Wednesday, April 14, 2021

Physicists develop theoretical model for neural activity of mouse brain

"One of the wonderful things about our model is that it's simple," says Mia Morrell, who did the research as an Emory senior majoring in physics. Morrell graduated last year and is now in New Mexico, above, where she is completing a post-baccalaureate physics program at Los Alamos National Laboratory.

By Carol Clark

The dynamics of the neural activity of a mouse brain behave in a peculiar, unexpected way that can be theoretically modeled without any fine tuning, suggests a new paper by physicists at Emory University. Physical Review Letters published the research, which adds to the evidence that theoretical physics frameworks may aid in the understanding of large-scale brain activity. 

“Our theoretical model agrees with previous experimental work on the brains of mice to a few percent accuracy — a degree which is highly unusual for living systems,” says Ilya Nemenman, Emory professor of physics and biology and senior author of the paper. 

The first author is Mia Morrell, who did the research for her honors thesis as an Emory senior majoring in physics. She graduated from Emory last year and is now in a post-baccalaureate physics program at Los Alamos National Laboratory in New Mexico. 

“One of the wonderful things about our model is that it’s simple,” says Morrell, who will start a Ph.D. program in physics at New York University in the fall. “A brain is really complex. So to distill neural activity to a simple model and find that the model can make predictions that so closely match experimental data is exciting.” 

The new model may have applications for studying and predicting a range of dynamical systems that have many components and have varying inputs over time, from the neural activity of a brain to the trading activity of a stock market. 

Co-author of the paper is Audrey Sederberg, a former post-doctoral fellow in Nemenman’s group, who is now on the faculty at the University of Minnesota. 

The work is based on a physics concept known as critical phenomena, used to explain phase transitions in physical systems, such as water changing from liquid to a gas. 

In liquid form, water molecules are strongly correlated to one another. In a solid, they are locked into a predictable pattern of identical crystals. In a gas phase, however, every molecule is moving about on its own. 

“At what is known as a critical point for a liquid, you cannot distinguish whether the material is liquid or vapor,” Nemenman explains. “The material is neither perfectly ordered nor disordered. It’s neither totally predictable nor totally unpredictable. A system at this ‘just right’ Goldilocks spot is said to be ‘critical.’” 

Very high temperature and pressure generate this critical point for water. And the structure of critical points is the same in many seemingly unrelated systems. For example, water transitioning into a gas and a magnet losing its magnetism as it is heated up are described by the same critical point, so the properties of these two transitions are similar. 

In order to actually observe a material at a critical point to study its structure, physicists must tightly control experiments, adjusting the parameters to within an extraordinarily precise range, a process known as fine-tuning. 

In recent decades, some scientists began thinking about the human brain as a critical system. Experiments suggest that brain activity lies in a Goldilocks spot — right at a critical transition point between perfect order and disorder. 

“The neurons of the brain don’t function just as one big unit, like an army marching together, but they are also not behaving like a crowd of people running in all different directions,” Nemenman says. “The hypothesis is that, as you increase the effective distance between neurons, the correlations between their activity are going to fall, but they will not fall to zero. The entire brain is coupled, acting like a big, interdependent machine, even while individual neurons vary in their activity.” 

Researchers began searching for actual signals of critical phenomena within brains. They explored a key question: What fine tunes the brain to reach criticality? 

In 2019, a team at Princeton University recorded neurons in the brain of a mouse as it was running in a virtual maze. They applied theoretical physics tools developed for non-living systems to the neural activity data from the mouse brain. Their results suggested that the neural activity exhibits critical correlations, allowing predictions about how different parts of the brain will correlate with one another over time and over effective distances within the brain. 

For the current paper, the Emory researchers wanted to test whether fine-tuning of particular parameters were necessary for the observation of criticality in the mouse brain experiments, or whether the critical correlations in the brain could be achieved simply through the process of it receiving external stimuli. The idea came from previous work that Nemenman’s group collaborated on, explaining how biological systems can exhibit Zipf’s law — a unique pattern of activity found in disparate systems. 

“We previously created a model that showed Zipf’s law in a biological system, and that model did not require fine tuning,” Nemenman says. “Zipf’s law is a particular form of criticality. For this paper, we wanted to make that model a bit more complicated, to see if could predict the specific critical correlations observed in the mouse experiments.” 

The model’s key ingredient is a set of a few hidden variables that modulate how likely individual neurons are to be active. 

Morrell wrote the computer code to run simulations and test the model on her home desktop computer. “The biggest challenge was to write the code in a way that would allow it to run fast even when simulating a large system with limited computer memory without a huge server,” she says. 

The model was able to closely reproduce the experimental results in the simulations. The model does not require the careful tuning of parameters, generating activity that is apparently critical by any measure over a wide range of parameter choices. 

“Our findings suggest that, if you do not view a brain as existing on its own, but you view it as a system receiving stimuli from the external world, then you can have critical behavior with no need for fine tuning,” Nemenman says. “It raises the question of whether something similar could apply to non-living physical systems. It makes us re-think the very notion of criticality, which is a fundamental concept in physics.” 

The computer code for the model is now available online, so that anyone with a laptop computer can access it and run the code to simulate a dynamic system with varying inputs over time. 

“The model we developed may apply beyond neuroscience, to any system in which widespread coupling to hidden variables is extant,” Nemenman says. “Data from many biological or social systems are likely to appear critical via the same mechanism, without fine-tuning.” 

The current paper was partially supported by grants from the National Institutes of Health and the National Science Foundation.

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Tuesday, April 6, 2021

Chemists develop tools that may help improve cancer diagnostics, therapeutics

A process known as methylation helps regulate on-and-off switches to keep a host of systems in the body functioning normally. "But the process can get hijacked, creating modifications that may lead to diseases," explains Ogonna Nwajiobi (above), an Emory Ph.D. student in chemistry and first author of the paper.

By Carol Clark

Chemists developed a method to detect changes in proteins that may signal the early stages of cancer, Alzheimer’s, diabetes and other major diseases. Angewandte Chemie published the work, led by chemists at Emory University and Auburn University. The results offer a novel strategy for studying links between unique protein modifications and various pathologies. 

“The knowledge we gain using our new, chemical method holds the potential to improve the ability to detect diseases such as lung cancer earlier, when treatment may be more effective,” says Monika Raj, senior author of the paper and Emory associate professor of chemistry. “A detailed understanding of protein modifications may also help guide personalized, targeted treatment for patients to improve a drug’s efficacy against cancer.” 

The researchers provided a proof of concept for using their method to detect single protein modifications, or monomethylation. Their lab experiments were conducted on the protein lysine expressed from E.coli and other non-human organisms. 

Lysine is one of the nine essential amino acids that is critical to life. After lysine is synthesized in the human body, changes to the protein, known as methylation, can occur. Methylation is a biochemical process that transfers one carbon atom and three hydrogen atoms from one substance to another. Such modifications can occur in single (monomethylation), double (dimethylation) or triple (trimethylation) forms. Demethylation reverses these modifications. 

The small tweaks of methylation and demethylation regulate biological on-off switches for a host of systems in the body, such as metabolism and DNA production. 

“In a normal state, the methylation process creates modifications that are needed to keep your body functioning and healthy,” says Ogonna Nwajiobi, an Emory Ph.D. student in chemistry and first author of the paper. “But the process can get hijacked, creating modifications that may lead to diseases.”

Modifications to lysine, in particular, he adds, have been linked to the development of many cancers and other diseases in humans. 

Sriram Mahesh, from Auburn University is co-first author of the paper. Xavier Streety, also from Auburn, is a co-author. 

The Raj lab, which specializes in developing organic chemistry tools to understand and solve problems in biology, wanted to devise a method to detect monomethylation marks to lysine that have been expressed by an organism. Monomethylation is especially challenging to detect since it leaves negligible changes in the bulk, charge or other characteristics of a lysine modification.

The researchers devised chemical probes, electron-rich diazonium ions, that couple only with monomethlyation sites at certain biocompatible conditions that they can control, including a particular pH level and electron density. They used mass spectroscopy and nuclear magnetic resonance techniques to show that they had selectively hit the correct targets, and to confirm the coupling of atoms at the sites. 

The method is unique because it directly targets the monomethylation sites. Another unique feature of the method is that it is reversible under acidic conditions, allowing the researchers to uncouple the atoms and regenerate the original state of a monomethylation site. 

The Raj lab now plans to collaborate with researchers at Emory’s Winship Cancer Institute to test the new method on tissue samples taken from lung cancer patients. The goal is to home in on differences in lysine monomethylation sites of people with and without lung cancer. 

“It’s like a fishing expedition,” Nwajiobi explains. “The first step is to use our method to find the lysine monomethylation sites in tissue samples, which is difficult to do because of their low abundance. Once we’ve found the sites, our method then allows us to reverse the coupling with our chemical probe, so the functions of the sites can be studied in their intact, original forms.” 

Practical methods for early detection of many diseases, like lung cancer, are needed to help improve patient outcomes. “If we can develop more ways to identify lung cancer earlier, that may open the door for treatments that greatly improve the survival rate,” Raj says. 

The researchers hope to study lysine monomethylation differences between samples taken from patients at different stages of lung cancer, between patients with or without a family history of the disease, and between those who have smoked and those who have not. Knowledge gained from such analyses could set the stage for more personalized, targeted treatments, Raj says. 

Her lab is also developing chemical tools to selectively detect lysine dimethylation and trimethylation sites, in order to help more fully characterize the role of lysine methylation in disease. 

“We hope that other researchers will also apply our methods, and the chemical tools we are developing, to better understand a range of cancers and many other diseases associated with lysine methylation,” Raj says. 

The work was funded by the National Science Foundation.

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