A collaborative study from researchers in the Molnár, Mann, Bannerman and Lak labs from DPAG and Psychology Department has uncovered a previously overlooked population of brain cells that could play a critical role in how we experience stress and anxiety. This breakthrough study (Messore et al., 2025 - https://doi.org/10.1038/s41398-025-03350-2), combining cutting-edge genetic and brain activity techniques, may help pave the way for new treatments for anxiety disorders. The collaborative team focused on a special group of neurons deep within the brain’s cortex—layer 6b neurons, descendants of an early, mostly transient population known as subplate neurons. While subplate neurons are known to play a key role in early brain development, their function in adults has remained a mystery—until now.
“This unique set of neurons in the adult seems to act as a hub, linking stress signals from deeper brain regions to areas involved in thought, emotion, and behavior,” said Dr Fernando Messore, one of the co-first authors of the paper. “Our findings suggest they could be central to how the brain processes anxiety.”
“Since the number and distribution of these subplate remnant neurons is known to be altered in cognitive disorders such as schizophrenia and autism, linking these cells to anxiety can start to explain key symptoms associated with these conditions.” said Professor Zoltán Molnár.
Stress, especially when chronic, is known to contribute to a wide range of mental health conditions, including anxiety and depression. The brain’s response to stress is coordinated by the hypothalamus and heavily influenced by a hormone called orexin, which affects sleep, appetite, cognition, and emotional responses. Women are twice as likely as men to suffer from anxiety-related disorders—possibly due to genetic differences in how the brain responds to orexin.
In this study—An orexin-sensitive subpopulation of layer 6 neurons regulates cortical excitability and anxiety behaviour—the team silenced a small, orexin-sensitive population of neurons in the prefrontal cortex. These neurons were found to be uniquely responsive to orexin and directly connected to stress and arousal centres in the brain. Using a combination of brain mapping, electrical recordings, genetic engineering, and behavioural testing in mice, the collaborating teams discovered that silencing these neurons decreased anxiety-like behaviours —suggesting that this tiny population of cells might be key players in how the brain generates feelings of stress. “These neurons appear to serve as a gatekeeper,” said co-corresponding author Professor Edward Mann. “When they’re active, they ramp up the brain’s response to stress. When they’re quiet, that response is dialled down.” The results were striking without input from these cells, the mice showed significantly reduced anxiety behaviours, pointing to their potential as a new target for anxiety treatments.
“This is an exciting step toward understanding how different parts of the brain contribute to mental health—and how we might one day intervene more precisely,” said Professor Armin Lak who is an author of the paper.
The study’s authors include Fernando Messore, Rajeevan Narayanan Therpurakal, Jean-Philippe Dufour, Anna Hoerder-Suabedissen, Luiz Guidi, Kim Korrell, Marissa Mueller, Mohammed Abuelem, Armin Lak, David M. Bannerman, Edward O. Mann, and Zoltán Molnár.
Read the paper here