biostudies-literatureRen LYU.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and StrokeNIMH NIH HHSLundbeckfondenU.S. Department of Health & Human Services | NIH | National Institute of Mental HealthLundbeck Foundation3795-3805https://www.ebi.ac.uk/biostudies/studies/S-EPMC9846583biostudies-literatureUnknown27(9)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.Molecular psychiatryStress-induced changes of the cholinergic circuitry promote retrieval-based generalization of aversive memories.PMC9846583T32MH067564F30 MH122130F30MH122130R310-2018-3611R01 MH108837MH108837T32 MH067564NS115543MH078064310-2018-3611R01 MH078064Gao PRadulovic JPetrovic ZZhang HGuedea ALLin YMeyer MASun XRen LYCicvaric AfalseStress-induced changes of the cholinergic circuitry promote retrieval-based generalization of aversive memories.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.2022-01-01T00:00:00Z2022 Sep2024-10-18T10:33:48.037Z2024-10-18T10:33:48.037ZS-EPMC98465833555124610.1038/s41380-022-01610-x