Tallinn University of Technology
For the brain to function normally, it needs a protein called BDNF. Low levels of this protein have been linked to depression, schizophrenia, and Alzheimer’s disease. A recent scientific discovery may one day lead to new treatments that don’t supply the brain with extra BDNF but instead instruct it to produce the protein on demand.
The article was originally published by Novaator.
Eesti teadlaste leid võib sillutada teed uutmoodi depressiooniravile
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BDNF plays a crucial role in brain function. It acts like fertilizer for brain cells—promoting the growth of neurons, forming new neural connections, and maintaining existing ones. This supports the brain's plasticity, which affects learning, memory, and even behavior.
Disruptions in BDNF balance have been linked to several neurological and psychiatric disorders, including depression, anxiety disorders, and neurodegenerative diseases such as Alzheimer’s and Huntington’s.

Researchers at Tallinn University of Technology (TalTech) have discovered a new regulatory layer in gene expression that helps the brain control when and how to produce BDNF. Lead author Eli-Eelika Esvald explained that while it is well known that BDNF is essential for brain health—and that low levels are associated with depression, schizophrenia, and Alzheimer’s—until now, it wasn’t clear what exactly regulates its production. “We’ve now taken several steps forward,” she said.

Närvirakud toodavad valku
DNA has been introduced into neurons, enabling them to produce a specific protein. The green fluorescence indicates which neurons are expressing the protein under investigation. | Photo: Eli-Eelika Esvald, TalTech

To gain this new insight, the researchers studied rats, focusing on the molecular mechanisms that switch the BDNF gene on and off. They concentrated on two key signals that affect BDNF production: neuronal activity, which plays a major role in learning, and feedback signals from the BDNF protein itself.

The research team identified key proteins that bind to the regions regulating BDNF gene expression and guide its activation. In addition, they confirmed that these proteins bind to the BDNF genes in the brain tissue of laboratory animals. In total, TalTech scientists identified three key regulatory proteins: ATF2, MYT1L, and EGR1. Although these proteins have previously been studied in the context of the nervous system, the TalTech team’s work provides a significantly more detailed understanding of how BDNF production is precisely regulated in the brain.

Figuratively speaking, these proteins act like members of an orchestra. When neurons begin to decline or receive chemical signals, the "conductors" step in to either amplify or suppress BDNF gene activity as needed. The study showed that the proteins don’t act independently but form a dynamic and finely tuned system, capable of binding to the same regulatory regions of the BDNF gene. Sometimes they compete, and sometimes they enhance each other’s effects—much like a well-rehearsed orchestra.
Depending on which protein or combination of proteins is bound to the gene, BDNF production may increase, decrease, or remain unchanged. This complex system of competition and cooperation allows the brain to fine-tune BDNF levels according to immediate needs.

The study also demonstrated for the first time that some of the proteins regulating the BDNF gene respond very specifically to certain signals. For example, the USF family of proteins is activated mainly by increased neuronal activity, while AP1 proteins respond primarily to feedback from the BDNF protein itself. This specificity enables the brain to more accurately distinguish between different situations and react accordingly.

A better understanding of how BDNF levels are regulated could help develop more targeted treatments for depression or neurodevelopmental disorders. Instead of delivering the protein artificially or broadly stimulating neurons, future therapies could target the specific regulatory proteins or mechanisms identified in this study.

“We don’t just want to supply BDNF from the outside—we want to understand how the brain could be made to produce it naturally and at the right time,” explained research group leader Tõnis Timmusk. Figuratively, pharmacologists would no longer be using a hammer to influence the brain, but a precision scalpel.

The study was published in the high-impact journal The Journal of Neuroscience.