Stress Neurons Mapped the Brain, Exposing Estrogen Link

Summary: Researchers pinpointed a specific group of nerve cells in the mouse brain that play a role in negative emotional states and chronic stress.

The neurons, which were mapped using a variety of advanced techniques, were found to possess estrogen receptors. This discovery potentially explains why women, as a population, are more susceptible to stress compared to men.

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

Key Facts:

  1. Advanced techniques like Patch-seq, Neuropixels, and optogenetics were pivotal in the study’s success, aiding neuron mapping and behavioral control.
  2. Researchers, via optogenetics, were able to influence mice behavior, underscoring these neurons’ direct role 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 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 estrogen, which could explain why women as a group are more sensitive to stress than men.

The study is published in Nature Neuroscience.

This shows neurons.
Just which networks in the brain give rise to negative emotions (aversion) and chronic stress have long been unknown to science. Credit: Neuroscience News

Just which networks in the brain give rise to negative emotions (aversion) and chronic stress have long been unknown to science.

By using a combination of advanced techniques, such as Patch-seq, large-scale electrophysiology (Neuropixels) and optogenetics (see factbox), KI researchers Konstantinos Meletis and Marie Carlén and their team 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.

Opens the way for novel treatments for depression

“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, Karolinska Institutet.

“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.”

The study was led by three postdocs at 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 neuronal pathways and neurons that control emotions and behaviour.

Sensitive to estrogen levels

Another interesting discovery is that the neurons linked to aversion have a receptor for estrogen, making 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 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.”

The study was mainly financed 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 makes it possible record the activity of hundreds of individual neurons simultaneously.

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

About this stress and neuroscience research news

Author: Konstantinos Meletis
Source: Karolinska Institute
Contact: Konstantinos Meletis – Karolinska Institute
Image: The image is credited to Neuroscience News

Original Research: Open access.
Esr1+ hypothalamic-habenula neurons shape aversive states” by Konstantinos Meletis et al. Nature Neuroscience


Esr1+ hypothalamic-habenula neurons shape aversive states

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

Our classification identified six glutamatergic neuron types 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 estrogen receptor 1-expressing (Esr1+) LHA–LHb neurons induce aversion, whereas neuropeptide Y-expressing (Npy+) LHA–LHb neurons control rearing behavior.

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

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

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

Join our Newsletter
I agree to have my personal information transferred to AWeber for Neuroscience Newsletter ( more information )
Sign up to receive our recent neuroscience headlines and summaries sent to your email once a day, totally free.
We hate spam and only use your email to contact you about newsletters. You can cancel your subscription any time.
  1. It is well known that estrogen exacerbates the stress response and and sets the stage for negative affective states. This makes sense give the QOL data presented in the Women’s Health Initiative showed that estrogen-only therapy caused adverse effects on the social/emotional role subscales. (Estrogen-progestin on the other hand led to improvements in pain levels, physical and emotional functioning, and overall wellbeing.) On the flipside, the aromatase inhibitor, letrozole, was actually found to improve emotional role vs placebo. Estrogen does a lot of other lovely things as well, including intensification of PTSD symptoms, more rapid onset of chemical dependency (especially alcohol and opioids), and worsens verbal memory.

  2. 1)which area in the brain is called ‘habenula’?
    2)if estrogen recepors are making women prone for stress & anxiety,why incidence of later increase perimenopausally,when estrogen levels decline?

    1. Estrogen levels decrease 90% after menopause and stay low, but they swing dramatically in perimenopause and average 30% higher than they were in the teens-20s. Perimenopause does bring vasomotor symptoms (hot flashes/night sweats) but there are also symptoms of estrogen excess and low progesterone during this time – heavy flow, an increased risk of fibroids and endometriosis, sore breasts, fluid retention, and worsening migraines. The high stress response observed during perimenopause is actually a symptom of high, not low estrogen

Comments are closed.