Ever wonder why premenstrual symptoms (PMS) can leave you feeling down? Turns out, there’s a reason those premenstrual mood swings can feel like a rollercoaster ride. Scientists have mapped the brain circuitry responsible for those emotional ups and downs, and it’s all thanks to some helpful mice. So, just what is it about the last week before your period that gets you so depressed?
Why do I feel depressed before my period?
Californian researchers claim specific brain pathways are disrupted when estrogen levels drop, offering potential new targets for treating depression in women. In this 2023 study, published in Nature Neuroscience, scientists reveal the intricate brain circuitry responsible for depression-like symptoms in mice experiencing hormone withdrawal, mimicking conditions like postpartum depression and menopause.1 No, you are not imagining it, you could well be feeling irrationally depressed or angry in the days before your period, and there’s a biological reason behind it.
While it’s long been known that hormonal shifts can influence women’s mental health, the precise mechanisms at play in the brain have remained elusive.
The scientists zeroed in on a brain area called the medial preoptic area (MPOA), a kind of control center for mood and emotions. Could this part of the brain be responsible for depression-like feelings before your period? Could it have a role in post partum depression?
Dr. Li I Zhang and colleagues from the University of Southern California found that when they removed the ovaries of mice (mimicking menopause), these mice started acting depressed. Why? It turns out that a special type of brain cell in the MPOA, called GABAergic neurons, weren’t working as well. These neurons are like the little mood regulators in your brain, and when hormone levels drop, they become less active. Simulating the steep estrogen withdrawal that happens just before a period, seems to make the mice feel depressed.
Specifically, these GABAergic neurons had lower levels of a protein called estrogen receptor-1 (Esr1), which is like a docking station for estrogen. Less estrogen, fewer docking stations, and boom – your mood takes a hit.
When estrogen levels take a nosedive, certain brain pathways go haywire, turning your control center from cheerful to gloomy. It’s not your personality, it’s just how your brain works.
This discovery opens up new possibilities for treating depression in women, particularly those experiencing hormonal shifts due to conditions like postpartum depression and menopause. So, while we can’t completely escape the hormonal roller coaster, at least now we have a better understanding of how it works – and how to smooth out the ride.
Hormone drops trigger your period and low mood
To study how hormone changes affect mood, the scientists used female mice, carefully controlling their living conditions and tracking their reproductive cycles. Some mice had their ovaries removed to mimic the hormone withdrawal that happens with postpartum or menopause, while others received continuous estrogen to serve as a control group.
The researchers followed a specific schedule of hormone (estradiol and progesterone) injections and withdrawals. This was done to induce depressive-like behavior in the mice. In some experiments, they directly infused estradiol or an estrogen receptor antagonist into the medial preoptic area.
Did mimicking pre-menstrual conditions make mice feel depressed?
The scientists put the mice through a series of behavioral challenges to gauge depressive behaviors. First, they checked if they were still enjoying life’s sweet pleasures with a taste test – sugar water versus plain water. Then came the “hanging out” session, where researchers measured how long the mice just hung there when suspended by their tails, followed by a forced swim to see if they’d just give up and float. To top it off, the mice had to navigate mazes and open spaces to measure their spatial awareness. And finally, a playdate with other mice to see if these hormonal shifts had turned them anti-social.
So what did the researchers find when they triggered a rapid drop in estrogen levels? Some very depressed mice, that’s what! The mice experiencing hormone withdrawal showed a range of depressive-like behaviors: anhedonia, helplessness, increased anxiety, and reduced sociability. This confirmed that fluctuating reproductive hormones can significantly impact mood. So from some pretty miserable souris to pre menstrual syndrome, it seems like feeling depressed before your period is a regular part of brain function.
What’s going on in the medial preoptic area?
Then they zeroed in on the MPOA brain region and used special imaging technology to look at the activity of individual neurons. They specifically focused on two types of neurons: GABAergic neurons, which act like the brain’s “brakes,” and glutamatergic neurons, which act like “accelerators.”
First, the scientists used a technique that uses light to control brain cells. They could activate neurons on demand with pulses of blue LED light – essentially giving the “brake pedal” in the brain a little tap. And voilà! This brain cell light show led to a noticeable improvement in the mice’s behavior, dialing down depressive symptoms and encouraging them to socialize more.
In a second experiment, they used a special drug that can silence specific neurons. Think of it as a “mute” button for those chatty GABAergic neurons. When they administered this drug, the mice, both male and female, started acting like they were having a really bad day, displaying a whole range of depressive-like behaviors. This confirmed that just quieting these neurons down is enough to bring on the gloom, even without messing with hormones. So, it seems like these GABAergic neurons are key players in keeping our spirits up, and when they’re not firing on all cylinders, it can really throw a wrench in our mood machinery.
Mapping the mood circuitry
The researchers went on a mapping expedition inside the mouse brain to chart the precise routes that GABAergic neurons use to influence mood. They discovered that these neurons in the MPOA send signals to three key areas (VTA, vlPAG, and LHA), each involved in different aspects of motivation, reward, and stress. Using sophisticated cell biology techniques, they were able to selectively silence the pathways to each of these areas, like cutting different “brake lines” to see which one controlled which aspect of mood.
They found that silencing the VTA pathway led to a loss of pleasure-seeking and social withdrawal, while silencing the vlPAG pathway increased helplessness and anxiety. Sounds a lot like the depression-like symptoms many women get before their period.
To double-check their findings, the researchers then did the opposite – they activated each pathway to see what would happen. And sure enough, activating the VTA pathway boosted pleasure and sociability, while activating the vlPAG pathway reduced helplessness and anxiety. This confirmed that these two pathways act like separate mood dials in the brain, each controlling distinct aspects of emotional well-being. Yep, that included your mood and potential to feel down before your period.
This discovery shines a light on the intricate wiring of the brain’s mood regulation system offering avenues for developing targeted treatments for mood disorders, particularly those linked to hormonal fluctuations like menopause.
Brain circuitry of period-blues
Researchers homed in on a specific group of GABAergic neurons in the MPOA that might be the key orchestrators of mood changes related to hormone withdrawal. These neurons, known as Esr1+ neurons, are sensitive to estrogen and are already known to play a role in social behavior and reward. Using advanced techniques, the scientists discovered that these Esr1+ neurons make up a significant portion of the “brake lines” connecting the MPOA to other brain areas involved in mood regulation, namely the VTA and vlPAG.
To further clarify the role of these neurons, the researchers compared them to another group of GABAergic neurons that lack the Esr1 protein. They found a key difference: only the Esr1+ neurons extended their “brake lines” to the vlPAG, the brain area responsible for controlling helplessness and anxiety. This suggests that these estrogen-sensitive neurons may be particularly important in driving the mood disturbances associated with fluctuating estrogen levels, such as those experienced during menopause.
Essentially, the researchers were able to cure a mouse’s deprepression by directly adding estrogen to the medial preoptic area. When they injected the mouse’s brain with the hormone, her behavior would change, taking more interest in her surroundings and socializing more. So could preventing pre-menstrual depression and low mood be as simple as taking an estrogen pill?
MPOA: a new target for therapies addressing mood and hormones
Does this work bring us any closer to escaping feeling so depressed before our period? Maybe. This study highlights the medial preoptic area as a control center for mood swings linked to hormones. By understanding these specific brain circuits and how they are affected by hormone fluctuations, researchers aim to develop more targeted treatments for conditions such as postpartum depression, premenstrual dysphoric disorder, and menopause-related mood swings.
References
- Tao C, Zhang GW, Huang JJ, Li Z, Tao HW, Zhang LI. The medial preoptic area mediates depressive-like behaviors induced by ovarian hormone withdrawal through distinct GABAergic projections. Nat Neurosci. 2023;26(9):1529-1540. doi:10.1038/s41593-023-01397-2
- Burke SM, van de Giessen E, de Win M, et al. Serotonin and dopamine transporters in relation to neuropsychological functioning, personality traits and mood in young adult healthy subjects. Psychol Med. 2011;41(2):419-429. doi:10.1017/S0033291710000486
Ever wonder why premenstrual symptoms (PMS) can leave you feeling down? Turns out, there’s a reason those premenstrual mood swings can feel like a rollercoaster ride. Scientists have mapped the brain circuitry responsible for those emotional ups and downs, and it’s all thanks to some helpful mice. So, just what is it about the last week before your period that gets you so depressed? Californian researchers claim specific brain pathways are disrupted when estrogen levels drop, offering potential new targets for treating depression in women. In this 2023 study, published in Nature Neuroscience, scientists reveal the intricate brain circuitry responsible for depression-like symptoms in mice experiencing hormone withdrawal, mimicking conditions like postpartum depression and menopause.1 No, you are not imagining it, you could well be feeling irrationally depressed or angry in the days before your period, and there’s a biological reason behind it. While it’s long been known that hormonal shifts can influence women’s mental health, the precise mechanisms at play in the brain have remained elusive. The scientists zeroed in on a brain area called the medial preoptic area (MPOA), a kind of control center for mood and emotions. Could this part of the brain be responsible for depression-like feelings before your period? Could it have a role in post partum depression? Dr. Li I Zhang and colleagues from the University of Southern California found that when they removed the ovaries of mice (mimicking menopause), these mice started acting depressed. Why? It turns out that a special type of brain cell in the MPOA, called GABAergic neurons, weren’t working as well. These neurons are like the little mood regulators in your brain, and when hormone levels drop, they become less active. Simulating the steep estrogen withdrawal that happens just before a period, seems to make the mice feel depressed. Specifically, these GABAergic neurons had lower levels of a protein called estrogen receptor-1 (Esr1), which is like a docking station for estrogen. Less estrogen, fewer docking stations, and boom – your mood takes a hit. When estrogen levels take a nosedive, certain brain pathways go haywire, turning your control center from cheerful to gloomy. It’s not your personality, it’s just how your brain works. This discovery opens up new possibilities for treating depression in women, particularly those experiencing hormonal shifts due to conditions like postpartum depression and menopause. So, while we can’t completely escape the hormonal roller coaster, at least now we have a better understanding of how it works – and how to smooth out the ride. To study how hormone changes affect mood, the scientists used female mice, carefully controlling their living conditions and tracking their reproductive cycles. Some mice had their ovaries removed to mimic the hormone withdrawal that happens with postpartum or menopause, while others received continuous estrogen to serve as a control group. The researchers followed a specific schedule of hormone (estradiol and progesterone) injections and withdrawals. This was done to induce depressive-like behavior in the mice. In some experiments, they directly infused estradiol or an estrogen receptor antagonist into the medial preoptic area. The scientists put the mice through a series of behavioral challenges to gauge depressive behaviors. First, they checked if they were still enjoying life’s sweet pleasures with a taste test – sugar water versus plain water. Then came the “hanging out” session, where researchers measured how long the mice just hung there when suspended by their tails, followed by a forced swim to see if they’d just give up and float. To top it off, the mice had to navigate mazes and open spaces to measure their spatial awareness. And finally, a playdate with other mice to see if these hormonal shifts had turned them anti-social. So what did the researchers find when they triggered a rapid drop in estrogen levels? Some very depressed mice, that’s what! The mice experiencing hormone withdrawal showed a range of depressive-like behaviors: anhedonia, helplessness, increased anxiety, and reduced sociability. This confirmed that fluctuating reproductive hormones can significantly impact mood. So from some pretty miserable souris to pre menstrual syndrome, it seems like feeling depressed before your period is a regular part of brain function. Then they zeroed in on the MPOA brain region and used special imaging technology to look at the activity of individual neurons. They specifically focused on two types of neurons: GABAergic neurons, which act like the brain’s “brakes,” and glutamatergic neurons, which act like “accelerators.” First, the scientists used a technique that uses light to control brain cells. They could activate neurons on demand with pulses of blue LED light – essentially giving the “brake pedal” in the brain a little tap. And voilà! This brain cell light show led to a noticeable improvement in the mice’s behavior, dialing down depressive symptoms and encouraging them to socialize more. In a second experiment, they used a special drug that can silence specific neurons. Think of it as a “mute” button for those chatty GABAergic neurons. When they administered this drug, the mice, both male and female, started acting like they were having a really bad day, displaying a whole range of depressive-like behaviors. This confirmed that just quieting these neurons down is enough to bring on the gloom, even without messing with hormones. So, it seems like these GABAergic neurons are key players in keeping our spirits up, and when they’re not firing on all cylinders, it can really throw a wrench in our mood machinery. The researchers went on a mapping expedition inside the mouse brain to chart the precise routes that GABAergic neurons use to influence mood. They discovered that these neurons in the MPOA send signals to three key areas (VTA, vlPAG, and LHA), each involved in different aspects of motivation, reward, and stress. Using sophisticated cell biology techniques, they were able to selectively silence the pathways to each of these areas, like cutting different “brake lines” to see which one controlled which aspect of mood. They found that silencing the VTA pathway led to a loss of pleasure-seeking and social withdrawal, while silencing the vlPAG pathway increased helplessness and anxiety. Sounds a lot like the depression-like symptoms many women get before their period. To double-check their findings, the researchers then did the opposite – they activated each pathway to see what would happen. And sure enough, activating the VTA pathway boosted pleasure and sociability, while activating the vlPAG pathway reduced helplessness and anxiety. This confirmed that these two pathways act like separate mood dials in the brain, each controlling distinct aspects of emotional well-being. Yep, that included your mood and potential to feel down before your period. This discovery shines a light on the intricate wiring of the brain’s mood regulation system offering avenues for developing targeted treatments for mood disorders, particularly those linked to hormonal fluctuations like menopause. Researchers homed in on a specific group of GABAergic neurons in the MPOA that might be the key orchestrators of mood changes related to hormone withdrawal. These neurons, known as Esr1+ neurons, are sensitive to estrogen and are already known to play a role in social behavior and reward. Using advanced techniques, the scientists discovered that these Esr1+ neurons make up a significant portion of the “brake lines” connecting the MPOA to other brain areas involved in mood regulation, namely the VTA and vlPAG. To further clarify the role of these neurons, the researchers compared them to another group of GABAergic neurons that lack the Esr1 protein. They found a key difference: only the Esr1+ neurons extended their “brake lines” to the vlPAG, the brain area responsible for controlling helplessness and anxiety. This suggests that these estrogen-sensitive neurons may be particularly important in driving the mood disturbances associated with fluctuating estrogen levels, such as those experienced during menopause. Essentially, the researchers were able to cure a mouse’s deprepression by directly adding estrogen to the medial preoptic area. When they injected the mouse’s brain with the hormone, her behavior would change, taking more interest in her surroundings and socializing more. So could preventing pre-menstrual depression and low mood be as simple as taking an estrogen pill? Does this work bring us any closer to escaping feeling so depressed before our period? Maybe. This study highlights the medial preoptic area as a control center for mood swings linked to hormones. By understanding these specific brain circuits and how they are affected by hormone fluctuations, researchers aim to develop more targeted treatments for conditions such as postpartum depression, premenstrual dysphoric disorder, and menopause-related mood swings. References
Why do I feel depressed before my period?
Hormone drops trigger your period and low mood
Did mimicking pre-menstrual conditions make mice feel depressed?
What’s going on in the medial preoptic area?
Mapping the mood circuitry
Brain circuitry of period-blues
MPOA: a new target for therapies addressing mood and hormones
