SH2B1 Tunes Hippocampal ERK Signaling to Influence Fluid Intelligence in Humans and Mice  

作　　者：Xiujuan Du Yuhua Yan Juehua Yu Tailin Zhu Chu-Chung Huang Lingli Zhang Xingyue Shan Ren Li Yuan Dai Hui LV Xiao-Yong Zhang Jianfeng Feng Wei-Guang Li Qiang Luo Fei Li 

机构地区：[1]Developmental and Behavioral Pediatric Department,Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research and Ministry of Education-Shanghai Key Laboratory for Children's Environmental Health,Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200092,China [2]Developmental and Behavioral Pediatric Department,Shanghai Xinhua Children's Hospital,Shanghai 200092,China [3]National Clinical Research Center for Aging and Medicine at Huashan Hospital,Institute of Science and Technology for Brain-lnspired Intelligence,Ministry of Education-Key Laboratory of Computational Neuroscience and Brain-lnspired Intelligence,Fudan University,Shanghai 200433,China [4]State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science,Institutes of Brain Science and Human Phenom Institute,Fudan University,Shanghai 200032,China [5]Shanghai Key Laboratory of Brain Functional Genomics(Ministry of Education),School of Life Sciences,East China Normal University,Shanghai 200062,China [6]Department of Rehabilitation Medicine,Huashan Hospital,Institute for Translational Brain Research,State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science,Fudan University,Shanghai 200032,China [7]Center for Experimental Studies and Research,The First Affliated Hospital of Kunming Medical University,Kunming 650032,China [8]Shanghai Research Center for Brain Science and Brain-lnspired Intelligence,Shanghai201210,China [9]Institute of Cognitive Neuroscience,School of Psychology and Cognitive Science,East China Normal University,Shanghai 200062,China.

出　　处：《Research》2024年第3期369-389,共21页研究（英文）

基　　金：grants from the National Key Research and Development Program of China (2023YFE0109700);the National Natural Science Foundation of China (82125032, 81930095, 32071023, 82272079, and 32200967);the Science and Technology Commission of Shanghai Municipality (23Y21900500, 2018SHZDZX01, 22XD1420700, 23XD142300, and 23YF1425700);the Shanghai Municipal Commission of Health and Family Planning (GWV-11.1-34, 2020CXJQ01, 2018YJRC03, and 2022XD046);the Innovative research team of high-level local universities in Shanghai (SHSMU-ZDCX20211100);the Guangdong Key Project (2018B030335001);University of Sydney - Fudan University BISA Flagship Research Program. Y.Y. and T.Z. were awarded the fellowship of China Postdoctoral Science Foundation (2021M700851, 2023T160117, and 2022M712125).

摘　　要：Fluid intelligence is a cognitive domain that encompasses general reasoning, pattern recognition, and problem-solving abilities independent of task-specific experience. Understanding its genetic and neural underpinnings is critical yet challenging for predicting human development, lifelong health, and well-being. One approach to address this challenge is to map the network of correlations between intelligence and other constructs. In the current study, we performed a genome-wide association study using fluid intelligence quotient scores from the UK Biobank to explore the genetic architecture of the associations between obesity risk and fluid intelligence. Our results revealed novel common genetic loci (SH2B1, TUFM, ATP2A1, and FOXO3) underlying the association between fluid intelligence and body metabolism. Surprisingly, we demonstrated that SH2B1 variation influenced fluid intelligence independently of its effects on metabolism but partially mediated its association with bilateral hippocampal volume. Consistently, selective genetic ablation of Sh2b1 in the mouse hippocampus, particularly in inhibitory neurons, but not in excitatory neurons, significantly impaired working memory, short-term novel object recognition memory, and behavioral flexibility, but not spatial learning and memory, mirroring the human intellectual performance. Single-cell genetic profiling of Sh2B1-regulated molecular pathways revealed that Sh2b1 deletion resulted in aberrantly enhanced extracellular signal-regulated kinase (ERK) signaling, whereas pharmacological inhibition of ERK signaling reversed the associated behavioral impairment. Our cross-species study thus provides unprecedented insight into the role of SH2B1 in fluid intelligence and has implications for understanding the genetic and neural underpinnings of lifelong mental health and well-being.

关 键 词：METABOLISM IMPAIRED reversed 

分 类 号：R285.5[医药卫生—中药学]