Learning About New Chronic Stress Pathways

Researchers at Karolinska Institutet in Sweden have identified a group of nerve cells in the mouse brain that are involved in creating negative emotional states and chronic stress. The neurons, which have been mapped with a combination of advanced techniques, also have receptors for oestrogen, which could explain why women as a group are more sensitive to stress than men.

By using a combination of advanced techniques, such as Patch-seq, large-scale electrophysiology and optogenetics,  researchers have been able to map out a specific neuronal pathway in the mouse brain leading from the hypothalamus to the habenula that controls aversion.

The researchers used optogenetics to activate the pathway when the mice entered a particular room, and found that the mice soon started to avoid the room even though there was nothing in it.

“We discovered this connection between the hypothalamus and the habenula in a previous study but didn’t know what types of neurons the pathway was made up of,” says Konstantinos Meletis, professor at the Department of Neuroscience. “It’s incredibly exciting to now understand what type of neuron in the pathway controls aversion. If we can understand how negative signals in the brain are created, we can also find mechanisms behind affective diseases like depression, which will open the way for novel drug treatments.”

Another interesting discovery is that the neurons linked to aversion have a receptor for oestrogen, making them sensitive to oestrogen levels. When male and female mice were subjected to the same type of unpredictable mild aversive events, the female mouse developed a much more lasting stress response than the male.

“It has long been known that anxiety and depression are more common in women than in men, but there hasn’t been any biological mechanism to explain it,” says Marie Carlén, professor at the Department of Neuroscience. “We’ve now found a mechanism that can at least explain these sex differences in mice.”


Daniela Calvigioni, Janos Fuzik, Pierre Le Merre, Marina Slashcheva, Felix Jung, Cantin Ortiz, Antonio Lentini, Veronika Csillag, Marta Graziano, Ifigeneia Nikolakopoulou, Moritz Weglage, Iakovos Lazaridis, Hoseok Kim, Irene Lenzi, Hyunsoo Park, Björn Reinius, Marie Carlén, Konstantinos Meletis. Esr1+ hypothalamic-habenula neurons shape aversive states. Nature Neuroscience, 2023; DOI: 10.1038/s41593-023-01367-8

Karolinska Institutet. “Chronic stress-related neurons identified.” ScienceDaily. ScienceDaily, 22 June 2023. <www.sciencedaily.com/releases/2023/06/230622120922.htm>.

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Photo by Nikko Macaspac