In a study in PLOS Computational Biology, scientists at The Picower Institute for Learning and Memory compared measurements of brain cell activity in an animal performing a working memory task with the output of various computer models representing two theories of the underlying mechanism for holding information in mind. The results strongly favored the newer notion that a network of neurons stores the information by making short-lived changes in the pattern of their connections, or synapses, and contradicted the traditional alternative that memory is maintained by neurons remaining persistently active (like an idling engine).

While both models allowed for information to be held in mind, only the versions that allowed for synapses to transiently change connections (“short-term synaptic plasticity”) produced neural activity patterns that mimicked what was actually observed in real brains at work. The idea that brain cells maintain memories by being always “on” may be simpler, acknowledged senior author Earl K. Miller, but it doesn’t represent what nature is doing and can’t produce the sophisticated flexibility of thought that can arise from intermittent neural activity backed up by short-term synaptic plasticity.

“You need these kinds of mechanisms to give working memory activity the freedom it needs to be flexible,” said Miller, Picower Professor Neuroscience in MIT’s Department of Brain and Cognitive Sciences (BCS). “If working memory was just sustained activity alone, it would be as simple as a light switch. But working memory is as complex and dynamic as our thoughts.”

Co-lead author Leo Kozachkov, who earned his PhD at MIT in November for theoretical modeling work including this study, said matching computer models to real-world data was crucial.

“Most people think that working memory ‘happens’ in neurons — persistent neural activity gives rise to persistent thoughts. However, this view has come under recent scrutiny because it does not really agree with the data,” said Kozachkov who was co-supervised by co-senior author Jean-Jacques Slotine, a professor in BCS and mechanical engineering. “Using artificial neural networks with short-term synaptic plasticity, we show that synaptic activity (instead of neural activity) can be a substrate for working memory. The important takeaway from our paper is: these ‘plastic’ neural network models are more brain-like, in a quantitative sense, and also have additional functional benefits in terms of robustness.”

Matching models with nature

Alongside co-lead author John Tauber, an MIT graduate student, Kozachkov’s goal was not just to determine how working memory information might be held in mind, but to shed light on which way nature actually does it. That meant starting with “ground truth” measurements of the electrical “spiking” activity of hundreds of neurons in the prefrontal cortex of an animal as it played a working memory game. In each of many rounds the animal was shown an image that then disappeared. A second later it would see two images including the original and had to look at the original to earn a little reward. The key moment is that intervening second, called the “delay period,” in which the image must be kept in mind in advance of the test.

The team consistently observed what Miller’s lab has seen many times before: The neurons spike a lot when seeing the original image, spike only intermittently during the delay, and then spike again when the images must be recalled during the test (these dynamics are governed by an interplay of beta and gamma frequency brain rhtyhms). In other words, spiking is strong when information must be initially stored and when it must be recalled but is only sporadic when it has to be maintained. The spiking is not persistent during the delay.

Moreover, the team trained software “decoders” to read out the working memory information from the measurements of spiking activity. They were highly accurate when spiking was high, but not when it was low, as in the delay period. This suggested that spiking doesn’t represent information during the delay. But that raised a crucial question: If spiking doesn’t hold information in mind, what does?

Researchers including Mark Stokes at the University of Oxford have proposed that changes in the relative strength, or “weights,” of synapses could store the information instead. The MIT team put that idea to the test by computationally modeling neural networks embodying two versions of each main theory. As with the real animal, the machine learning networks were trained to perform the same working memory task and to output neural activity that could also be interpreted by a decoder.

The upshot is that the computational networks that allowed for short-term synaptic plasticity to encode information spiked when the actual brain spiked and didn’t when it didn’t. The networks featuring constant spiking as the method for maintaining memory spiked all the time including when the natural brain did not. And the decoder results revealed that accuracy dropped during the delay period in the synaptic plasticity models but remained unnaturally high in the persistent spiking models.

In another layer of analysis, the team created a decoder to read out information from the synaptic weights. They found that during the delay period, the synapses represented the working memory information that the spiking did not.

Among the two model versions that featured short-term synaptic plasticity the most realistic one was called “PS-Hebb,” which features a negative feedback loop that keeps the neural network stable and robust, Kozachkov said.

Workings of working memory

In addition to matching nature better, the synaptic plasticity models also conferred other benefits that likely matter to real brains. One was that the plasticity models retained information in their synaptic weightings even after as many as half of the artificial neurons were “ablated.” The persistent activity models broke down after losing just 10-20 percent of their synapses. And, Miller added, just spiking occasionally requires less energy than spiking persistently.

Furthermore, Miller said, quick bursts of spiking rather than persistent spiking leaves room in time for storing more than one item in memory. Research has shown that people can hold up to four different things in working memory. Miller’s lab plans new experiments to determine whether models with intermittent spiking and synaptic weight-based information storage appropriately match real neural data when animals must hold multiple things in mind rather than just one image.

In addition to Miller, Kozachkov, Tauber and Slotine, the paper’s other authors are Mikael Lundqvist and Scott Brincat.

The Office of Naval Research, the JPB Foundation, and ERC and VR Starting Grants funded the research.

Rich Get Richer

Therefore, they need financial resources and scientists. “Early investment in emerging areas of research is a key driver of scientific dominance,” he continues. Once the pioneer has established an area or technology, researchers are also more likely to move into this new, stimulating environment. This “get-rich-richer” phenomenon underlies the development of scientific strength in a region. And scientists’ mobility drives the development of scientific disciplines. The question is, then, how many scientists does a region need to hire so that other scientists find its environment attractive and join its institutions?

No Critical Mass

The team found no evidence for the existence of a minimum number of researchers to hire. Or in technical terms: there is no critical mass to start and carry on a new research field successfully. Here, the scientists focused on three scientific areas: semiconductors, embryonic stem cells (ESC) and internet research.

“In a way, this contradicts the generally held belief that you need a minimum number or critical mass of researchers to make a field successful. In our study, it becomes apparent that this is not the case,” Stefan Thurner from CSH states.

Be a Pioneer

In fact, regions seem to be successful when they manage to jump early on a train and become pionEe rs in a field. “We also find, as common sense suggests, that regions moving early into new technologies tend to dominate the corresponding scientific fields in the future,” Thurner explains.

China: Expensive Race to Catch Up

If a region was not a pioneer, but still wants to achieve leadership in a given area of research it has to make extraordinary efforts to catch up. “Strategic interventions must be sustained over decades to compete for a leading position in a field, as is evident, for example, in Chinese semiconductor science, where the catch up-process began in the late 1970s and has led to a dominant role today,” Servedio says.

A model specially developed by the researchers can explain the development pattern of China — how they take over specific research areas and grow the number of scientists publishing in those fields. “After all, China has some of the fastest-growing institutions worldwide. With our model, you can clearly see that China is closing the gap with the US, potentially taking on huge costs, but also showing their ability to effectively engage with high impact research. While first movers may have an advantage in some contexts, it is not necessarily impossible for late-comers to catch up or even surpass first movers in a scientific field.” CSH researcher Márcia R. Ferreira says.

Three Research Fields and Millions of Data

With the help of the Dimensions database, the researchers at CSH could track scientists moving across regions of the world (they derived these movements from the scientists’ affiliations) in three fields — namely semiconductors, embryonic stem cells (ESC) and internet research. “In this way, we analyzed data spanning several decades with information on millions of publications, 20 million researchers and more than 98,000 research institutions worldwide,” Servedio states.

In the field of semiconductor research, they tracked 5,062,639 articles and 2,011,170 researchers in 1,633 regions worldwide between 1941 and 2019; in the field of stem cell research, they tracked 1,083,100 articles and 752,575 researchers in 1,161 regions worldwide over the same period; and in the field of internet research, they tracked 246,953 articles and 109,098 researchers in 1,032 regions worldwide between 1956 and 2019.

“What our results clearly show is if regions want to become a leader in a field, they must try to get involved early on. It is possible to catch up, but this comes at tremendous costs,” Thurner and Servedio state. “Nonetheless, our model of scientific capacity building is a simplification. There are other factors contributing to the success of a field that we have not yet been able to explore here and which will be the subject of future analysis,” Ferreira states.

Approximately 40% of stroke survivors experience aphasia, a difficulty to comprehend or produce spoken or written language caused by a cerebrovascular accident. In half of these cases the language impairment still persists one year post-stroke. Aphasia has wide-ranging effects on the ability to function and quality of life of stroke survivors and easily leads to social isolation.

According to a recent study conducted at the University of Helsinki, singing-based group rehabilitation can support communication and speech production of patients and increase social activity even at the chronic phase of stroke. The burden experienced among the family caregivers participating in the study also decreased notably.

“Our study is the first where caregivers participated in rehabilitation and their psychological wellbeing was evaluated,” says Postdoctoral Researcher Sini-Tuuli Siponkoski.

Versatile use of music supports recovery

Previous research has established that the ability to sing can be retained even in severe aphasia. However, the use of singing, especially choral singing, in aphasia rehabilitation has not been widely studied.

“Our study utilised a wide variety of singing elements, such as choral singing, melodic intonation therapy and tablet-assisted singing training,” clarifies Doctoral Researcher Anni Pitkäniemi.

In melodic intonation therapy, speech production is practised gradually by utilising melody and rhythm to progress from singing towards speech production.

In the study, rehabilitation sessions were led by a trained music therapist and a trained choir conductor.

New and effective forms of rehabilitation needed

In addition to speech therapy, melodic intonation therapy has been used to some extent in aphasia rehabilitation. Therapy has typically been implemented as individual therapy, requiring a great deal of resources.

According to the researchers, singing-based group rehabilitation should be utilised in healthcare as part of aphasia rehabilitation.

“In addition to training in speech production, group-based rehabilitation provides an excellent opportunity for peer support both for the patients and their families,” says Sini-Tuuli Siponkoski.

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Materials provided by University of Helsinki. Note: Content may be edited for style and length.

The team, led by Duygu Kuzum, a faculty member in the University of California San Diego Department of Electrical and Computer Engineering, details their findings in the Dec. 26 issue of the journal Nature Communications. Kuzum’s team collaborated with researchers from Anna Devor’s lab at Boston University; Alysson R. Muotri’s lab at UC San Diego; and Fred H. Gage’s lab at the Salk Institute.

Human cortical organoids are derived from human induced pluripotent stem cells, which are usually derived themselves from skin cells. These brain organoids have recently emerged as promising models to study the development of the human brain, as well as a range of neurological conditions.

But until now, no research team had been able to demonstrate that human brain organoids implanted in the mouse cortex were able to share the same functional properties and react to stimuli in the same way. This is because the technologies used to record brain function are limited, and are generally unable to record activity that lasts just a few milliseconds.

The UC San Diego-led team was able to solve this problem by developing experiments that combine microelectrode arrays made from transparent graphene, and two-photon imaging, a microscopy technique that can image living tissue up to one millimeter in thickness.

“No other study has been able to record optically and electrically at the same time,” said Madison Wilson, the paper’s first author and a Ph.D. student in Kuzum’s research group at UC San Diego. “Our experiments reveal that visual stimuli evoke electrophysiological responses in the organoids, matching the responses from the surrounding cortex.”

The researchers hope that this combination of innovative neural recording technologies to study organoids will serve as a unique platform to comprehensively evaluate organoids as models for brain development and disease, and investigate their use as neural prosthetics to restore function to lost, degenerated or damaged brain regions.

“This experimental setup opens up unprecedented opportunities for investigations of human neural network-level dysfunctions underlying developmental brain diseases,” said Kuzum.

Kuzum’s lab first developed the transparent graphene electrodes in 2014 and has been advancing the technology since then. The researchers used platinum nanoparticles to lower the impedance of graphene electrodes by 100 times while keeping them transparent. The low-impedance graphene electrodes are able to record and image neuronal activity at both the macroscale and single cell levels.

By placing an array of these electrodes on top of the transplanted organoids, researchers were able to record neural activity electrically from both the implanted organoid and the surrounding host cortex in real time. Using two-photon imaging, they also observed that mouse blood vessels grew into the organoid providing necessary nutrients and oxygen to the implant.

Researchers applied a visual stimulus-an optical white light LED-to the mice with implanted organoids, while the mice were under two-photon microscopy. They observed electrical activity in the electrode channels above the organoids showing that the organoids were reacting to the stimulus in the same way as surrounding tissue. The electrical activity propagated from the area closest to the visual cortex in the implanted organoids area through functional connections. In addition, their low noise transparent graphene electrode technology enabled electrical recording of spiking activity from the organoid and the surrounding mouse cortex. Graphene recordings showed increases in the power of gamma oscillations and phase locking of spikes from organoids to slow oscillations from mouse visual cortex. These findings suggest that the organoids had established synaptic connections with surrounding cortex tissue three weeks after implantation, and received functional input from the mouse brain. Researchers continued these chronic multimodal experiments for eleven weeks and showed functional and morphological integration of implanted human brain organoids with the host mice cortex.

Next steps include longer experiments involving neurological disease models, as well as incorporating calcium imaging in the experimental set up to visualize spiking activity in organoid neurons. Other methods could also be used to trace axonal projections between organoid and mouse cortex.

“We envision that, further along the road, this combination of stem cells and neurorecording technologies will be used for modeling disease under physiological conditions; examining candidate treatments on patient-specific organoids; and evaluating organoids’ potential to restore specific lost, degenerated or damaged brain regions,” Kuzum said.

The work was funded through the National Institutes of Health and the Research Council of Norway, as well as the National Science Foundation.

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Materials provided by University of California – San Diego. Original written by Ioana Patringenaru. Note: Content may be edited for style and length.

Could therapies that remove senescent cells — called senotherapeutics — also improve the health of humans as we age? Answering this question and more has the potential to significantly advance human health, and the National Institutes of Health (NIH) has launched an extensive research initiative for this very purpose.

The SenNet Consortium, a collaboration of institutions from throughout the United States, was initially launched in 2021 with centers established to gather and analyze human data. The researchers will collect and analyze 18 tissues from healthy humans across lifespan to discern the full scope of senescent cells and how they may contribute to the aging process. The work of the SenNet Consortium was recently presented in a paper published in Nature Aging.

Along with colleagues from Mayo Clinic, University of Texas Health Science center at San Antonio, and UConn Health, JAX Professor Paul Robson, Ph.D. is taking part in the mapping of four human tissue types (kidney, adipose, pancreas, and placenta) within the KAPP-Sen Tissue Mapping Center. The Robson Lab also leads the Biological Analysis Core, and the Data Analysis Core of KAPP-Sen TMC is led by JAX Associate Professor Duygu Ucar, Ph.D., and JAX Professor Jeff Chuang, Ph.D.

SenNet has also grown over the past year to add mouse-focused investigators, and JAX was designated as a Tissue Mapping Center (TMC) for SenNet in August 2022, supported by a four-year, $10.7 million grant from the National Institute on Aging. JAX-Sen is led by Professor and Maxine Groffsky Endowed Chair Nadia Rosenthal, Ph.D., FMedSci with co-principal investigators Robson, JAX Associate Professor Ron Korstanje, Ph.D., and UConn Health’s Ming Xu, Ph.D. Associate Professor Sheng Li and Principal Computational Scientist Matt Mahoney lead the Data Analysis Core of the JAX-Sen TMC.

JAX is poised to make substantial contributions to SenNet by profiling senescent cells in kidney, placenta, pancreas, and heart, all tissues that are relevant to chronic diseases of aging. The team will draw upon its genetically diverse mouse resources, including Diversity Outbred mouse populations, to model a range of molecular senescence traits, as well as inbred mice specifically engineered to help visualize senescent cell subsets.

As three of the tissues (kidney, pancreas, and placenta) in the mouse JAX-Sen TMC are shared with the human KAPP-Sen TMC, these efforts align well with the JAX institutional initiative to continue to build the human-mouse interface. The goal of SenNet goes beyond building an atlas of senescent cells in the body and knowing more about senescent cell biology. The potential benefits of senotherapeutics for healthy human aging are exciting, as are other possible clinical advances, such as identifying individuals at higher risk for age-related disease.

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Materials provided by Jackson Laboratory. Original written by Mark Wanner. Note: Content may be edited for style and length.