Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
Neuropsychopharmacology. 2023 Oct;48(11):1668-1679. doi: 10.1038/s41386-023-01611-6. Epub 2023 Jun 5.
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.
恐惧泛化是一种神经生物学过程,通过该过程,生物体将新刺激解释为威胁,因为它与先前学习的引起恐惧的刺激相似。由于最近的研究表明,少突胶质前体细胞(OPCs)与表达钙结合蛋白 parvalbumin(PV)的 GABA 能神经元(PV 神经元)之间的通讯可能在与应激相关的障碍中发挥关键作用,因此我们研究了这些细胞在恐惧泛化中的参与。我们首先测试了用强烈的电击进行传统恐惧条件反射(cFC)和改良 FC(mFC)的小鼠模型的行为特征,发现 mFC 处理的小鼠中观察到恐惧泛化,而 cFC 处理的小鼠中则没有。mFC 小鼠腹侧海马中与 OPCs、少突胶质细胞(OLs)和髓鞘相关的基因表达水平低于 cFC 小鼠。与 cFC 小鼠相比,mFC 小鼠腹侧海马中的 OPCs 和 OLs 密度降低。mFC 小鼠腹侧海马中 PV 神经元的髓鞘化比例低于 cFC 小鼠。mFC 小鼠腹侧海马中 PV 神经元的化学遗传激活降低了恐惧泛化。激活 PV 神经元后,mFC 小鼠腹侧海马中与 OPCs、OLs 和髓鞘相关的基因表达水平得到恢复。最后,激活 PV 神经元后,PV 神经元的髓鞘化比例增加。我们的研究结果表明,腹侧海马中与 PV 神经元轴突相关的 OLs 的异常调节可能是严重应激暴露后远程恐惧记忆泛化的基础。
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