1、皮层-海马神经环路的记忆编码机制
记忆是人类高级认知活动的基础，然而记忆存储和提取的生物学和神经环路机制并不明确。特异性的神经细胞活动中是否有记忆的印迹？如果存在记忆的印迹，它们在脑中的存储方式和网络构成是如何的？我们研究组以小鼠为主要研究材料，探索学习活动在哺乳动物大脑中留下印迹并有序提取的生物学机制。通过发展大规模单神经元解析度的在体成像，我们在不同的时间尺度上记录神经元集群（尤其是皮层环路）如何响应外界刺激信号，并在关联学习时发生改变，从而留下印迹的。我们也关注海马活动在记忆提取的过程中如何实现对神经元集群里储存的信息的提取机制。我们使用在体多电极、细胞群钙信号、细胞群体及早基因表达信号、光遗传学、病毒介导的神经示踪等技术来研究这些问题。
2、长期记忆储存的组蛋白调控机制
我们前期的工作发现了神经元活动依赖的组蛋白修饰机制，其修饰主导了记忆环路的稳定性变化。我们同时发现，在一定条件下，例如诱发性记忆再巩固过程，这种组蛋白修饰会发生去修饰。即，神经活动造成的表观修饰变化并非永久性变化，在某些生理与病理过程中会发生逆转，从而有可能使得已经收录的记忆环路被修改。这种表观遗传修饰的灵活变化与长期记忆的灵活性很可能有密切的关系。这个可逆过程的缺失很可能是自闭症等神经系统疾病的原因之一。我们将利用单细胞测序技术与在体染色质分离方法研究记忆印迹神经元中的记忆相关基因表达变化与组蛋白修饰，寻找自闭症、抽动秽语症、创伤后应激综合症等神经系统疾病可能性的组蛋白调控机制，发现新的药物靶点和相关疾病的病理学机制。
3、多感知协同下的学习与记忆提取机制
高等认知功能的中的学习与记忆过程通常包括了多感知信息的整合。其中皮层中复杂的神经网络实现了多感知信息下的融合学习等过程。而海马体对记忆的提取、位置记忆以及场景记忆具有重要的贡献。通过多实验室合作，我们期望能对皮层神经网络与皮层下神经网络结构组成信息进行系统分析并对其外界刺激触发下的动态信号进行记录并关联网络结构信息进行研究，探索多感知融合下高效学习的神经网络调控机制。利用光遗传学、双光子成像和多种行为学手段，研究多感知学习的生物学机制。

Luo, Wenhan*; Yun, Di; Hu, Yi; Tian, Miaomiao; Yang, Jiajun; Xu, Yifan; Tang, Yong; Zhan, Yang; Xie, Hong; Guan, Ji-Song#.Acquiring new memories in neocortex of hippocampal-lesioned mice.NATURE COMMUNICATIONS. 24 Mar 2022. 13(1).

Yan, Yuze*; Tian, Miaomiao; Li, Meng; Zhou, Gang; Chen, Qinan; Xu, Mingrui; Hu, Yi; Luo, Wenhan; Guo, Xiuxian; Zhang, Cheng; Xie, Hong; Wu, Qing-Feng; Xiong, Wei#; Liu, Shiguo#; Guan, Ji-Song#.ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links Eph receptor gene to autism spectrum disorder.NEURON. 06 Apr 2022. 110(7).

Shiguo Liu , Miaomiao Tian， Fan He,  Jiani Li, Hong Xie, Wenmiao Liu, Yeting Zhang,  Ru Zhang, Mingji Yi, Fengyuan Che, Xu Ma, Yi Zheng,  Hao Deng, Guiju Wang,  Lang Chen, Xue Sun, Yinglei Xu, Jingli Wang, Yucui Zang, Mengmeng Han, Xiuhai Wan, Hongzai Guan, Yinlin Ge, Chunmei Wu, Haiyan Wang, Hui Liang, Hui Li, Ni Ran, Zhaochuan Yang, Huanhuan Huang, Yanzhao Wei, Xueping Zheng, Xiangrong Sun, Xueying Feng, Lanlan Zheng, Tao Zhu, Wenhan Luo,Qinan Chen, Yuze Yan, Zuzhou Huang, Zhongcui Jing, Yixia Guo, Xuzhan Zhang, Christian P. Schaaf, Jinchuan Xing, Chuanyue Wang

Dong Li^*, Guangyu Wang^*, Hong Xie, Yi Hu, Ji-Song Guan^#, Claus C Hilgetag^# (2019) Multimodal memory components and their long-term dynamics identified in cortical layers II/III but not layer V. Frontiers in Integrative Neuroscience 13:54 

Guangyu Wang^*, Lun Wang^*, Hong Xie^*, Wenhan Luo, Yixiang Wang, Jun Jiang, Chun Xiao, Feng Xing, Ji-Song Guan^#（2019）Switching from fear to no fear by different neural ensembles in mouse retrosplenial cortex. Cerebral Cortex  Dec 17; 29(12): 5085-5097 

Jun Jiang, Guangyu Wang, Wenhan Luo, Hong Xie, Ji-Song Guan^#. (2018) Mammillary body regulates state-dependent fear by alternating cortical oscillations. Sci Rep. 6: 26597. Sep 7;8(1):13471. doi: 10.1038/s41598-018-31622-z 

Ruxing Fu, Wenhan Luo, Roy Nazempour, Daxin Tan, He Ding, Kaiyuan Zhang, Lan Yin, Ji-Song Guan#, Xin Sheng#, (2018) Implantable and Biodegradable Poly(L-lactic acid) Fibers for Optical Neural Interfaces,  Advanced Optical Materials, Feb, 3(6):1700941 10.1002/adom.201700941 

Xinlu Ding, SanXiong Liu, Miaomiao Tian, Wenhao Zhang, Tao Zhu, Dongdong Li, Jiawei Wu, HaiTeng Deng, Yichang Jia, Wei Xie, Hong Xie & Ji-Song Guan#(2017) Activity-induced histone modifications govern Neurexin-1 mRNA splicing and memory preservation. Nat Neurosci. May;20(5):690-699, doi:10.1038/nn.4536 

Zhu Τ, Liang C, Li D, Tian M, Liu S, Gao G and Guan JS#. (2016) Histone methyltransferase Ash1L mediates activity-dependent repression of neurexin-1α. Sci Rep. 6: 26597. 

Guan JS#, Jiang J, Xie H and Liu K-Y. (2016) How does the sparse memory "Engram": Neurons encode the memory of a spatial-temporal event? Front. Neural Circuits 10: 61. 

Hong Xie, Yu Liu, Youzhi Zhu, Xinlu Ding, Yuhao Yang, Ji-Song Guan#. In vivo imaging of immediate early gene expression reveals layer-specific memory traces in the mammalian brain. Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2788-93. doi: 10.1073/pnas.1316808111. Epub 2014 Feb 3.Epub 2014 Feb 3 

Peng Liu, Tao Zhu, Chen Liang,  Bing Bai, Guanjun Gao, Ji-Song Guan#, A one-step screening system for multi-zinc finger proteins targeting a long-DNA sequence. SCIENTIA SINICA Vitae, 2014, 44: 1061–1072, doi: 10.1360/052014-77 

Grff J, Rei D, Guan JS, Wang WY, Seo J, Hennig KM, Nieland TJ, Fass DM, Kao PF, Kahn M, Su SC, Samiei A, Joseph N, Haggarty SJ, Delalle I, Tsai LH. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature. 2012 Feb 29;483(7388):222-6. 

Guan JS*, Su SC*, Gao J, Joseph N, Xie Z, Zhou Y, Durak O, Zhang L, Zhu JJ, Clauser KR, Carr SA, Tsai LH. Cdk5 Is Required for Memory Function and Hippocampal Plasticity via the cAMP Signaling Pathway. PLoS One. 2011; 6(9): e25735.  Epub 2011 Sep 30. 

Ji-Song Guan*, Stephen J. Haggarty*, Emanuela Giacometti*, Jan-Hermen Dannenberg*, Nadine Joseph, Jun Gao, Thomas J.F. Nieland, Ying Zhou, Xinyu Wang, Ralph Mazitschek, James E. Bradner, Ronald A. DePinho, Rudolf Jaenisch, Li-Huei Tsai. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459(7243): 55-60; May 2009 (full research article) 

Ji-Song Guan*, Zhen-Zhong Xu*, Hua Gao, Shao-Qiu He, Guo-Qiang Ma, Tao Sun, Li-Hua Wang, Zhen-Ning Zhang, Isabelle Lena, Ian Kitchen, Robert Elde, Andreas Zimmer, Cheng He, Gang Pei, Lan Bao and Xu Zhang. Interaction with Vesicle Luminal Protachykinin Regulates Surface Expression of δ-Opioid Receptors and Opioid Analgesia.  Cell 122: 619-631, 2005 

其他论文 

Zhang X, Wang F, Hu Y, Chen R, Meng D, Guo L, Lv H, Guan JS, Jia Y.(2020) In vivo stress granule misprocessing evidenced in a FUS knock-in ALS mouse model. Brain. May 1: awaa076. doi: 10.1093/brain/awaa076

Li, D., Zavaglia, M., Wang, G., Xie, H., Hu, Y., Werner, R., Guan, J., and Hilgetag, C^#. (2019). Discrimination of the hierarchical structure of cortical layers in 2-photon microscopy data by combined unsupervised and supervised machine learning. Scientific Reports 9, 7424. 

Xu K, Su H, Zhu J, Guan JS and Zhang B. (2016) Neuron segmentation based on CNN with semi-supervised regularization. Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition Workshops. 2016. pp 20-28. 

Wagner FF, Zhang YL, Fass DM, Joseph N, Gale JP, We？wer M, McCarren P, Fisher SL, Kaya T, Zhao WN, Reis SA, Hennig KM, Thomas M, Lemercier BC, Lewis MC, Guan JS, Moyer MP, Scolnick E, Haggarty SJ, Tsai LH, Holson EB. Kinetically Selective Inhibitors of Histone Deacetylase 2(HDAC2) as Cognition Enhancers. Chem Sci. 2015 Jan 1;6(1):804-815. 

Ji-Song Guan#, Hong Xie, Xinlu Ding. The role of epigenetic regulation in learning and memory. Exp Neurol. 2015 Jun;268:30-6. doi: 10.1016/j.expneurol.2014.05.006. Epub 2014 May 14. Review. 

Jinsoo Seo, Paola Giusti-Rodríguez, Ying Zhou, Andrii Rudenko, Sukhee Cho, Kristie T. Ota, Christine Park, Holger Patzke7, Ram Madabhushi, Ling Pan, Alison E. Mungenast, Ji-Song Guan, Ivana Delalle, Li-Huei Tsai. Activity-Dependent p25 Generation Regulates Synaptic Plasticity and Aβ-Induced Cognitive Impairment. Cell 2014 Apr 10;157:486-98. 

Zhang J, Cao Q, Li S, Lu X, Zhao Y, Guan JS, Chen JC, Wu Q, Chen GQ.3-hydroxybutyrate methyl ester as a potential drug against Alzheimer's disease via mitochondria protection mechanism. Biomaterials. 2013 Oct;34(30):7552-62. 

Fass DM, Reis SA, Ghosh B, Hennig KM, Joseph NF, Zhao WN, Nieland TJ, Guan JS, Kuhnle CE, Tang W, Barker DD, Mazitschek R, Schreiber SL, Tsai LH, Haggarty SJ. Crebinostat: a novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity. Neuropharmacology. 2013 Jan;64:81-96. 

Jun Gao*, Wen-Yuan Wang*, Ying-Wei Mao, Johannes Gra¨ff, Ji-Song Guan, Ling Pan, Gloria Mak, Dohoon Kim, Susan C. Su & Li-Huei Tsai. A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature, 2010, 466(7310):1105-9  

Dohoon Kim, Christopher L. Frank, Matthew M. Dobbin, Rachel K. Tsunemoto, Weihong Tu, Peter L. Peng, Ji-Song Guan, Byung-Hoon Lee, Lily Y. Moy, Paola Giusti, Nisha Broodie, Ralph Mazitschek, Ivanna Delalle, Stephen J. Haggarty, Rachael L. Neve, YouMing Lu and Li-Huei Tsai. Deregulation of HDAC1 by p25/Cdk5 in Neurotoxicity.Neuron 60(5):803-17; Dec 2008 

Hai-Bo Wang, Ji-Song Guan, Lan Bao and Xu Zhang. Distinct Subcellular Distribution of δ-Opioid Receptor Fused with Various Tags in PC12 Cells. Neurochemical Research, 33(10):2028-34 Oct 2008 

Xu Zhang, Lan Bao, Ji-Song Guan. Role of delivery and trafficking of δ-opioid receptors in opioid analgesia and tolerance. Trends in pharmacological sciences , 27 (6): 324-329 JUN 2006 (Review) 

Lan Bao*, Shan-Xue Jin*, Chen Zhang*, Li-Hua Wang, Zhen-Zhong Xu, Fang-Xiong Zhang, Lie-Chen Wang, Feng-Shou Ning, Hai-Jiang Cai, Ji-Song Guan, Hua-Sheng Xiao, Zhi-Qing D. Xu, Cheng He, Tomas H？kfelt, Zhuan Zhou, and Xu Zhang. Activation of Delta Opioid Receptors Induces Receptor Insertion and Neuropeptide Secretion. Neuron 37, 121-133,2003

实验室网址：https://slst.shanghaitech.edu.cn/gjs/main.htm
E-mail: guanjs@shanghaitech.edu.cn
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