The hippocampus is crucial for acquiring and retrieving episodic and contextual memories. In previous studies, the inactivation of dentate gyrus (DG) neurons by chemogenetic- and optogenetic-mediated hyperpolarization led to opposing conclusions about DG’s role in memory retrieval. One study used Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-mediated clozapine N-oxide (CNO)-induced hyperpolarization and reported that the previously formed memory was erased, thus concluding that denate gyrus is needed for memory maintenance. The other study used optogenetic with halorhodopsin induced hyperpolarization and reported and dentate gyrus is needed for memory retrieval. We hypothesized that this apparent discrepancy could be due to the length of hyperpolarization in previous studies; minutes by optogenetics and several hours by DREADD/CNO. Since hyperpolarization interferes with anterograde and retrograde neuronal signaling, it is possible that the memory engram in the dentate gyrus and the entorhinal to hippocampus trisynaptic circuit was erased by long-term, but not with short-term hyperpolarization. We developed and applied an advanced chemogenetic technology to selectively silence synaptic output by blocking neurotransmitter release without hyperpolarizing DG neurons to explore this apparent discrepancy. We performed in vivo electrophysiology during trace eyeblink in a rabbit model of associative learning. Our work shows that the DG output is required for memory retrieval. Based on previous and recent findings, we propose that the actively functional anterograde and retrograde neuronal signaling is necessary to preserve synaptic memory engrams along the entorhinal cortex to the hippocampal trisynaptic circuit.

海马体对于获取和检索情景记忆和情境记忆至关重要。在之前的研究中，化学遗传学和光遗传学介导的超极化导致齿状回 (DG) 神经元失活，导致关于 DG 在记忆检索中的作用的相反结论。一项研究使用设计药物专门激活的设计受体 (DREADD) 介导的氯氮平 N-氧化物 (CNO) 诱导的超极化，并报道先前形成的记忆被擦除，从而得出结论，记忆维持需要变性回。另一项研究使用光遗传学和盐视紫红质诱导的超极化，并报告记忆检索需要齿状回。我们假设这种明显的差异可能是由于之前研究中超极化的长度造成的。光遗传学需要几分钟，DREADD/CNO需要几个小时。由于超极化会干扰顺行和逆行神经元信号传导，因此齿状回和内嗅至海马三突触回路中的记忆印迹可能被长期消除，但短期超极化则不会。我们开发并应用了先进的化学遗传学技术，通过阻止神经递质释放来选择性地沉默突触输出，而不使 DG 神经元超极化，以探索这种明显的差异。我们在兔子联想学习模型中进行了微量眨眼期间的体内电生理学研究。我们的工作表明 DG 输出是记忆检索所必需的。基于之前和最近的发现，我们提出，活跃的顺行和逆行神经元信号传导对于保留沿着内嗅皮层到海马三突触回路的突触记忆印迹是必要的。