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  3. The astrocytic ensemble acts as a multiday trace to stabilize memory

The astrocytic ensemble acts as a multiday trace to stabilize memory

  • Nature. 2025 Oct 15. doi: 10.1038/s41586-025-09619-2.
Ken-Ichi Dewa # 1,  Kodai Kaseda # 1 2,  Aoi Kuwahara 1 2,  Hideaki Kubotera 1,  Ayato Yamasaki 3,  Natsumi Awata 4,  Atsuko Komori 1,  Mika A Holtz 1,  Atsushi Kasai 5 6 7,  Henrik Skibbe 8 9,  Norio Takata 10,  Tatsushi Yokoyama 11 12 13 14,  Makoto Tsuda 15 16,  Genri Numata 17 18,  Shun Nakamura 19,  Eiki Takimoto 18 20,  Masayuki Sakamoto 11 12 13 21,  Minako Ito 4 7,  Takahiro Masuda 3,  Jun Nagai 22 23 24
Affiliations

Affiliations

  • 1 Laboratory for Glia-Neuron Circuit Dynamics, RIKEN Center for Brain Science, Wako, Japan.
  • 2 Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, TWIns, Waseda University, Tokyo, Japan.
  • 3 Division of Molecular Neuroimmunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
  • 4 Division of Allergy and Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
  • 5 Systems Neuropharmacology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
  • 6 Laboratory of Molecular Neuropharmacology, Graduate School of Pharamceutical Sciences, Osaka University, Suita, Japan.
  • 7 Japan Science and Technology Agency (JST), Fusion Oriented REsearch for disruptive Science and Technology (FOREST), Kawaguchi, Japan.
  • 8 Brain Image Analysis Unit, RIKEN Center for Brain Science, Wako, Japan.
  • 9 Department of Informatics, Faculty of Informatics, Matsuyama University, Ehime, Japan.
  • 10 Division of Brain Sciences, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.
  • 11 Department of Optical Neural and Molecular Physiology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
  • 12 Center for Living Systems Information Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
  • 13 Department of Brain Development and Regeneration, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
  • 14 Laboratory of Deconstruction of Stem Cells, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
  • 15 Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
  • 16 Kyushu University Institute for Advanced Study, Fukuoka, Japan.
  • 17 Isotope Science Center, The University of Tokyo, Tokyo, Japan.
  • 18 Department of Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo, Japan.
  • 19 Department of Cardiovascular Medicine, Institute of Science Tokyo, Tokyo, Japan.
  • 20 Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
  • 21 Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Kawaguchi, Japan.
  • 22 Laboratory for Glia-Neuron Circuit Dynamics, RIKEN Center for Brain Science, Wako, Japan. jun.nagai@riken.jp.
  • 23 Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, TWIns, Waseda University, Tokyo, Japan. jun.nagai@riken.jp.
  • 24 Japan Science and Technology Agency (JST), Fusion Oriented REsearch for disruptive Science and Technology (FOREST), Kawaguchi, Japan. jun.nagai@riken.jp.
  • # Contributed equally.
PMID: 41094146 DOI: 10.1038/s41586-025-09619-2
Abstract

Recalled memories become transiently labile and require stabilization1-3. The mechanism for stabilizing memories of survival-critical experiences, which are often emotionally salient and repeated, remains unclear4. Here we identify an astrocytic ensemble that is transcriptionally primed by emotional experience and functionally triggered by repeated experience to stabilize labile memory. Using a novel brain-wide Fos tagging and imaging method, we found that astrocytic Fos ensembles were preferentially recruited in regions with neuronal engrams5 and were more widespread during fear recall than during conditioning. We established the induction mechanism of the astrocytic ensemble, which involves two steps: (1) an initial fear experience that induces day-long, slow astrocytic state changes with noradrenaline receptor upregulation; and (2) enhanced noradrenaline responses during recall, a repeated experience, enabling astrocytes to integrate coincident signals from local engrams and long-range noradrenergic projections, which induce secondary astrocytic state changes, including the upregulation of Fos and the neuromodulatory molecule IGFBP2. Pharmacological and genetic perturbation of the astrocytic ensemble signalling modulate engrams, and memory stability and precision. The astrocytic ensemble thus acts as a multiday trace in a subset of astrocytes after experience-dependent neural activity, which are eligible to capture future repeated experiences for stabilizing memories.

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