Why do some memories last a lifetime and some can only exist for a few minutes? How does short-term memory translate into long-term memory? I think everyone remembers that in the movie "50 First Loves", the heroine suffered a brain injury due to a car accident, and could only form a short-term memory and could not form a long-term memory. Although this special encounter has made the hero and heroine a romantic love story, the mechanism of long-term memory formation has always plagued scientists.
Poster for the movie "50 First Loves"
Recently, scientists have made new progress in this area of research. Bi Guoqiang's research group at the School of Life Sciences of the University of Science and Technology of China and the Cheng Heping Research Group of the Institute of Molecular Medicine of Peking University found that the "mitochondrial dazzle signal" of neuronal dendrites may play a key role in the transformation of synaptic transmission of short-term memory to long-term memory, and the relevant results were published online at Nature Communications on June 26, 2017.
First, let's get to know the little guy mitochondria. Mitochondria are the "energy factory" of the cell and are an important place for eukaryotes to synthesize the energy currency ATP. Not only that, in recent years, scientists have found that mitochondria play a key regulatory role in a variety of important physiological and pathological processes such as apoptosis and necrosis.
In 2008, Cheng Heping's group first reported a new cell biology phenomenon that occurs at the level of individual mitochondria, mitochondrial glare. Unlike most traditional intracellular signals, mitochondrial dazzle is a "full or no" quantized signal, in just tens of seconds, mitochondrial reactive oxygen species explosion increase, matrix instantaneous alkalinization, membrane potential instantaneous drop, and only one minute these indicators return to the previous state.
Scientists believe that mitochondrial dazzle is a completely new form of mitochondrial basic function event. A series of subsequent studies have shown that mitochondrial glitches are widely present in multiple species. From single-celled yeasts to multicellular simple biological nematodes, from complex mammalian mice to advanced humans, there are mitochondrial flash signals as long as there are functional mitochondria. It can be said that the mitochondrial xuan on the evolution line has a strong conservatism.
After understanding the "mitochondrial dazzle" signal, let's look at what "synapses" are. Synapses are the basic structural units of memory encoding and storage. Neurons in the brain are connected to each other through synapses, and the strength of synaptic connections reflects the efficiency of information transfer between neurons. The strength of the synaptic connections is variable, called synaptic plasticity, which is the neural basis for learning and memory.
Synaptic plasticity can be divided into long-term plasticity and short-term plasticity according to the length of duration. It is generally believed that short-term memory is related to short-term plasticity, and long-term memory is related to long-term plasticity. For example, if we block the formation of long-term plasticity, experimental animals cannot form long-term memory. Under the regulation of different types of neural activity, synaptic plasticity in short-term courses can only last from a few seconds to minutes, while synaptic plasticity in long-term courses can be maintained for tens of minutes to hours or even longer. The mechanism by which short-term plasticity changes to long-term plasticity has long been a hot topic in memory research.
After a long period of research and exploration, researchers speculated that mitochondrial xuan was likely to be involved in some kind of signal transduction process of synaptic plasticity. To this end, the researchers chose the classical cellular model of learning memory, the hippocampal neurons of rats, as the object of study.
Since the study of long-term synaptic plasticity requires several hours of long-term observation of synapses, researchers have designed special microscopic imaging conditions to minimize damage to neurons, while maintaining neurons in an environment similar to that in vivo to meet the requirements of long-term continuous imaging. In addition, since mitochondrial glare is a spontaneous phenomenon, in order to accurately manipulate it and then study its function, researchers have established a two-photon femtosecond pulse activation of mitochond dazzle method, that is, the femtosecond laser machine to generate a specific wavelength and a short time of light to stimulate the mitochonds at a fixed point.
The researchers were pleasantly surprised to find that the long-term enhancement of synapses induced by chemical and electrical stimulation methods is always accompanied by one or more mitochondrial dazzle signals near the synapses; while artificial activation of mitochondrial dazzle signals can promote the transformation of adjacent synapses from short-term enhancement to long-term enhancement; more interestingly, mitochondrial dazzles have a definite time window (effective within 30 minutes after stimulation) and spatial range (effective within 2 microns). The specificity and accuracy of the mechanism of mitochondrial dazzling regulation of synaptic plasticity are shown. Further studies have found that the production of mitochondrial dazzle relies on neural activity calcium signaling and calcium-dependent kinases, and the reactive oxygen species signal released by mitochondrial dazzle may be the key signaling molecule to promote synaptic long-term enhancement.
"Dazzling"
Mitochondrial flashes promote long-term enhancement of neuronal synapses (red part indicates enhanced synapses; bread-shaped is mitochondrial; surrounding whitening represents the mitochondria where mitochondrial glare is occurring)
This work is the first to report the important role of mitochondria as a digital biological signal in the process of synaptic plasticity in the reception, integration and transmission of signals by mitochondrials, and its scientific value lies in the first time to reveal the bidirectional signaling mechanism between dendritic mitochondria and synapses. At the same time, it provides an example for understanding the biological significance of mitochondrial glare, that is, local, transient reactive oxygen species bursts provide a possible molecular and subcellular mechanism for long-term memory of "firing" synaptic levels.
Imagine if one day we can apply this technology to the human brain, not only to help ordinary people learn and remember better, like the heroine in the movie "First Love 50 Times" who can't form a long-term memory due to injury, but also may get better treatment and remember every heartbeat moment in life.
The co-first author of the research work is Fu Zhongxiao, a doctoral student at the Hefei National Laboratory for Physical Sciences at the Microscale, and TanXiao, a doctoral student at the School of Life Sciences of the University of Science and Technology of China, and the corresponding authors are Associate Researcher Wang Xianhua (Peking University), Professor Cheng Heping (Peking University) and Professor Bi Guoqiang (University of Science and Technology of China). The project is supported by the Chinese Academy of Sciences Pilot Project, the 973 Program and the National Natural Science Foundation of China.