Stress neurons mapped the brain, exposing the estrogen link

Summary: Researchers have identified a specific group of nerve cells in mouse brains that play a role in negative emotional states and chronic stress.

Neurons, which were mapped using various advanced techniques, were found to possess estrogen receptors. This finding potentially explains why women, as a population, are more sensitive to stress than men.

This breakthrough has potential implications for the treatment of depression and anxiety disorders.


  1. Advanced techniques such as Patch-seq, Neuropixels and optogenetics played a central role in the success of the study, facilitating neuron mapping and behavioral control.
  2. The researchers, via optogenetics, were able to influence the behavior of mice, highlighting the direct role of these neurons in guiding behavior.
  3. This research could lead to the development of new treatments for depression and anxiety disorders by targeting these specific neurons and understanding how negative signals in the brain are generated.

Source: Karolinska Institute

Researchers at the Karolinska Institutet in Sweden have identified a group of nerve cells in mouse brains that are involved in creating negative emotional states and chronic stress.

The neurons, which have been mapped using a combination of advanced techniques, also possess estrogen receptors, which could explain why women as a group are more susceptible to stress than men.

The study is published in Natural neuroscience.

This shows neurons.
The brain networks behind negative emotions (aversion) and chronic stress have long been unknown to science. Credit: Neuroscience News

The brain networks behind negative emotions (aversion) and chronic stress have long been unknown to science.

Using a combination of advanced techniques, such as Patch-seq, large-scale electrophysiology (Neuropixels), and optogenetics (see box), KI researchers Konstantinos Meletis and Marie Carlén and their team were able to map a neural pathway specific in the mouse brain leading from the hypothalamus to the habenula which controls aversion.

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

Leads the way to new treatments for depression

“We discovered this link between the hypothalamus and the habenula in a previous study, but we didn’t know what types of neurons the pathway was made up of,” says Konstantinos Meletis, a professor in the Department of Neuroscience at Karolinska Institutet.

“It’s incredibly exciting to now understand which type of neuron in the pathway controls aversiveness. If we can understand how negative signals are created in the brain, we can also find mechanisms behind affective illnesses like depression, which will pave the way for new drug treatments.

The study was led by three post-docs from the same department, Daniela Calvigioni, Janos Fuzik and Pierre Le Merre, and as Professor Meletis explains, is an example of how scientists can use advanced techniques to identify neural pathways and neurons that control emotions and behavior.

Sensitive to estrogen levels

Another interesting finding is that aversion-related neurons possess an estrogen receptor, which makes them sensitive to estrogen levels. When male and female mice were subjected to the same type of unpredictable mild aversive events, the female mouse developed a much longer 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 is no biological mechanism to explain it,” explains Marie Carlén, professor in the Department of Neurosciences.

“We have now found a mechanism that can at least explain these sex differences in mice.”

The study was primarily funded by the Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Swedish Brain Foundation, and the David and Astrid Hagelén Foundation. The researchers report no potential conflicts of interest.

Factbox: Here are the techniques used

Patch-seq: Patch-seq combines measurements of the electrical properties of individual cells with measurements of gene expression (RNA sequencing) and makes it possible to map the different types of neurons in the brain.

Neuropixels: The Neuropixels probe is a new type of electrode for large-scale electrophysiological measurements that allows simultaneous recording of the activity of hundreds of individual neurons.

Optogenetics: Optogenetics is used to control how and when selected neurons are active. The method consists of introducing light-sensitive proteins (such as channel proteins from the membranes of single-celled organisms) into the neurons to be studied. The light can then be used to monitor individual cell types in the mouse brain to determine their function.

About this news about stress and neuroscience research

Author: Constantin Meletis
Source: Karolinska Institute
Contact: Konstantinos Meletis – Karolinska Institutet
Picture: Image is credited to Neuroscience News

Original research: Free access.
“Hypothalamic band Esr1+ neurons shape aversive states” by Konstantinos Meletis et al. Natural neuroscience


Esr1+ hypothalamic-habenula neurons shape aversive states

Excitatory projections from the lateral hypothalamic area (LHA) to the lateral habenula (LHb) elicit aversive responses. We used patch-sequencing-guided multimodal classification (Patch-seq) to define the structural and functional heterogeneity of the LHA–LHb pathway.

Our classification identified six types of glutamatergic neurons with unique electrophysiological properties, molecular profiles and projection patterns.

We found that genetically defined LHA-LHb neurons signal distinct aspects of emotional or naturalistic behaviors, such as expression of estrogen receptor 1 (Esr1+) LHA–LHb neurons induce aversion, whereas the Y-expressing neuropeptide (Npy+) LHA-LHb neurons control herding behavior.

Repeated optogenetic training of Esr1+ LHA–LHb neurons induce a behaviorally persistent aversive state, and large-scale recordings showed region-specific neural representation of aversive cues in the prelimbic region of the prefrontal cortex.

We further found that exposure to unpredictable mild shocks induced a sex-specific susceptibility to develop a stress state in female mice, which was associated with a specific change in the intrinsic burst-like properties of Esr1.+ LHA–LHb neurons.

In summary, we describe the diversity of LHA-LHb neuron types and provide evidence for the role of Esr1+ aversion neurons and sexually dimorphic stress sensitivity.

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