The astrocytic ensemble acts as a multiday trace to stabilize memory
Ken‐ichi Dewa, Kodai Kaseda, Aoi Kuwahara, H. Kubotera, Ayato Yamasaki, Natsumi Awata, Atsuko Komori, M Holtz, Atsushi Kasai, Henrik Skibbe, Norio Takata, Tatsushi Yokoyama, Makoto Tsuda, Genri Numata, Shun Nakamura, Eiki Takimoto, Masayuki Sakamoto, Minako Ito, Takahiro Masuda, Jun Nagai
Abstract
Abstract Recalled memories become transiently labile and require stabilization 1–3 . The mechanism for stabilizing memories of survival-critical experiences, which are often emotionally salient and repeated, remains unclear 4 . 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 engrams 5 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.