Neurobiology, Psychiatry and Psychology Departments and Integrative Center for Learning and Memory, University of California Los Angeles, Los Angeles, CA, USA.
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, USA.
Nature. 2022 Jun;606(7912):146-152. doi: 10.1038/s41586-022-04783-1. Epub 2022 May 25.
Real-world memories are formed in a particular context and are often not acquired or recalled in isolation. Time is a key variable in the organization of memories, as events that are experienced close in time are more likely to be meaningfully associated, whereas those that are experienced with a longer interval are not. How the brain segregates events that are temporally distinct is unclear. Here we show that a delayed (12-24 h) increase in the expression of C-C chemokine receptor type 5 (CCR5)-an immune receptor that is well known as a co-receptor for HIV infection-after the formation of a contextual memory determines the duration of the temporal window for associating or linking that memory with subsequent memories. This delayed expression of CCR5 in mouse dorsal CA1 neurons results in a decrease in neuronal excitability, which in turn negatively regulates neuronal memory allocation, thus reducing the overlap between dorsal CA1 memory ensembles. Lowering this overlap affects the ability of one memory to trigger the recall of the other, and therefore closes the temporal window for memory linking. Our findings also show that an age-related increase in the neuronal expression of CCR5 and its ligand CCL5 leads to impairments in memory linking in aged mice, which could be reversed with a Ccr5 knockout and a drug approved by the US Food and Drug Administration (FDA) that inhibits this receptor, a result with clinical implications. Altogether, the findings reported here provide insights into the molecular and cellular mechanisms that shape the temporal window for memory linking.
真实世界中的记忆是在特定的背景下形成的，通常不是孤立地获取或回忆的。时间是记忆组织的一个关键变量，因为时间上接近的经历更有可能被有意义地关联，而那些经历时间间隔较长的则不然。大脑如何将时间上明显不同的事件分开尚不清楚。在这里，我们发现，在形成情境记忆后，CC 趋化因子受体 5（CCR5）的表达延迟（12-24 小时）——一种众所周知的 HIV 感染辅助受体——决定了与随后的记忆相关联或链接该记忆的时间窗口的持续时间。这种在小鼠背侧 CA1 神经元中 CCR5 的延迟表达导致神经元兴奋性降低，进而负调节神经元记忆分配，从而减少背侧 CA1 记忆集合之间的重叠。降低这种重叠会影响一个记忆触发另一个记忆回忆的能力，从而关闭了记忆链接的时间窗口。我们的研究结果还表明，CCR5 和其配体 CCL5 在神经元中的表达随年龄的增长而增加，导致老年小鼠记忆链接受损，而用 Ccr5 基因敲除和一种美国食品和药物管理局（FDA）批准的抑制该受体的药物可以逆转这种情况，这一结果具有临床意义。总之，这里报道的研究结果提供了对塑造记忆链接时间窗口的分子和细胞机制的深入了解。
