Neuroscience
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Scientist Discover How Circadian Rhythm Can Be Both Strong and Flexible
Study reveals that master and slave oscillators function via different molecular mechanisms
From tiny fruit flies to human beings, all animals on Earth maintain their daily rhythms based on their internal circadian clock. The circadian clock enables organisms to undergo rhythmic changes in behavior and physiology based on a 24-hour circadian cycle. For example, our own biological clock tells our brain to release melatonin, a sleep-inducing hormone, at night time.
The discovery of the molecular mechanism of the circadian clock was bestowed the Nobel Prize in Physiology or Medicine 2017. From what we know, no one centralized clock is responsible for our circadian cycles. Instead, it operates in a hierarchical network where there are “master pacemaker” and “slave oscillator”.
The master pacemaker receives various input signals from the environment such as light. The master then drives the slave oscillator that regulates various outputs such as sleep, feeding, and metabolism. Despite the different roles of the pacemaker neurons, they are known to share common molecular mechanisms that are well conserved in all lifeforms. For example, interlocked systems of multiple transcriptional-translational feedback loops (TTFLs) composed of core clock proteins have been deeply studied in fruit flies.
However, there is still much that we need to learn about our own biological clock. The hierarchically-organized nature of master and slave clock neurons leads to a prevailing belief that they share an identical molecular clockwork. At the same time, the different roles they serve in regulating bodily rhythms also raise the question of whether they might function under different molecular clockworks.
Research team led by Professor Kim Jae Kyoung from the Department of Mathematical Sciences, a chief investigator at the Biomedical Mathematics Group at the Institute for Basic Science, used a combination of mathematical and experimental approaches using fruit flies to answer this question. The team found that the master clock and the slave clock operate via different molecular mechanisms.
In both master and slave neurons of fruit flies, a circadian rhythm-related protein called PER is produced and degraded at different rates depending on the time of the day. Previously, the team found that the master clock neuron (sLNvs) and the slave clock neuron (DN1ps) have different profiles of PER in wild-type and Clk-Δ mutant Drosophila. This hinted that there might be a potential difference in molecular clockworks between the master and slave clock neurons.
However, due to the complexity of the molecular clockwork, it was challenging to identify the source of such differences. Thus, the team developed a mathematical model describing the molecular clockworks of the master and slave clocks. Then, all possible molecular differences between the master and slave clock neurons were systematically investigated by using computer simulations. The model predicted that PER is more efficiently produced and then rapidly degraded in the master clock compared to the slave clock neurons. This prediction was then confirmed by the follow-up experiments using animal.
Then, why do the master clock neurons have such different molecular properties from the slave clock neurons? To answer this question, the research team again used the combination of mathematical model simulation and experiments. It was found that the faster rate of synthesis of PER in the master clock neurons allows them to generate synchronized rhythms with a high level of amplitude. Generation of such a strong rhythm with high amplitude is critical to delivering clear signals to slave clock neurons.
However, such strong rhythms would typically be unfavorable when it comes to adapting to environmental changes. These include natural causes such as different daylight hours across summer and winter seasons, up to more extreme artificial cases such as jet lag that occurs after international travel. Thanks to the distinct property of the master clock neurons, it is able to undergo phase dispersion when the standard light-dark cycle is disrupted, drastically reducing the level of PER. The master clock neurons can then easily adapt to the new diurnal cycle. Our master pacemaker’s plasticity explains how we can quickly adjust to the new time zones after international flights after just a brief period of jet lag.
It is hoped that the findings of this study can have future clinical implications when it comes to treating various disorders that affect our circadian rhythm. Professor Kim notes, “When the circadian clock loses its robustness and flexibility, the circadian rhythms sleep disorders can occur. As this study identifies the molecular mechanism that generates robustness and flexibility of the circadian clock, it can facilitate the identification of the cause of and treatment strategy for the circadian rhythm sleep disorders.” This work was supported by the Human Frontier Science Program.
-PublicationEui Min Jeong, Miri Kwon, Eunjoo Cho, Sang Hyuk Lee, Hyun Kim, Eun Young Kim, and Jae Kyoung Kim, “Systematic modeling-driven experiments identify distinct molecularclockworks underlying hierarchically organized pacemaker neurons,” February 22, 2022, Proceedings of the National Academy of Sciences of the United States of America
-ProfileProfessor Jae Kyoung KimDepartment of Mathematical SciencesKAIST
2022.02.23 View 7082 -
Prof. Sang Wan Lee Selected for 2021 IBM Academic Award
Professor Sang Wan Lee from the Department of Bio and Brain Engineering was selected as the recipient of the 2021 IBM Global University Program Academic Award. The award recognizes individual faculty members whose emerging science and technology contains significant interest for universities and IBM.
Professor Lee, whose research focuses on artificial intelligence and computational neuroscience, won the award for his research proposal titled A Neuroscience-Inspired Approach for Metacognitive Reinforcement Learning. IBM provides a gift of $40,000 to the recipient’s institution in recognition of the selection of the project but not as a contract for services.
Professor Lee’s project aims to exploit the unique characteristics of human reinforcement learning. Specifically, he plans to examines the hypothesis that metacognition, a human’s ability to estimate their uncertainty level, serves to guide sample-efficient and near-optimal exploration, making it possible to achieve an optimal balance between model-based and model-free reinforcement learning.
He was also selected as the winner of the Google Research Award in 2016 and has been working with DeepMind and University College London to conduct basic research on decision-making brain science to establish a theory on frontal lobe meta-enhance learning.
"We plan to conduct joint research for utilizing brain-based artificial intelligence technology and frontal lobe meta-enhanced learning technology modeling in collaboration with an international research team including IBM, DeepMind, MIT, and Oxford,” Professor Lee said.
2021.06.25 View 9173 -
Before Eyes Open, They Get Ready to See
- Spontaneous retinal waves can generate long-range horizontal connectivity in visual cortex. -
A KAIST research team’s computational simulations demonstrated that the waves of spontaneous neural activity in the retinas of still-closed eyes in mammals develop long-range horizontal connections in the visual cortex during early developmental stages.
This new finding featured in the August 19 edition of Journal of Neuroscience as a cover article has resolved a long-standing puzzle for understanding visual neuroscience regarding the early organization of functional architectures in the mammalian visual cortex before eye-opening, especially the long-range horizontal connectivity known as “feature-specific” circuitry.
To prepare the animal to see when its eyes open, neural circuits in the brain’s visual system must begin developing earlier. However, the proper development of many brain regions involved in vision generally requires sensory input through the eyes.
In the primary visual cortex of the higher mammalian taxa, cortical neurons of similar functional tuning to a visual feature are linked together by long-range horizontal circuits that play a crucial role in visual information processing.
Surprisingly, these long-range horizontal connections in the primary visual cortex of higher mammals emerge before the onset of sensory experience, and the mechanism underlying this phenomenon has remained elusive.
To investigate this mechanism, a group of researchers led by Professor Se-Bum Paik from the Department of Bio and Brain Engineering at KAIST implemented computational simulations of early visual pathways using data obtained from the retinal circuits in young animals before eye-opening, including cats, monkeys, and mice.
From these simulations, the researchers found that spontaneous waves propagating in ON and OFF retinal mosaics can initialize the wiring of long-range horizontal connections by selectively co-activating cortical neurons of similar functional tuning, whereas equivalent random activities cannot induce such organizations.
The simulations also showed that emerged long-range horizontal connections can induce the patterned cortical activities, matching the topography of underlying functional maps even in salt-and-pepper type organizations observed in rodents. This result implies that the model developed by Professor Paik and his group can provide a universal principle for the developmental mechanism of long-range horizontal connections in both higher mammals as well as rodents.
Professor Paik said, “Our model provides a deeper understanding of how the functional architectures in the visual cortex can originate from the spatial organization of the periphery, without sensory experience during early developmental periods.”
He continued, “We believe that our findings will be of great interest to scientists working in a wide range of fields such as neuroscience, vision science, and developmental biology.”
This work was supported by the National Research Foundation of Korea (NRF). Undergraduate student Jinwoo Kim participated in this research project and presented the findings as the lead author as part of the Undergraduate Research Participation (URP) Program at KAIST.
Figures and image credit: Professor Se-Bum Paik, KAIST
Image usage restrictions: News organizations may use or redistribute these figures and image, with proper attribution, as part of news coverage of this paper only.
Publication:
Jinwoo Kim, Min Song, and Se-Bum Paik. (2020). Spontaneous retinal waves generate long-range horizontal connectivity in visual cortex. Journal of Neuroscience, Available online athttps://www.jneurosci.org/content/early/2020/07/17/JNEUROSCI.0649-20.2020
Profile: Se-Bum Paik
Assistant Professor
sbpaik@kaist.ac.kr
http://vs.kaist.ac.kr/
VSNN Laboratory
Department of Bio and Brain Engineering
Program of Brain and Cognitive Engineering
http://kaist.ac.kr
Korea Advanced Institute of Science and Technology (KAIST) Daejeon, Republic of Korea
Profile: Jinwoo Kim
Undergraduate Student
bugkjw@kaist.ac.kr
Department of Bio and Brain Engineering, KAIST
Profile: Min Song
Ph.D. Candidate
night@kaist.ac.kr
Program of Brain and Cognitive Engineering, KAIST
(END)
2020.08.25 View 10258 -
Professor Sue-Hyun Lee Listed Among WEF 2020 Young Scientists
Professor Sue-Hyun Lee from the Department of Bio and Brain Engineering joined the World Economic Forum (WEF)’s Young Scientists Community on May 26. The class of 2020 comprises 25 leading researchers from 14 countries across the world who are at the forefront of scientific problem-solving and social change. Professor Lee was the only Korean on this year’s roster.
The WEF created the Young Scientists Community in 2008 to engage leaders from the public and private sectors with science and the role it plays in society. The WEF selects rising-star academics, 40 and under, from various fields every year, and helps them become stronger ambassadors for science, especially in tackling pressing global challenges including cybersecurity, climate change, poverty, and pandemics.
Professor Lee is researching how memories are encoded, recalled, and updated, and how emotional processes affect human memory, in order to ultimately direct the development of therapeutic methods to treat mental disorders. She has made significant contributions to resolving ongoing debates over the maintenance and changes of memory traces in the brain.
In recognition of her research excellence, leadership, and commitment to serving society, the President and the Dean of the College of Engineering at KAIST nominated Professor Lee to the WEF’s Class of 2020 Young Scientists Selection Committee. The Committee also acknowledged Professor Lee’s achievements and potential for expanding the boundaries of knowledge and practical applications of science, and accepted her into the Community.
During her three-year membership in the Community, Professor Lee will be committed to participating in WEF-initiated activities and events related to promising therapeutic interventions for mental disorders and future directions of artificial intelligence.
Seven of this year’s WEF Young Scientists are from Asia, including Professor Lee, while eight are based in Europe. Six study in the Americas, two work in South Africa, and the remaining two in the Middle East. Fourteen, more than half, of the newly announced 25 Young Scientists are women.
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2020.05.26 View 9925 -
A Single Biological Factor Predicts Distinct Cortical Organizations across Mammalian Species
-A KAIST team’s mathematical sampling model shows that retino-cortical mapping is a prime determinant in the topography of cortical organization.-
Researchers have explained how visual cortexes develop uniquely across the brains of different mammalian species. A KAIST research team led by Professor Se-Bum Paik from the Department of Bio and Brain Engineering has identified a single biological factor, the retino-cortical mapping ratio, that predicts distinct cortical organizations across mammalian species.
This new finding has resolved a long-standing puzzle in understanding visual neuroscience regarding the origin of functional architectures in the visual cortex. The study published in Cell Reports on March 10 demonstrates that the evolutionary variation of biological parameters may induce the development of distinct functional circuits in the visual cortex, even without species-specific developmental mechanisms.
In the primary visual cortex (V1) of mammals, neural tuning to visual stimulus orientation is organized into one of two distinct topographic patterns across species. While primates have columnar orientation maps, a salt-and-pepper type organization is observed in rodents.
For decades, this sharp contrast between cortical organizations has spawned fundamental questions about the origin of functional architectures in the V1. However, it remained unknown whether these patterns reflect disparate developmental mechanisms across mammalian taxa, or simply originate from variations in biological parameters under a universal development process.
To identify a determinant predicting distinct cortical organizations, Professor Paik and his researchers Jaeson Jang and Min Song examined the exact condition that generates columnar and salt-and-pepper organizations, respectively. Next, they applied a mathematical model to investigate how the topographic information of the underlying retinal mosaics pattern could be differently mapped onto a cortical space, depending on the mapping condition.
The research team proved that the retino-cortical feedforwarding mapping ratio appeared to be correlated to the cortical organization of each species. In the model simulations, the team found that distinct cortical circuitries can arise from different V1 areas and retinal ganglion cell (RGC) mosaic sizes. The team’s mathematical sampling model shows that retino-cortical mapping is a prime determinant in the topography of cortical organization, and this prediction was confirmed by neural parameter analysis of the data from eight phylogenetically distinct mammalian species.
Furthermore, the researchers proved that the Nyquist sampling theorem explains this parametric division of cortical organization with high accuracy. They showed that a mathematical model predicts that the organization of cortical orientation tuning makes a sharp transition around the Nyquist sampling frequency, explaining why cortical organizations can be observed in either columnar or salt-and-pepper organizations, but not in intermediates between these two stages.
Professor Paik said, “Our findings make a significant impact for understanding the origin of functional architectures in the visual cortex of the brain, and will provide a broad conceptual advancement as well as advanced insights into the mechanism underlying neural development in evolutionarily divergent species.”
He continued, “We believe that our findings will be of great interest to scientists working in a wide range of fields such as neuroscience, vision science, and developmental biology.”
This work was supported by the National Research Foundation of Korea (NRF).
Image credit: Professor Se-Bum Paik, KAIST
Image usage restrictions: News organizations may use or redistribute this image, with proper attribution, as part of news coverage of this paper only.
Publication:
Jaeson Jang, Min Song, and Se-Bum Paik. (2020). Retino-cortical mapping ratio predicts columnar and salt-and-pepper organization in mammalian visual cortex. Cell Reports. Volume 30. Issue 10. pp. 3270-3279. Available online at https://doi.org/10.1016/j.celrep.2020.02.038
Profile:
Se-Bum Paik
Assistant Professor
sbpaik@kaist.ac.kr
http://vs.kaist.ac.kr/
VSNN Laboratory
Department of Bio and Brain Engineering
Program of Brain and Cognitive Engineering
http://kaist.ac.kr
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon, Republic of Korea
Profile:
Jaeson Jang
Ph.D. Candidate
jaesonjang@kaist.ac.kr
Department of Bio and Brain Engineering, KAIST
Profile:
Min Song
Ph.D. Candidate
night@kaist.ac.kr
Program of Brain and Cognitive Engineering, KAIST
(END)
2020.03.11 View 11660 -
Two Professors Receive the Asan Medical Award
(Professor Ho Min Kim and Chair Profesor Eunjoon Kim (from far right)
Chair Professor Eunjoon Kim of the Department of Biological Sciences and Professor Ho Min Kim from the Graduate School of Medical Science & Engineering won the 11th Asan Medical Award in the areas of basic medicine and young medical scholar on March 21.
The Asan Medical Award has been recognizing the most distinguished scholars in the areas of basic and clinical medicines annually since 2007.
Chair Professor Kim won the 300 million KRW award in recognition of his research in the mechanism of synaptic brain dysfunction and its relation with neural diseases.
The young medical scholar’s award recognizes a promising scholar under the age of 40. Professor Kim won the award for identifying the key protein structure and molecular mechanism controlling immunocytes and neurons. He earned a 50 million KRW prize.
2018.03.26 View 7444 -
Brain Cognitive Engineering Experts from Korea and Abroad Gather at KAIST
The symposium presents recent and future research trends in brain and cognitive engineering.
KAIST hosted the Brain Cognitive Engineering Symposium on September 24, 2015, at the Dream Hall of the Chung Moon Soul building on campus. Around 100 experts in the field of neuroscience participated.
Organized by the Department of Bio and Brain Engineering at KAIST, the symposium celebrated the establishment of the Brain Cognitive Engineering Program at the university and examined the recent research trends in neuroscience.
Six neuroscience experts presented their research and held discussions.
Professor Paul M. Thompson of the University of Southern California (USC), a renowned scientist in neurology imaging genetics, gave a speech entitled “The ENIGMA Project: Mapping Disease and Genetic Effects on the Human Brain in 30,000 People Worldwide.”
Professor Jae-seung Jeong of KAIST’s Department of Bio and Brain Engineering, Director Sung-Gi Kim of IBS Center for Neuroscience Imaging Research, Professor Sung-Hwan Lee of Korea University’s Department of Brain Engineering, Professor Cheil-Moon of DGIST’s Department of Brain and Cognitive Science, and Professor Jun-Tani of KAIST’s Department of Electrical Engineering also participated in the symposium.
Participants discussed the most recent findings in the field of brain science such as the education and research trends of brain cognitive engineering, trends of the world’s brain integrated science, the prospects of brain cognitive engineering program, brain activities that induce blood flow and fMRI, activity production in the brain cortex model as well as the development of functional hierarchy for the motor visual perception, and the neurorobotics research.
Professor Jeong said that “this symposium is a place for examination of the most recent research findings in the field of neuroscience as well as for discussion of its education,”and that “it would be an important opportunity for learning research on brain’s basic mechanisms as well as its applications.”
2015.09.25 View 7666 -
A KAIST startup, YBrain, builds a wearable device to cure Alzheimer's
A group of KAIST graduates from the Departments of Bio and Brain Engineering, Computer Science, Materials Science Engineering, and Industrial Design created a startup called YBrain (http://ybrain.com/). YBrain develops a wearable neuroscience technology to treat or reduce the symptoms of degenerative brain diseases such as dementia and Alzheimer’s. Their recent technological developments were covered in e27, one of the leading blogs based in Singapore. The blog covers topics like the latest technology innovation, startups, and entrepreneurship in Asia. A news article follows below:
e27, June 24, 2014
“This wearable tech may be able to combat effects of Alzheimer’s”
http://e27.co/this-wearable-tech-may-be-able-combat-effects-of-alzheimers-20140624/
2014.06.25 View 10808 -
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).
2006.09.21 View 14728