Offline ensemble co-reactivation links memories across days

Yosif Zaki, Zachary T. Pennington, Denisse Morales-Rodriguez, Madeline E. Bacon, BumJin Ko, Taylor R. Francisco, Alexa R. LaBanca, Patlapa Sompolpong, Zhe Dong, Sophia Lamsifer, Hung-Tu Chen, Simón Carrillo Segura, Zoé Christenson Wick, Alcino J. Silva, Kanaka Rajan, Matthijs Meer, André Fenton, Tristan Shuman and Denise J. Cai ()
Additional contact information
Yosif Zaki: Icahn School of Medicine at Mount Sinai
Zachary T. Pennington: Icahn School of Medicine at Mount Sinai
Denisse Morales-Rodriguez: Icahn School of Medicine at Mount Sinai
Madeline E. Bacon: Icahn School of Medicine at Mount Sinai
BumJin Ko: Icahn School of Medicine at Mount Sinai
Taylor R. Francisco: Icahn School of Medicine at Mount Sinai
Alexa R. LaBanca: Icahn School of Medicine at Mount Sinai
Patlapa Sompolpong: Icahn School of Medicine at Mount Sinai
Zhe Dong: Icahn School of Medicine at Mount Sinai
Sophia Lamsifer: Icahn School of Medicine at Mount Sinai
Hung-Tu Chen: Dartmouth College
Simón Carrillo Segura: New York University
Zoé Christenson Wick: Icahn School of Medicine at Mount Sinai
Alcino J. Silva: University of California, Los Angeles
Kanaka Rajan: Icahn School of Medicine at Mount Sinai
Matthijs Meer: Dartmouth College
André Fenton: New York University
Tristan Shuman: Icahn School of Medicine at Mount Sinai
Denise J. Cai: Icahn School of Medicine at Mount Sinai

Nature, 2025, vol. 637, issue 8044, 145-155

Abstract: Abstract Memories are encoded in neural ensembles during learning1–6 and are stabilized by post-learning reactivation7–17. Integrating recent experiences into existing memories ensures that memories contain the most recently available information, but how the brain accomplishes this critical process remains unclear. Here we show that in mice, a strong aversive experience drives offline ensemble reactivation of not only the recent aversive memory but also a neutral memory formed 2 days before, linking fear of the recent aversive memory to the previous neutral memory. Fear specifically links retrospectively, but not prospectively, to neutral memories across days. Consistent with previous studies, we find that the recent aversive memory ensemble is reactivated during the offline period after learning. However, a strong aversive experience also increases co-reactivation of the aversive and neutral memory ensembles during the offline period. Ensemble co-reactivation occurs more during wake than during sleep. Finally, the expression of fear in the neutral context is associated with reactivation of the shared ensemble between the aversive and neutral memories. Collectively, these results demonstrate that offline ensemble co-reactivation is a neural mechanism by which memories are integrated across days.

Date: 2025
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DOI: 10.1038/s41586-024-08168-4

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