Stress-induced changes of the cholinergic circuitry promote retrieval-based generalization of aversive memories

Lynn Y. Ren, Ana Cicvaric, Hui Zhang, Mariah Aa Meyer, Anita L. Guedea, Pan Gao, Zorica Petrovic, Xiaochen Sun, Yingxi Lin, Jelena Radulovic

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Generalization, the process of applying knowledge acquired in one context to other contexts, often drives the expression of similar behaviors in related situations. At the cellular level, generalization is thought to depend on the activity of overlapping neurons that represent shared features between contexts (general representations). Using contextual fear conditioning in mice, we demonstrate that generalization can also occur in response to stress and result from reactivation of specific, rather than general context representations. We found that generalization emerges during memory retrieval, along with stress-induced abnormalities of septohippocampal oscillatory activity and acetylcholine release, which are typically found in negative affective states. In hippocampal neurons that represent aversive memories and drive generalization, cholinergic septohippocampal afferents contributed to a unique reactivation pattern of cFos, Npas4, and repressor element-1 silencing transcription factor (REST). Together, these findings suggest that generalization can be triggered by perceptually dissimilar but valence-congruent memories of specific aversive experiences. Through promoting the reactivation of such memories and their interference with ongoing behavior, abnormal cholinergic signaling could underlie maladaptive cognitive and behavioral generalization linked to negative affective states.

Original languageEnglish (US)
Pages (from-to)3795-3805
Number of pages11
JournalMolecular Psychiatry
Issue number9
StatePublished - Sep 2022

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience


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