Science . . . GuYan/Wang Lang team reveals that immune cells in the brain are the 'masterminds' of memory forgetting

Memory is one of the most important functions of the brain and one of the most studied brain functions.memory occurs at any time, while forgetting is accompanied by a shadow.the hippocampus, located between the thalamus and the medial temporal lobe, is an important brain area responsible for memory coding and storage.here, memory information is encoded in some neurons, called memory imprinted cells.with the development of scientific research, researchers have found that the reactivation of imprinted cells is the "engine" of memory retrieval, and the synaptic connection between imprinted cells is the "warehouse" of memory storage.how does memory fade over time in the hippocampus? This problem has not been fully studied in the scientific community.on February 7, 2020, the research group of Guyan, Zhejiang University School of medicine, and Wang Lang, an associate researcher of Zhejiang University (the co first authors are Wang Chao, a 2016 grade doctoral student and Yue Huimin, a 2017 grade doctoral student) published an article on science, For the first time, it was found that microglia for immune function cause memory forgetting by clearing synapses, and further found that complement signaling pathway is involved in microglia mediated forgetting and depends on the activity of memory imprinted cells.forgetting is "forgotten". Memory and forgetting are like two sides of a coin, which are inseparable.but for a long time, researchers have shown a strong interest in the generation, storage and retrieval of human brain memory, and the research is also relatively in-depth, but there is not much attention paid to the phenomenon of forgetting.even if we discuss the causes of memory loss, we usually consider it from the perspective of memory storage and retrieval problems.forgetting is "forgotten".however, Gu Yan is very curious about this issue. He joked: "I have a poor memory, so I am very interested in the research of forgetting."how to calculate how much memory is retained? In the memory forgetting experiment of mice, the research group used the classical conditioned fear memory behavior model.the researchers applied electric stimulation to mice in a scene to establish their memory of the environment.after 35 days, the mice were asked to return to the scene again to see if the mice would recall the pain of the shock and then show fear."this behavioral paradigm was originally used to test the memory of fear behavior, but from another perspective, it's forgetting." according to Gu Yan, normal mice are always curious about the environment and move around. However, if they have a fear memory, they will stay there because of fear (i.e., freezing state), "we calculate that the mice are still in a unit time The time of immobility was used to measure the memory retention of mice."figure 1. Memory forgetting occurs gradually with time. the researchers found that after 35 days of training, the freezing time of mice was significantly lower than that of 5 days, indicating that the longer the time, the more significant the memory forgetting. do research like "detective". From the mouse experiment, the researchers found that memory fades over time. the main way of memory retrieval in hippocampus is through the activation of memory imprinting cells which encode these memory information. by labeling memory imprinted cells, the researchers found that forgetting was accompanied by a decrease in the activation rate of imprinted cells. so what causes the decrease in the activation rate of imprinted cells? Researchers are looking at another type of microglia in the brain. microglia account for about 10-15% of the total number of brain cells. previously, scientists have identified that microglia are the main immune cells in the central nervous system. when the brain is injured and infected and bacteria enter the cortex, microglia act as an important "defense guard" to "resist and kill the enemy". more and more studies have shown that microglia not only participate in the immune regulation of the nervous system, but also play an important regulatory role in the development of the nervous system, the activity of neurons and the function of neural circuits. the researchers specifically removed microglia from the brain and found that not only forgetting was inhibited, but also the decline in the reactivation rate of imprinted cells was also inhibited. "this discovery is very accidental. We have carried out a series of experiments in mice with microglia clearance, including memory formation and retrieval, anxiety, etc., but the results have a significant impact on memory forgetting. "the fear response of the mice with microglia removal was more obvious than that of the control group, and the resting time was more than twice as long as that of the control mice. to this end, the research group continued to carry out the experiment in depth, and found that when the microglia were removed, the activation of memory imprinted cells did not appear obvious decline. Fig. 2. Microglia clearance inhibited forgetting. A-B: the amnesia of mice was inhibited after the microglia were specifically cleared by the CSF-1 inhibitor plx3397 (PLX). C-D: PLX inhibited the decrease of activation rate of imprinted cells with amnesia. since microglia do affect the activation of memory imprinted cells and lead to forgetting, how do they cause a decrease in the activation rate of imprinted cells? Is it by destroying the information transmission between memory imprinted cells? Previous studies have shown that microglia can clear the excessive synapses in infant brain development and regulate the dynamic changes of synaptic connections between neurons. do microglia have the same function in adult brain? Therefore, the researchers continued to solve the case. Through immunostaining and high-resolution imaging, they found that synaptophysin and PSD95 were located in presynaptic and postsynaptic microglia in the "belly" of microglia in the hippocampus, and Co located with lysosomes in small glial cells (co localization: cells with two proteins in the same spatial position) These results suggest that microglia in adult hippocampus still have the ability to "eat" synaptic structure. when the phagocytosis of microglia in mice was inhibited, memory forgetting was significantly blocked. these results suggest that microglia mediate forgetting by "eating" synapses. Synaptic specific components such as synaptophysin (syn, a) and postsynaptic protein PSD95 (b) were found in microglia and co labeled with the lysosomal marker lamp1 of microglia. the mechanism of forgetting begins with the molecular "navigation". Researchers have found that memory is activated and transmitted on the "road" composed of imprinted cells, in which the synapses between memory imprinted cells are not only the "bridge" between roads, but also the "warehouse" for storing memories. microglia are like "demolition teams". When the "bridge" is removed, the memory information stored in it can not be passed on, and eventually leads to memory forgetting. so, what molecular mechanism has made microglia, originally the "guard" of the brain, become the "demolition team"? High resolution microscopy revealed that the complement molecule C1q not only Co located with some dendritic spines of imprinted cells, but also existed in microglia lysosomes together with PSD95, suggesting that complement signaling pathway may mediate the synaptic clearance of memory imprinted cells by microglia. by comparison, the researchers found that blocking the complement signaling pathway in imprinted cells can effectively inhibit memory forgetting and the decrease of activation rate of imprinted cells. and the C1q complement signaling pathway is like a hunter's dog. It looks for and marks some synapses of memory imprinted cells, so that microglia, like a navigation map, can aim at the target and launch attacks, and take one's time. "review is not easy to forget" has a scientific basis, a common sense in life, learning a new knowledge, if you always review, it is not easy to forget, and if you do not review, you will soon forget. the researchers have proved this through experiments. the research group specifically introduced pharmacological genetic receptors into the memory trace cells. After the injection of drug CNO, the activity of memory imprinted cells can be selectively inhibited, making them less excited. at this time, the researchers found that the forgetting of memory was accelerated, just as it was easy to forget without review. and this accelerated forgetting can also be inhibited by microglia clearance or by blocking complement pathway. from another point of view, review is to make the memory imprinted cells and corresponding synaptic connections more active, as if the synaptic bridge was reinforced with reinforced concrete. if we do not review, the "bridge" will be in disrepair for a long time, and will be identified and removed by the "demolition team" of microglia. Synaptic clearance of microglia may be a universal mechanism of amnesia. The dentate gyrus of hippocampus can continuously produce new neurons, called neurogenesis. according to previous reports in science, the integration of new neurons in dentate gyrus leads to the reorganization and replacement of a large number of synapses in the hippocampal neural circuit, resulting in the forgetting of previously established memories, especially in infancy. in order to find out the relationship between microglia mediated forgetting and neurogenic mediated forgetting, researchers manipulated both hippocampal neurogenesis and microglia, and found that microglia mediated synaptic clearance was involved in both neurogenic and neurogenic amnesia. therefore, synaptic phagocytosis of microglia may be a more common mechanism of mediating amnesia in brain regions without neurogenesis or in mammalian brains lacking neurogenesis. Gu Yan said that with the deepening of research, we may have a clearer understanding of memory damage and memory loss caused by diseases in the future. in the long run, this work also provides a forward-looking foundation for the study of consolidation of long-term memory and elimination of bad memory. reviewers said the study had "ingenious experimental design and strategy" and made "interesting and important findings". this work was jointly completed by Guyan laboratory, Department of basic medicine, Zhejiang University Medical College, and Wang Lang laboratory, Institute of systemic neurology and cognitive science, Zhejiang University Medical College. the work was carried out by Wang Liang, Wang Xiaodong, Zhejiang University Medical College