Fear generalization is a neurobiological process by which an organism interprets a novel stimulus as threatening because of its similarity to previously learned fear-inducing stimuli. Because recent studies have suggested that the communication between oligodendrocyte precursor cells (OPCs) and parvalbumin (PV)-expressing GABAergic neurons (PV neurons) may play critical roles in stress-related disorders, we examined the involvement of these cells in fear generalization. We first tested the behavioral characteristics of mouse models for conventional fear conditioning (cFC) and modified FC (mFC) with severe electric foot shocks and found that fear generalization was observed in mice treated with mFC but not in mice treated with cFC. The expression levels of genes related to OPCs, oligodendrocytes (OLs), and myelin in the ventral hippocampus were lower in mFC mice than in cFC mice. The densities of OPCs and OLs were decreased in the ventral hippocampus of mFC mice compared to cFC mice. The myelination ratios of PV neurons in the ventral hippocampus were lower in mFC mice than in cFC mice. The chemogenetic activation of PV neurons in the ventral hippocampus of mFC mice reduced fear generalization. The expression levels of genes related to OPCs, OLs, and myelin were recovered following the activation of PV neurons. Finally, the myelination ratios of PV neurons were increased after the activation of PV neurons. Our results suggest that altered regulation of OLs specifically associated with axons of PV neurons in the ventral hippocampus may underlie the generalization of remote fear memory following severe stress exposure.
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The dataset generated and/or analyzed during the current study is available from the corresponding authors upon reasonable request.
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We thank Ms. Saki Kanegae for her technical assistance and Editage (www.editage.jp) for English language editing. We also appreciate the technical assistance from the Research Support Center, Research Center for Human Disease Modeling, Kyushu University Graduate School of Medical Sciences.
This work was supported in part by JSPS KAKENHI (grant numbers JP19K06924 [to JY], JP22K06459 [to JY], JP19H05022 [to SJ], JP19K22812 [to SJ] 20H04105 [to SJ], JP21H05630 [to SJ], and JP22K19713 [to SJ]).
The authors declare no competing interests.
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Yamada, J., Maeda, S., Tojo, M. et al. Altered regulation of oligodendrocytes associated with parvalbumin neurons in the ventral hippocampus underlies fear generalization in male mice. Neuropsychopharmacol. (2023). https://doi.org/10.1038/s41386-023-01611-6