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

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

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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.

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

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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

Developmental and Behavioral Pediatric Department,Shanghai Xinhua Children's Hospital,Shanghai 200092,China

National Clinical Research Center for Aging and Medicine at Huashan Hospital,Institute

Shanghai Key Laboratory of Brain Functional Genomics(Ministry of Education),School of L

Center for Experimental Studies and Research,The First Affiliated Hospital of Kunming M

Institute of Cognitive Neuroscience,School of Psychology and Cognitive Science,East China Normal University,Shanghai 200062,China

National Clinical Research Center for Aging and Medicine at Huashan Hospital,Institute of Science and Technology for Brain-Inspired Intelligence,Ministry of Education-Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence,Fudan University,Shanghai 200433,China

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

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

Shanghai Research Center for Brain Science and Brain-Inspired Intelligence,Shanghai 201

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2024

10.34133/research.0269

研究(英文)

研究(英文)

CSTPCD
ISSN：
年,卷(期)：2024.2024(3)