward delivery caused a decrease in the peak time of anticipatory licking in the next trial.Electrophysiological recordings from the ALM showed that the response profiles preceded by short and long inter-reinforcement intervals exhibited task-engagement-dependent temporal scaling.Thus,interval timing is adaptive to recent experience of the temporal interval,and ALM activity during time estimation reflects recent experience of interval.

关键词： Peak-interval timing procedure Temporal context Trial history Secondary motor cortex Temporal scaling

The Secondary Motor Cortex-striatum Circuit Contributes to Suppressing Inappropriate Responses in Perceptual Decision Behavior

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Neuroscience Bulletin 2023年第10期39卷 1544-1560页

作者： Jing Liu Dechen Liu Xiaotian Pu Kexin Zou Taorong Xie Yaping Li Haishan Yao institute of Neuroscience State Key Laboratory of NeuroscienceCAS Center for Excellence in Brain Science and Intelligence TechnologyChinese Academy of SciencesShanghai 200031China University of Chinese Academy of Sciences Beijing 100049China Shanghai Center for brain Science and brain-Inspired intelligence Technology Shanghai 201210China

The secondary motor cortex(M2)encodes choice-related information and plays an important role in cue-guided actions.M2 neurons innervate the dorsal striatum(DS),which also contributes to decision-making behavior,yet how M2 modulates signals in the DS to influence perceptual decision-making is unclear.Using mice performing a visual Go/No-Go task,we showed that inactivating M2 projections to the DS impaired performance by increasing the false alarm(FA)rate to the reward-irrelevant No-Go stimulus.The choice signal of M2 neurons correlated with behavioral performance,and the inactivation of M2 neurons projecting to the DS reduced the choice signal in the DS.By measuring and manipulating the responses of direct or indirect pathway striatal neurons defined by M2 inputs,we found that the indirect pathway neurons exhibited a shorter response latency to the No-Go stimulus,and inactivating their early responses increased the FA rate.These results demonstrate that the M2-to-DS pathway is crucial for suppressing inappropriate responses in perceptual decision behavior.

关键词： Secondary motor cortex Striatum Visual perceptual decision Choice signal Direct and indirect pathway striatal neurons

Accelerated passage of gene-modified monkeys by hormone-induced precocious puberty

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National Science Review 2021年第7期8卷 68-71页

作者： Zhen Liu Kui Li Yijun Cai Qiming Liu Tikui Zhang Yong Lu Yanhong Nie Yan Wang Zhiguang Yan Yinwei Qu Yuzhuo Li Zhanyang Wang Zhi-Qi Xiong Qiang Sun institute of Neuroscience State Key Laboratory of Neuroscience CAS Key Laboratory of Primate Neurobiology CAS Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences Shanghai Research Center for Brain Science and Brain-Inspired Intelligence

Mosaicism occurs in most founder genemodified monkeys generated by virus infection and programmable-nucleases[1–3]. In addition, macaque monkeys have a long preadolescence period, with four or more years usually required for male macaque monkeys to become sexually mature [4,5]. The mosaicism and long time to sexual maturity have largely prevented wide usage of gene-modified monkey models.

关键词： non-human primates gene editing passage acceleration precocious puberty

Acquired immunity and Alzheimer's disease

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The Journal of Biomedical Research 2023年第1期37卷 15-29页

作者： Weixi Feng Yanli Zhang Peng Sun Ming Xiao Jiangsu Key Laboratory of Neurodegeneration Nanjing Medical UniversityNanjingJiangsu 211166China institute of Neuroscience State Key Laboratory of NeuroscienceCAS Center for Excellence in Brain Science and Intelligence TechnologyShanghai Research Center for Brain Science and Brain-Inspired IntelligenceChinese Academy of SciencesShanghai 200031China brain institute Nanjing Brain HospitalNanjing Medical UniversityNanjingJiangsu 210029China

Alzheimer’s disease(AD) is an age-related neurodegenerative disease characterized by progressive cognitive defects. The role of the central immune system dominated by microglia in the progression of AD has been extensively investigated. However, little is known about the peripheral immune system in AD pathogenesis.Recently, with the discovery of the meningeal lymphatic vessels and glymphatic system, the roles of the acquired immunity in the maintenance of central homeostasis and neurodegenerative diseases have attracted an increasing attention. The T cells not only regulate the function of neurons, astrocytes, microglia, oligodendrocytes and brain microvascular endothelial cells, but also participate in the clearance of β-amyloid(Aβ) plaques. Apart from producing antibodies to bind Aβ peptides, the B cells affect Aβ-related cascades via a variety of antibodyindependent mechanisms. This review systemically summarizes the recent progress in understanding pathophysiological roles of the T cells and B cells in AD.

关键词： Alzheimer’s disease acquired immunity lymphocytes brain lymphatic system immune cell therapy

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