@article{86ea5292e2e74d2aaa3f1468da4d2987,
title = "Activation of a hippocampal CREB-pCREB-miRNA-MEF2 axis modulates individual variation of spatial learning and memory capability",
abstract = "Phenotypic variation is a fundamental prerequisite for cell and organism evolution by natural selection. Whereas the role of stochastic gene expression in phenotypic diversity of genetically identical cells is well studied, not much is known regarding the relationship between stochastic gene expression and individual behavioral variation in animals. We demonstrate that a specific miRNA (miR-466f-3p) is upregulated in the hippocampus of a portion of individual inbred mice upon a Morris water maze task. Significantly, miR-466f-3p positively regulates the neuron morphology, function and spatial learning, and memory capability of mice. Mechanistically, miR-466f-3p represses translation of MEF2A, a negative regulator of learning/memory. Finally, we show that varied upregulation of hippocampal miR-466f-3p results from randomized phosphorylation of hippocampal cyclic AMP (cAMP)-response element binding (CREB) in individuals. This finding of modulation of spatial learning and memory via a randomized hippocampal signaling axis upon neuronal stimulation represents a demonstration of how variation in tissue gene expression lead to varied animal behavior.",
keywords = "hippocampal miRNAs, individual variation, MEF2, phospho-CREB, spatial learning and memory",
author = "Wang, {I. Fang} and Yihan Wang and Yang, {Yi Hua} and Huang, {Guo Jen} and Tsai, {Kuen Jer} and Shen, {Che Kun James}",
note = "Funding Information: We thank the National RNAi Core Facility at Academia Sinica for recombinant lentivirus preparation, the Neuroscience Core Facility at Academia Sinica (AS-CFII-108-106) for fEPSP recording techniques and whole-cell recording in cultured neurons, and the Institute of Molecular Biology Imaging Core and Bioinformatics Core for technical assistance. We also thank Dr. Hsien-Sung Huang (National Taiwan University) for providing the lentiviral vector pFUGW-dsRed. This research was supported by Taipei Medical University, the Frontier of Science Award (MOST 107-2321-B-001-016); grants from the Ministry of Science and Technology (MOST), Taipei, Taiwan (MOST 108-2320-B-038-066 and MOST 109-2320-B-038-071); and a Senior Investigator Award from Academia Sinica, Taipei, Taiwan. I.-F.W. K.-J.T. and C.-K.J.S. designed the experiments. G.-J.H. did the Golgi staining. I.-F.W. with the help of Y.W. and Y.-H.Y. performed all other experiments. I.-F.W. did the data analysis. I.-F.W. and C.-K.J.S. wrote the manuscript. The authors declare no competing interests. We worked to ensure sex balance in the selection of non-human subjects. We worked to ensure diversity in experimental samples through the selection of the cell lines. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Funding Information: We thank the National RNAi Core Facility at Academia Sinica for recombinant lentivirus preparation, the Neuroscience Core Facility at Academia Sinica (AS-CFII-108-106) for fEPSP recording techniques and whole-cell recording in cultured neurons, and the Institute of Molecular Biology Imaging Core and Bioinformatics Core for technical assistance. We also thank Dr. Hsien-Sung Huang (National Taiwan University) for providing the lentiviral vector pFUGW-dsRed. This research was supported by Taipei Medical University , the Frontier of Science Award ( MOST 107-2321-B-001-016 ); grants from the Ministry of Science and Technology (MOST), Taipei, Taiwan ( MOST 108-2320-B-038-066 and MOST 109-2320-B-038-071 ); and a Senior Investigator Award from Academia Sinica , Taipei, Taiwan. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = aug,
doi = "10.1016/j.celrep.2021.109477",
language = "English",
volume = "36",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}