Elevation of Hippocampal Neurogenesis Induces a Temporally Graded Pattern of Forgetting of Contextual Fear Memories
Elevation of Hippocampal Neurogenesis Induces a Temporally Graded Pattern of Forgetting of Contextual Fear Memories
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DOI：
10.1523/jneurosci.3126-17.2018
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发表时间：
2018-03-28
影响因子：
5.3
通讯作者：
Frankland, Paul W.
中科院分区：
文献类型：
--
作者：
Gao, Aijing;Xia, Frances;Frankland, Paul W.
终其一生，海马的亚颗粒区不断产生神经元。随后，新生成的神经元的整合改变了齿状回输入和输出连接的模式，可能会使已经存储在这些回路中的记忆更难被访问。与这一预测一致，我们之前的研究表明，训练后海马神经发生的增加会导致海马依赖记忆的遗忘，包括情境恐惧记忆。然而，支持情境恐惧记忆的大脑区域随着时间的变化而变化，这种时间依赖性的记忆重组可能调节情境恐惧记忆对海马神经发生波动的敏感性。通过病毒表达由设计药物激活的抑制设计受体hM4Di，我们首次证实了海马背侧神经元的化学发生抑制会损害雄性小鼠近期（1天大）而非远期（1个月）情境恐惧记忆的恢复。然后，我们对比了在情境恐惧条件反射后，雄性和雌性小鼠海马神经发生在最近和遥远时间点的增加的影响。训练后立即增加海马神经发生减少条件冻结，1个月后小鼠被替换。相比之下，当海马神经发生增加时，在远离训练的时间点，条件冻结水平在随后的测试中没有改变。通过环境和基因干预来增加海马神经发生，观察到这些暂时的分级遗忘效应。我们的实验将记忆年龄确定为神经发生介导的遗忘的边界条件，并表明，随着情境恐惧记忆的成熟，它们对海马体神经发生水平的变化变得不那么敏感，因为它们不再依赖海马体来表达。
Throughout life neurons are continuously generated in the subgranular zone of the hippocampus. The subsequent integration of newly generated neurons alters patterns of dentate gyrus input and output connectivity, potentially rendering memories already stored in those circuits harder to access. Consistent with this prediction, we previously showed that increasing hippocampal neurogenesis after training induces forgetting of hippocampus-dependent memories, including contextual fear memory. However, the brain regions supporting contextual fear memories change with time, and this time-dependent memory reorganization might regulate the sensitivity of contextual fear memories to fluctuations in hippocampal neurogenesis. By virally expressing the inhibitory designer receptor exclusively activated by designer drugs, hM4Di, we first confirmed that chemogenetic inhibition of dorsal hippocampal neurons impairs retrieval of recent (day-old) but not remote (month-old) contextual fear memories in male mice. We then contrasted the effects of increasing hippocampal neurogenesis at recent versus remote time points after contextual fear conditioning in male and female mice. Increasing hippocampal neurogenesis immediately following training reduced conditioned freezing when mice were replaced in the context 1 month later. In contrast, when hippocampal neurogenesis was increased time points remote to training, conditioned freezing levels were unaltered when micewere subsequently tested. These temporally graded forgetting effects were observed using both environmentalandgenetic interventions to increase hippocampal neurogenesis. Our experiments identify memory age as a boundary condition for neurogenesis-mediated forgetting and suggest that, as contextual fear memories mature, they become less sensitive to changes in hippocampal neurogenesis levels because they no longer depend on the hippocampus for their expression.