Bernier Brian E, Lacagnina Anthony F, Ayoub Adam, Shue Francis, Zemelman Boris V, Krasne Franklin B, Drew Michael R
Center for Learning and Memory, Department of Neuroscience, University of Texas at Austin, Austin, Texas 78712, and.
Department of Psychology, University of California at Los Angeles, Los Angeles, California 90095.
J Neurosci. 2017 Jun 28;37(26):6359-6371. doi: 10.1523/JNEUROSCI.3029-16.2017. Epub 2017 May 25.
Dentate gyrus (DG) is widely thought to provide a teaching signal that enables hippocampal encoding of memories, but its role during retrieval is poorly understood. Some data and models suggest that DG plays no role in retrieval; others encourage the opposite conclusion. To resolve this controversy, we evaluated the effects of optogenetic inhibition of dorsal DG during context fear conditioning, recall, generalization, and extinction in male mice. We found that (1) inhibition during training impaired context fear acquisition; (2) inhibition during recall did not impair fear expression in the training context, unless mice had to distinguish between similar feared and neutral contexts; (3) inhibition increased generalization of fear to an unfamiliar context that was similar to a feared one and impaired fear expression in the conditioned context when it was similar to a neutral one; and (4) inhibition impaired fear extinction. These effects, as well as several seemingly contradictory published findings, could be reproduced by BACON (Bayesian Context Fear Algorithm), a physiologically realistic hippocampal model positing that acquisition and retrieval both involve coordinated activity in DG and CA3. Our findings thus suggest that DG contributes to retrieval and extinction, as well as to the initial establishment of context fear. Despite abundant evidence that the hippocampal dentate gyrus (DG) plays a critical role in memory, it remains unclear whether the role of DG relates to memory acquisition or retrieval. Using contextual fear conditioning and optogenetic inhibition, we show that DG contributes to both of these processes. Using computational simulations, we identify specific mechanisms through which the suppression of DG affects memory performance. Finally, we show that DG contributes to fear extinction learning, a process in which learned fear is attenuated through exposures to a fearful context in the absence of threat. Our data resolve a long-standing question about the role of DG in memory and provide insight into how disorders affecting DG, including aging, stress, and depression, influence cognitive processes.
齿状回（DG）被广泛认为能提供一种教学信号，使海马体对记忆进行编码，但其在记忆提取过程中的作用却鲜为人知。一些数据和模型表明，DG在记忆提取中不起作用；另一些则支持相反的结论。为了解决这一争议，我们评估了在雄性小鼠的情境恐惧条件反射、回忆、泛化和消退过程中，对背侧DG进行光遗传学抑制的效果。我们发现：（1）训练期间的抑制会损害情境恐惧的习得；（2）回忆期间的抑制不会损害在训练情境中的恐惧表达，除非小鼠必须区分相似的恐惧和中性情境；（3）抑制会增加恐惧向与恐惧情境相似的陌生情境的泛化，并且当条件化情境与中性情境相似时，会损害在该情境中的恐惧表达；（4）抑制会损害恐惧消退。这些效应，以及一些看似矛盾的已发表研究结果，都可以通过BACON（贝叶斯情境恐惧算法）重现，这是一个生理上逼真的海马体模型，假定习得和提取都涉及DG和CA3中的协同活动。因此，我们的研究结果表明，DG有助于记忆提取和消退，以及情境恐惧的最初建立。尽管有大量证据表明海马体齿状回（DG）在记忆中起关键作用，但DG的作用是与记忆习得还是提取相关仍不清楚。通过情境恐惧条件反射和光遗传学抑制，我们表明DG对这两个过程都有贡献。通过计算模拟，我们确定了DG抑制影响记忆表现的具体机制。最后，我们表明DG有助于恐惧消退学习，这是一个通过在没有威胁的情况下暴露于恐惧情境来减弱习得恐惧的过程。我们的数据解决了一个关于DG在记忆中作用的长期问题，并深入了解了影响DG的疾病，包括衰老、压力和抑郁，如何影响认知过程。
