Loss of Function of Phosphodiesterase 11A4 Shows that Recent and Remote Long-Term Memories Can Be Uncoupled
Loss of Function of Phosphodiesterase 11A4 Shows that Recent and Remote Long-Term Memories Can Be Uncoupled
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DOI：
10.1016/j.cub.2019.06.018
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发表时间：
2019-07-22
期刊：
影响因子：
9.2
通讯作者：
Kelly, Michy P.
中科院分区：
文献类型：
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作者：
Pilarzyk, Katy;Klett, Jennifer;Kelly, Michy P.
系统巩固是一个过程，记忆最初需要海马体来提供最近的长期记忆 (LTM)，但随后变得越来越独立于海马体，并且更加依赖于皮层来提供远程 LTM。在这里，我们研究磷酸二酯酶 11A4 (PDE11A4) 在系统整合中的作用。 PDE11A4 可降解环磷酸腺苷 (cAMP) 和环磷酸鸟苷 (cGMP)，优先在 CA1、下托和相邻连接的杏仁核海马区域的神经元中表达。在雄性和雌性小鼠中，PDE11A 的缺失增强了社交气味识别和食物偏好社交传播 (STFP) 的远程 LTM，尽管消除或沉默了这些相同社交事件的近期 LTM。对神经元激活替代标记（即 Arc mRNA）的测量表明，最近在 Pde11a 敲除小鼠中观察到的 LTM 缺陷与腹侧 CA1 相对于野生型同窝小鼠的激活减少相对应。相比之下，在 Pde11a 敲除小鼠中观察到的增强的远程 LTM 与前扣带皮层、额叶联合皮层、副下皮层和内侧内嗅皮层浅层的激活增加和功能连接改变相对应。在远程 LTM 恢复期间，在 Pde11a 敲除小鼠的前额皮质中观察到的神经激活明显增加可能与 N-甲基-D-天冬氨酸受体亚基 NR1 和 NR2A 的上调有关。仅将 PDE11A4 病毒恢复为 vCA1 就足以挽救 Pde11a 敲除小鼠表现出的 LTM 表型和 NR1 上调。总之，我们的研究结果表明，远程 LTM 可以与近期 LTM 脱钩，这可能与与衰老、颞叶癫痫或短暂性全面遗忘相关的认知缺陷有关。
Systems consolidation is a process by which memories initially require the hippocampus for recent long-term memory (LTM) but then become increasingly independent of the hippocampus and more dependent on the cortex for remote LTM. Here, we study the role of phosphodiesterase 11A4 (PDE11A4) in systems consolidation. PDE11A4, which degrades cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), is preferentially expressed in neurons of CA1, the subiculum, and the adjacently connected amygdalohippocampal region. In male and female mice, deletion of PDE11A enhances remote LTM for social odor recognition and social transmission of food preference (STFP) despite eliminating or silencing recent LTM for those same social events. Measurement of a surrogate marker of neuronal activation (i.e., Arc mRNA) suggests the recent LTM deficits observed in Pde11a knockout mice correspond with decreased activation of ventral CA1 relative to wild-type littermates. In contrast, the enhanced remote LTM observed in Pde11a knockout mice corresponds with increased activation and altered functional connectivity of anterior cingulate cortex, frontal association cortex, parasubiculum, and the superficial layer of medial entorhinal cortex. The apparent increased neural activation observed in prefrontal cortex of Pde11a knockout mice during remote LTM retrieval may be related to an upregulation of the N-methyl-D-aspartate receptor subunits NR1 and NR2A. Viral restoration of PDE11A4 to vCA1 alone is sufficient to rescue both the LTM phenotypes and upregulation of NR1 exhibited by Pde11a knockout mice. Together, our findings suggest remote LTM can be decoupled from recent LTM, which may have relevance for cognitive deficits associated with aging, temporal lobe epilepsy, or transient global amnesia.