On March 15, 2018, a research team led by Professor Yi Zhong from the School of Life Sciences at Tsinghua University published a research article entitled Active Protection: Learning-Activated Raf/MAPK Activity Protects Labile Memory from Rac1-Independent Forgetting in Neuron. In this paper, authors found that learning itself activates Raf/MAPK pathway to protect the newly formed labile memory from non-associative disruption. In other words, if such protection mechanism is activated physiologically or by drug feeding, the English words you just learned will not be forgotten because of a sudden phone call or a fire emergency.
As early as 1885, German psychologist Hermann Ebbinghaus proposed the forgetting curve of the human brain for the newly acquired information. Since then, many researchers joined the exploration of the mystery of forgetting. In the next century, many researchers used experimental psychology methods to probe the mechanism of forgetting, and had proposed a variety of theories to explain the phenomenon. However, even today, there is still no unified explanation of forgetting. Although forgetting is such an important part of human memory and has been widely studied in psychology, little attention is paid to the neurobiology behind it, leaving forgetting a "forgotten" corner. Possible reason is that forgetting is widely considered as the opposite of memory and a passive process, thus the unique molecular mechanism that may exist for forgetting itself is long ignored.
In 2010, Zhong’s group revealed an active forgetting mechanism: learning itself activates Rac1 pathway to actively forget the newly formed memory (Shuai et al., 2010). Such forgetting mechanism did not affect acquisition of the memory. In contrast, this mechanism specifically affected the rate of forgetting. This research used Drosophila as experimental model and found that Rac1, a small G protein, can regulate the forgetting of labile memory lasting for several hours. This Rac1-dependent forgetting mechanism was reported to be highly conserved in mice in a recent paper of Zhong’s group (Liu et al., 2016). Moreover, Zhong’s group found that consolidated memory also has its specific active forgetting mechanism like labile memory. Such forgetting mechanism is regulated by Cdc42, another small G protein (Zhang et al., 2016). This study suggested that different memory components may have different forgetting mechanisms.
Although inhibiting Racl-dependent active forgetting significantly slowed down labile memory forgetting, memory decay still happened, indicating other forgetting mechanisms might coexist. In searching of these possible coexisting forgetting mechanisms, Zhong’s group found an active protection mechanism of labile memory: learning itself can activate Raf/MAPK pathway to protect newly formed memory from forgetting induced by non-associative experience, such as electric shock and temperature changes. Like Rac1-dependent forgetting, Raf/MAPK activity also did not affect memory acquisition but specifically suppressed forgetting of labile memory. Surprisingly, Rac1-depednent forgetting and Raf-suppressed forgetting seemed to be independent and additive to each other. Simultaneously blocking both mechanisms of forgetting led to no memory decay for more than three hours and reservation of large amount of labile memory for more than one day.
Figure 1. Dissection of labile memory forgetting
A subsequent question is why animals have two independent forgetting mechanisms just to forget a memory component lasting for only several hours. Researchers found that Rac1 pathway is only responsible for forgetting induced by associative experience including interference and reversal learning. They suggested that the purpose of this kind of forgetting might be to clear useless memory and to save memory storage space for more important information. On the other hand, Raf/MAPK pathway is only responsible for forgetting induced by non-associative experience e.g. electric shock or temperature changes. This may be to stabilize useful memory and protect it from unexpected disruptions. Working together, learning activates Rac1 pathway to actively clear the newly formed useless memory and activates Raf pathway to actively protect useful memory. Such sophisticated combination may allow animals to better adapt to the rapidly changing environment.
Figure 2. Active forgetting and active protection.
Alzheimer's disease features severe memory impairment. With the failure of many recent drugs, whether we can find medication to improve memory has become the focus of researchers. In the past, such research has been focusing on improving memory acquisition, until the discovery of active forgetting mechanisms independent of acquisition provides us with new perspectives.
Xuchen Zhang, a Ph.D student, and Qian Li, a postdoctoral fellow, at the School of Life Sciences at Tsinghua University, are the co-first authors of this article. Dr. Qian Li and Dr. Yi Zhong are correspondence authors of this article. Dr. Zhong-jian Liu is a co-director of Qian Li. Lianzhang Wang, Dr. Wantong Hu, Yunchuan Zhang, and Bohan Zhao also contributed to this study. The authors would like to acknowledge Wenjuan Wang and Yue Sun for their assistance at the Imaging Core Facility, Technology Center for Protein Sciences, Tsinghua University and for assistance in using Imaris software, the Zeiss LSM 710 META microscope, and the Zeiss Airyscan LSM880 super-resolution microscope. This work was supported by grants from the National Science Foundation of China, the National Basic Research Project (973 program) of the Ministry of Science and Technology of China, the Beijing Municipal Science and Technology Commission, the China Postdoctoral Science Foundation, and the Tsinghua-Peking Joint Center for Life Sciences.