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Neuromorphic Memory Device Simulates Neurons and Synapses
Simultaneous emulation of neuronal and synaptic properties promotes the development of brain-like artificial intelligence Researchers have reported a nano-sized neuromorphic memory device that emulates neurons and synapses simultaneously in a unit cell, another step toward completing the goal of neuromorphic computing designed to rigorously mimic the human brain with semiconductor devices. Neuromorphic computing aims to realize artificial intelligence (AI) by mimicking the mechanisms of neurons and synapses that make up the human brain. Inspired by the cognitive functions of the human brain that current computers cannot provide, neuromorphic devices have been widely investigated. However, current Complementary Metal-Oxide Semiconductor (CMOS)-based neuromorphic circuits simply connect artificial neurons and synapses without synergistic interactions, and the concomitant implementation of neurons and synapses still remains a challenge. To address these issues, a research team led by Professor Keon Jae Lee from the Department of Materials Science and Engineering implemented the biological working mechanisms of humans by introducing the neuron-synapse interactions in a single memory cell, rather than the conventional approach of electrically connecting artificial neuronal and synaptic devices. Similar to commercial graphics cards, the artificial synaptic devices previously studied often used to accelerate parallel computations, which shows clear differences from the operational mechanisms of the human brain. The research team implemented the synergistic interactions between neurons and synapses in the neuromorphic memory device, emulating the mechanisms of the biological neural network. In addition, the developed neuromorphic device can replace complex CMOS neuron circuits with a single device, providing high scalability and cost efficiency. The human brain consists of a complex network of 100 billion neurons and 100 trillion synapses. The functions and structures of neurons and synapses can flexibly change according to the external stimuli, adapting to the surrounding environment. The research team developed a neuromorphic device in which short-term and long-term memories coexist using volatile and non-volatile memory devices that mimic the characteristics of neurons and synapses, respectively. A threshold switch device is used as volatile memory and phase-change memory is used as a non-volatile device. Two thin-film devices are integrated without intermediate electrodes, implementing the functional adaptability of neurons and synapses in the neuromorphic memory. Professor Keon Jae Lee explained, "Neurons and synapses interact with each other to establish cognitive functions such as memory and learning, so simulating both is an essential element for brain-inspired artificial intelligence. The developed neuromorphic memory device also mimics the retraining effect that allows quick learning of the forgotten information by implementing a positive feedback effect between neurons and synapses.” This result entitled “Simultaneous emulation of synaptic and intrinsic plasticity using a memristive synapse” was published in the May 19, 2022 issue of Nature Communications. -Publication:Sang Hyun Sung, Tae Jin Kim, Hyera Shin, Tae Hong Im, and Keon Jae Lee (2022) “Simultaneous emulation of synaptic and intrinsic plasticity using a memristive synapse,” Nature Communications May 19, 2022 (DOI: 10.1038/s41467-022-30432-2) -Profile:Professor Keon Jae Leehttp://fand.kaist.ac.kr Department of Materials Science and EngineeringKAIST
Astrocytes Eat Connections to Maintain Plasticity in Adult Brains
Developing brains constantly sprout new neuronal connections called synapses as they learn and remember. Important connections — the ones that are repeatedly introduced, such as how to avoid danger — are nurtured and reinforced, while connections deemed unnecessary are pruned away. Adult brains undergo similar pruning, but it was unclear how or why synapses in the adult brain get eliminated. Now, a team of KAIST researchers has found the mechanism underlying plasticity and, potentially, neurological disorders in adult brains. They published their findings on December 23 in Nature. “Our findings have profound implications for our understanding of how neural circuits change during learning and memory, as well as in diseases,” said paper author Won-Suk Chung, an assistant professor in the Department of Biological Sciences at KAIST. “Changes in synapse number have strong association with the prevalence of various neurological disorders, such as autism spectrum disorder, schizophrenia, frontotemporal dementia, and several forms of seizures.” Gray matter in the brain contains microglia and astrocytes, two complementary cells that, among other things, support neurons and synapses. Microglial are a frontline immunity defense, responsible for eating pathogens and dead cells, and astrocytes are star-shaped cells that help structure the brain and maintain homeostasis by helping to control signaling between neurons. According to Professor Chung, it is generally thought that microglial eat synapses as part of its clean-up effort in a process known as phagocytosis. “Using novel tools, we show that, for the first time, it is astrocytes and not microglia that constantly eliminate excessive and unnecessary adult excitatory synaptic connections in response to neuronal activity,” Professor Chung said. “Our paper challenges the general consensus in this field that microglia are the primary synapse phagocytes that control synapse numbers in the brain.” Professor Chung and his team developed a molecular sensor to detect synapse elimination by glial cells and quantified how often and by which type of cell synapses were eliminated. They also deployed it in a mouse model without MEGF10, the gene that allows astrocytes to eliminate synapses. Adult animals with this defective astrocytic phagocytosis had unusually increased excitatory synapse numbers in the hippocampus. Through a collaboration with Dr. Hyungju Park at KBRI, they showed that these increased excitatory synapses are functionally impaired, which cause defective learning and memory formation in MEGF10 deleted animals. “Through this process, we show that, at least in the adult hippocampal CA1 region, astrocytes are the major player in eliminating synapses, and this astrocytic function is essential for controlling synapse number and plasticity,” Chung said. Professor Chung noted that researchers are only beginning to understand how synapse elimination affects maturation and homeostasis in the brain. In his group’s preliminary data in other brain regions, it appears that each region has different rates of synaptic elimination by astrocytes. They suspect a variety of internal and external factors are influencing how astrocytes modulate each regional circuit, and plan to elucidate these variables. “Our long-term goal is understanding how astrocyte-mediated synapse turnover affects the initiation and progression of various neurological disorders,” Professor Chung said. “It is intriguing to postulate that modulating astrocytic phagocytosis to restore synaptic connectivity may be a novel strategy in treating various brain disorders.” This work was supported by the Samsung Science & Technology Foundation, the National Research Foundation of Korea, and the Korea Brain Research Institute basic research program. Other contributors include Joon-Hyuk Lee and Se Young Lee, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST); Ji-young Kim, Hyoeun Lee and Hyungju Park; Research Group for Neurovascular Unit, Korea Brain Research Institute (KBRI); Seulgi Noh, and Ji Young Mun, Research Group for Neural Circuit, KBRI. Kim, Noh and Park are also affiliated with the Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST). -Profile Professor Won-Suk Chung Department of Biological Sciences Gliabiology Lab (https://www.kaistglia.org/) KAIST -Publication "Astrocytes phagocytose adult hippocampal synapses for circuit homeostasis" https://doi.org/10.1038/s41586-020-03060-3
Structure of Neuron-Connecting Synaptic Adhesion Molecules Discovered
A research team has found the three-dimensional structure of synaptic adhesion molecules, which orchestrate synaptogenesis. The research findings also propose the mechanism of synapses in its initial formation. Some brain diseases such as obsessive compulsive disorder (OCD) or bipolar disorders arise from a malfunction of synapses. The team expects the findings to be applied in investigating pathogenesis and developing medicines for such diseases. The research was conducted by a Master’s candidate Kee Hun Kim, Professor Ji Won Um from Yonsei University, and Professor Beom Seok Park from Eulji University under the guidance of Professor Homin Kim from the Graduate School of Medical Science and Engineering, KAIST, and Professor Jaewon Ko from Yonsei University. Sponsored by the Ministry of Science, ICT and Future Planning and the National Research Foundation of Korea, the research findings were published online in the November 14th issue of Nature Communications. A protein that exists in the neuronal transmembrane, Slitrk, interacts with the presynaptic leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) and forms a protein complex. It is involved in the development of synapses in the initial stage, and balances excitatory and inhibitory signals of neurons. It is known that a disorder in those two proteins cause a malfunction of synapses, resulting in neuropsychosis such as autism, epilepsy, OCD, and bipolar disorders. However, because the structure as well as synaptogenic function of these proteins were not understood, the development of cures could not progress. The research team discovered the three-dimensional structure of two synaptic adhesion molecules like Slitrk and LAR-RPTPs and identified the regions of interaction through protein crystallography and transmission electron microscopy (TEM). Furthermore, they found that the formation of the synapse is induced after the combination of two synaptic adhesion molecules develops a cluster. Professor Kim said, “The research findings will serve as a basis of understanding the pathogenesis of brain diseases which arises from a malfunction of synaptic adhesion molecules. In particular, this is a good example in which collaboration between structural biology and neurobiology has led to a fruitful result.” Professor Ko commented that “this will give new directions to synaptic formation-related-researches by revealing the molecular mechanism of synaptic adhesion molecules.” Figure 1: Overview of the PTPd Ig1–3/Slitrk1 LRR1 complex. Figure 2: Representative negative-stained electron microscopy images of Slitrk1 Full ectodomain (yellow arrows indicate the horseshoe-shaped LRR domains). The typical horseshoe-shaped structures and the randomness of the relative positions of each LRR domain can be observed from the two-dimensional class averages displayed in the orange box. Figure 3: Model of the two-step presynaptic differentiation process mediated by the biding of Slitrks to LAR-RPTPs and subsequent lateral assembly of trans-synaptic LAR-RPTPs/Slitrik complexes.
Professor Eunjoon Kim's team finds synapse-forming protein
Professor Eunjoon Kim’s team finds synapse-forming protein - discover a new protein ‘NGL’ that promotes the formation of neuronal synapses - can presume the cause of various brain disorders including schizophrenia - will be published at Nature Neuroscience Vol. 9 in September A new protein that promotes the formation of synapses in human brains was discovered by a Korean research team. The team led by Eunjoon Kim, Professor of Department of Biological Sciences and Head of Creative Research Group of Synapse Formation), announced that it had discovered a new fact that NGL protein promotes the formation of neuronal synapses and this fact would be published in Nature Neuroscience Vol. 9 on September 18. Professor Kim’s team discovered that a membrane protein named ‘NGL’ located at post synapse links with other membrane protein named netrin-G in pre synapse, acting as crosslink, and promotes the formation of a new synapse. ‘NGL’ is the second protein found to crosslink synapse, following neuoroligin. With the discovery of this new protein, the principle of synapse formation and the causes of various brain disorders can be presumed. In the human brain, about more than 100 billion neuron cells and about 10,000 synapses compose neural circuit. A synapse is the place where innervation occurs between neuron cells. The formation of synapse induces the formation of neural circuit, and neural circuit is deeply related with various brain disorders as well as normal development of brains or brain functions. “As netrin-G linked with NGL is related with schizonphrenia and neuoroligin and synapse crosslinking protein having a similar function with NGL is deeply related with mental retardation and autism, I think NGL is related with various brain disorders including schizophrenia.” <Explanation of attached photos> ■ Photo1: Experiment for confirming NGL’s ability to form synapse No. 1 Mix ordinary cell (green) revealing NGL at its surface and neuron cell. Axon grows toward NGL (ordinary cell) located in the middle of ten o’clock direction and meets NGL, where NGL induces the formation of pre synapse (red) in the contacting axon. Whether pre synapse has been formed can be told by the fluorescent dying (red) of pre synapse protein named Synapsin. - Figure a-b: formation of synapse by NGL - Figure c-d: transformed NGL losing synapse forming ability cannot form synapse ■ Photo 2: Experiment for confirming NGL’s ability to form synapse No. 2 When beads coated with NGL are scattered on neuron cell, the beads contact with the axon of the neuron cell (the beads are clearly visible at the phase differentiation image in the middle panel). At this time, NGL induces the formation of pre synapse (red) in the axon. Whether pre synapse has been formed can be told by the fluorescent dying (red) of pre synapse protein named SynPhy (panel a) or VGlut1 (panel b).
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