One in four adults suffer a stroke in their lifetime, leaving around half of them with residual damage such as paralysis or speech impairment because internal bleeding or a lack of oxygen supply kill brain cells irreversibly. No therapies currently exist to repair this kind of damage. "That's why it is essential to pursue new therapeutic approaches to potential brain regeneration after diseases or accidents," says Christian Tackenberg, the Scientific Head of Division in the Neurodegeneration Group at the University of Zurich (UZH) Institute for Regenerative Medicine.

Neural stem cells have the potential to regenerate brain tissue, as a team led by Tackenberg and postdoctoral researcher Rebecca Weber has now compellingly shown in two studies that were conducted in collaboration with a group headed by Ruslan Rust from the University of Southern California. "Our findings show that neural stem cells not only form new neurons, but also induce other regeneration processes," Tackenberg says.

New neurons from stem cells

The studies employed human neural stem cells, from which different cell types of the nervous system can form. The stem cells were derived from induced pluripotent stem cells, which in turn can be manufactured from normal human somatic cells. For their investigation, the researchers induced a permanent stroke in mice, the characteristics of which closely resemble manifestation of stroke in humans. The animals were genetically modified so that they would not reject the human stem cells.

One week after stroke induction, the research team transplanted neural stem cells into the injured brain region and observed subsequent developments using a variety of imaging and biochemical methods. "We found that the stem cells survived for the full analysis period of five weeks and that most of them transformed into neurons, which actually even communicated with the already existing brain cells," Tackenberg says.

Brain regenerates itself

The researchers also found other markers of regeneration: new formation of blood vessels, an attenuation of inflammatory response processes and improved blood-brain barrier integrity. "Our analysis goes far beyond the scope of other studies, which focused on the immediate effects right after transplantation," Tackenberg explains. Fortunately, stem cell transplantation in mice also reversed motor impairments caused by stroke. Proof of that was delivered in part by an AI-assisted mouse gait analysis.

Clinical application moving closer to reality

When he was designing the studies, Tackenberg already had his sights set on clinical applications in humans. That's why, for example, the stem cells were manufactured without the use of reagents derived from animals. The Zurich-based research team developed a defined protocol for that purpose in collaboration with the Center for iPS Cell Research and Application (CiRA) at Kyoto University. This is important for potential therapeutic applications in humans. Another new insight discovered was that stem cell transplantation works better when it is performed not immediately after a stroke but a week later, as the second study verified. In the clinical setting, that time window could greatly facilitate therapy preparation and implementation.

Despite the encouraging results of the studies, Tackenberg warns that there is still work to be done. "We need to minimize risks and simplify a potential application in humans," he says. Tackenberg's group, again in collaboration with Ruslan Rust, is currently working on a kind of safety switch system that prevents uncontrolled growth of stem cells in the brain. Delivery of stem cells through endovascular injection, which would be much more practicable than a brain graft, is also under development. Initial clinical trials using induced stem cells to treat Parkinson's disease in humans are already underway in Japan, Tackenberg reports. "Stroke could be one of the next diseases for which a clinical trial becomes possible."

These results, recently published in PLoS Computational Biology, show that this flexibility depends on the balance between two types of inhibitory mechanisms, which regulate the interaction between slow (theta) and fast (gamma) rhythms. Thanks to this mechanism, the brain can select different sources of information, such as sensory stimuli from the external environment or stored sensory experience from memory.

To reach these conclusions, the researchers combined computational models with experimental recordings in the hippocampus, a brain region crucial for memory and navigation. They observed that in familiar environments, where sensory experiences are already known, neurons favor a direct communication mode that facilitates transmission from the entorhinal cortex to the hippocampus. In this mode, the reactivation of established memory is prioritized. By contrast, when facing novelty, the brain activates another mode that integrates memory reactivation with novel sensory inputs. In this mode, memory updating is prioritized.

Until now, it was thought that the phase of slow brain rhythms organized the amplitude of faster activity; however, this study demonstrates that the relationship is bidirectional: "This work provides a mechanistic explanation of how the brain flexibly changes communication channels depending on the context," says Dimitrios Chalkiadakis, first author of the study. "By adjusting the balance between different types of inhibition, circuits define which inputs to prioritize, whether from memory-related pathways or from new sensory information," highlights the researcher.

Through a theoretical framework integrating electrophysiological data from rats exploring new and familiar environments, the experts identified two modes of operation: in one, feedforward inhibition leads to gamma-to-theta interactions, while in the other, feedback inhibition produces theta-to-gamma interactions. Neuronal circuits in the brain naturally implement both modes of inhibitory connectivity. The study shows that the transition between them is continuous, and prioritizing one or the other depends solely on the strength of synaptic connections between neurons in the circuit. This allows the mode of operation to be flexibly adjusted to context and cognitive demands.

Beyond memory

The study suggests that this flexible form of coordination between brain rhythms could extend to other cognitive functions, such as attention. In fact, recent work in humans shows patterns consistent with the computational model. This points to a general principle of the brain: the balance between inhibitory circuits is key to directing information within its complex network of connections.

"Our results help unify opposing views on how brain rhythms of different frequencies interact," explains Mirasso. "Rather than being purely local or inherited from earlier regions, these rhythms emerge from the interaction between external inputs and local inhibitory dynamics. This dual mechanism enables the brain to optimize information processing under different conditions," adds Canals.

Beyond memory and navigation, the findings could extend to other cognitive functions. Looking ahead, the researchers intend to expand their model to include a greater diversity of neuronal types and architectures specific to each brain region. The aim is to better understand how this balance is altered in pathologies such as epilepsy, addiction, or Alzheimer's disease: "Studying these dynamics at a mechanistic level could ultimately inspire new therapeutic intervention strategies," both authors conclude.

This work was made possible thanks to funding from the Spanish Ministry of Science, Innovation, and Universities through the R&D Project Program (Knowledge Generation and Research Challenges) and from the Spanish State Research Agency through the Severo Ochoa Centers of Excellence and the María de Maeztu Units of Excellence Program.