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Stress-induced generalization of negative memories is mediated by an extended hippocampal circuit

Abstract

Memories of negative experiences exert important control of behavior in the face of actual or anticipated threat. Sometimes, however, this control extends to non-threatening situations, a phenomenon known as overgeneralization of negative memories. Overgeneralization is a reliable cognitive phenotype of major depressive disorder, generalized anxiety disorder, and post-traumatic stress disorder. We therefore sought to develop an animal model to study stress-induced generalization of negative memories (SIG) and determine its dependence on the episodic-like memory circuit. We found that male and female mice, which were trained to differentiate a threatening from neutral context, exhibited robust SIG in response to subsequent social stress. Using chemogenetic circuit manipulations during memory retrieval, we demonstrated that both excitatory afferents to the dorsal hippocampus (DH) from the ventral tegmental area (VTA), and excitatory efferents from the DH to the retrosplenial cortex (RSC) contribute to SIG. Based on the known roles of these projections, we suggest that (1) by targeting subcortical VTA circuits that provide valence signals to the DH, stress prioritizes the retrieval of negative over neutral memories, and (2) by forwarding such information to the RSC, stress engages cortical mechanisms that support the retrieval of general relative to specific memory features. Altogether, these results suggest that various components of the extended hippocampal circuit can serve as treatment targets for memory overgeneralization.

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Fig. 1: Stress induces generalization of negative memories in male mice.
Fig. 2: Stress induces generalization of negative memories in female mice.
Fig. 3: Inhibition of vGlut2 + VTA projections to DH reduces stress-induced generalization in male and female mice.
Fig. 4: Inhibition of vGlut1 + DH projections to RSC reduces stress-induced generalization in male and female mice.

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Acknowledgements

We would like to thank Dr. John Kessler, Dr. Ana Cicvaric, Dr. Hui Zhang, and Dr. Vladimir Jovasevic for helpful discussions regarding the work described here.

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LYR and JR designed and LYR, MAAM, VSG and PG conducted the experiments. LYR and ALG bred and genotyped the transgenic mice. LYR analyzed the data. LYR and JR wrote the paper, and MAAM provided significant edits. All authors discussed and commented on the paper.

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Correspondence to Lynn Y. Ren or Jelena Radulovic.

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Ren, L.Y., Meyer, M.A.A., Grayson, V.S. et al. Stress-induced generalization of negative memories is mediated by an extended hippocampal circuit. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-021-01174-4

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