Tag Archives: serotonin

Potential new treatment for drug-resistant depression identified in mice — blocking histamines in the brain

Inflammation could have a direct impact on our mood through a molecule known as histamine, according to new research. Histamines are produced when white blood cells encounter a potential allergen, but their release in the blood also seems to interfere with serotonin, a mood-regulating neurotransmitter.

Histamine molecule. Image via Wikimedia.

Nobody likes allergies, but science has found a new reason to dislike them even more. Histamines, the molecules that mediate allergic responses, also seem to sour the mood of lab mice. New research from Imperial College London and the University of South Carolina reports that inflammation, and the release of histamines that accompanies it, interferes with serotonin in the brain. It also seems to affect how effective antidepressants can be at improving our mood, since these compounds also work by regulating serotonin production in the brain.

If these findings are replicated in humans, the team explains, we could open up new avenues of treatment for depression and treatment-resistant depression, which together form the most common mental health problem worldwide.

Unfortunate interaction

“Inflammation could play a huge role in depression, and there is already strong evidence that patients with both depression and severe inflammation are the ones most likely not to respond to antidepressants,” explains Dr. Parastoo Hashemi from Imperial’s Department of Bioengineering, lead author of the paper.

“Our work shines a spotlight on histamine as a potential key player in depression. This, and its interactions with the ‘feel-good molecule’ serotonin, may thus be a crucial new avenue in improving serotonin-based treatments for depression.”

While histamines are best known for the part they play in allergic reactions, they’re actually involved in basically every episode of inflammation in our bodies. Inflammation is an expansive term that refers to the process through which immune cells fight off pathogens and other threats. Swelling is one of the most obvious symptoms of inflammation, so the two terms are colloquially used to mean the same thing.

Inflammation is generally a response to infections, but can also be caused by stress, chronic diseases, obesity, neurodegenerative diseases, and allergic responses. Histamines mediate this process by increasing blood flow to affected areas and drawing immune cells to it.

Serotonin, colloquially known as the “happiness molecule”, is a key mood-regulating neurotransmitter. It is the chemical that makes you feel pleasure, and underpins our brains’ reward pathways. It’s also one of the main targets for today’s antidepressants. One of the most commonly prescribed classes of antidepressants today, selective serotonin reuptake inhibitors (SSRIs), helps to alleviate this condition by preventing our bodies from scrubbing serotonin from the brain — essentially, it doesn’t touch the happiness tap, but it does block the drain.

However, many patients are resistant to SSRIs. The team set out to determine whether specific interactions between serotonin and other neurotransmitters could explain this resistance. They applied serotonin-measuring microelectrodes to the brains of live mice, especially on the hippocampus area, as it’s known to play a part in regulating mood. The technique is known as fast scan cyclic voltammetry (FSCV) and allows for live measurements of serotonin levels without harming the brain.

After placing the microelectrodes, they injected half the mice with lipopolysaccharide (LPS), an inflammation-causing toxin found in some bacteria, and half the mice with a saline solution as a control.

Brain serotonin levels dropped sharply within minutes of the LPS injection, but remained constant in the control group. This shows how quickly inflammation can affect serotonin levels in the brain, the team explains, as LPS is unable to cross the blood-brain barrier — and therefore cannot be the cause of the drop.

Further investigation revealed that histamines released in response to the LPS in the brain inhibitied the release of serotonin by attaching to inhibitory receptors on the serotonin neurons. Humans also have these inhibitors, the team explains. SSRIs administered to these mice had very modest results in regards to boosting their brain serotonin levels.

However, when administered alongside histamine-reducing drugs, the SSRIs countered the observed drop, and serotonin levels rose to the same levels as seen in the control group. According to the authors, these drugs lower histamine levels throughout the body and are distinct from antihistamines taken for allergies, which block histamine’s effects on neurons — so don’t try to self-medicate with anti-allergy pills for depression.

That being said, if these findings can be replicated in humans, we’d gain access to a new and powerful avenue of treatment, especially for cases that do not respond to our current options. However, because the current findings are based solely on work with lab animals, there’s no guarantee that they will be replicated in humans.

The paper “Inflammation-Induced Histamine Impairs the Capacity of Escitalopram to Increase Hippocampal Extracellular Serotonin” has been published in the Journal of Neuroscience.

Neurons.

Depressed? It might be because your neurons got their branches tangled up

A team of Columbia researchers has found the gene that dictates how serotonin-releasing neurons branch out in the brain. Tests on mice engineered to lack this gene showed that their neurons’ dendrites (branches) became entangled, negatively impacted serotonin distribution in their brains and leading to signs of depression.

Neurons.

Image credits Colin Behrens.

The findings come from the lab of Tom Maniatis, PhD, a principal investigator at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute, the Isidore S. Edelman Professor and Chair of the department of Biochemistry & Molecular Biophysics at Columbia University Medical Center. Initially, Maniatis set out together with his colleagues to find out how individual neurons in the brain keep track of their neighbors so that their thousands of branches wind through the brain without getting tangled up with others.

They focused on a group of genes called clustered protocadherins (Pcdhs), as previous research has shown that these genes stamp barcode-like compounds on the cell’s surface, so each neuron can distinguish themselves from their other neurons. In broad lines, they work like this: each neuron’s Pcdh code is unique. In the case of a contact, each branch compares its code to the one it touches. If it’s the same, they steer clear of each other to avoid entanglements, a process known as self-avoidance.

In two new papers published in the journal Science, Maniatis and his team detail how in the case of olfactory sensory neurons (OSNs), a diverse range of Phcds work together to make up sufficient ‘codes’ to give each neuron its unique identity. But if there isn’t enough Phcd diversity for each neuron to receive a unique code, OSNs fail to wire properly in the brain and the mice can’t distinguish between different smells. The findings show how important neuronal wiring is to overall brain health and its ability to function properly.

Faulty wiring

Through a series of experiments in mice, Dr. Maniatis’ team identified a single gene within the Pcdh cluster, Pcdh-alpha-c2, that was responsible for the ability of serotonergic neurons to assemble into a tiled pattern throughout the brain and evenly distribute serotonin.

“The main job of these neurons is to distribute serotonin uniformly throughout the brain, which is responsible for maintaining mood balance. To do this, the neurons lay their branches out in a precise, evenly-spaced pattern — a process called axonal tiling. However, the exact mechanism that allows them to do this remained elusive,” said Dr. Maniatis, who is also director of Columbia’s Precision Medicine Initiative.

“We were surprised to find that, unlike other neurons that displays distinct barcodes of diverse Pcdhs, all serotonergic neurons display a single functional recognition protein. Thus, serotonergic axonal branches can recognize and repel one another, leading to their even spacing.”

But by deleting the Pcdh-alpha-c2 gene in these neurons, the team was able to make them tangle and clump together. When the cells released serotonin, it wasn’t evenly distributed through the brain, leading to striking changes in behavior. Pcdh-alpha-c2-deficient mice showed a reduced desire to escape (behavioral despair) and enhanced fear memory (increased freezing when frightened) — both classic signs of depression.

Serotonin imbalances have been linked to a range of psychiatric disorders such as depression, bipolar disorder, and schizophrenia. But most research focuses on problems with the production or uptake of serotonin and ignore the problem of neural wiring, Dr. Manitis adds. The results suggest that psychiatric disorders associated with serotonin imbalances — such as depression, bipolar disorder, schizophrenia, and autism — could be caused by errors in this wiring.

The first paper “Multicluster Pcdh diversity is required for mouse olfactory neural circuit assembly” has been published in the journal Science.

The second paper, “Pcdhαc2 is required for axonal tiling and assembly of serotonergic circuitries in mice” has been published in the journal Science.

 

Are you socially anxious? It might be your genes’ fault

Social anxiety is one of the banes of modern life. It happens so often and for so many people that it’s hard to simply ignore it. Now, a team of German researchers has revealed that the cause might be different to what we thought.

Image via Pixabay.

It might not be our upbringing and social habits that cause social anxiety, but our genes. For many people, being in large groups or speaking in front of other people causes stuttering, heart palpitations, shortness of breath, or trembling. This type of social phobia was generally thought to have environmental or psychological triggers, though genetic factors were also considered.

“There is still a great deal to be done in terms of researching the genetic causes of this illness,” says Dr. Andreas Forstner from the Institute of Human Genetics at the University of Bonn. “Until now, only a few candidate genes have been known that could be linked to this.”

Forstner and his colleagues from the Clinic and Policlinic for Psychosomatic Medicine and Psychotherapy at the University Hospital Bonn analyzed the DNA of 321 people who suffered from social anxiety and compared it to 804 control individuals. They focused on something called single nucleotide polymorphisms (SNPs) — the variability of DNA positioning in various people.

It’s estimated that there are over 13 million such variations in the human genome, and some of them have been discussed in regards to social phobia. In total, Forstner looked at 24 SNPs linked to mental disorders. This is the largest such study ever conducted on social anxiety.

“The result substantiates indications from previous studies that serotonin plays an important role in social phobia,” says associate professor (Privatdozent) Dr. Rupert Conrad from the Clinic and Policlinic for Psychosomatic Medicine and Psychotherapy.

They found that especially one SNP, in the serotonin transporter gene SLC6A4, is associated with the condition. The role of SLC6A4 has been linked to a number of conditions, including alcoholism, clinical depression, obsessive-compulsive disorder (OCD), as well as romantic love. It makes a lot of sense that something connected to serotonin is linked to the condition. Serotonin is well known to suppress negative feelings such as feelings of fear and depression. For a long time, doctors have treated depression and anxiety by increasing the concentration of serotonin in the brain, so it makes sense that serotonin also affects social phobia.

In the Department of Genomics at the Life & Brain research center: Dr. Andreas Forstner (seated at the front), associate professor (Privatdozent) Dr. Rupert Conrad and psychologist Stefanie Rambau. Image credits: University of Bonn.

For the future, researchers want to test their hypothesis with an even longer study — but they need volunteers. If you suffer from social anxiety or know someone who does, consider their next effort. Participating in the study can make a big difference for understanding the condition.

“In order to achieve this goal, we need many more study participants who suffer from social anxiety,” says the psychologist and study coordinator Stefanie Rambau from the Clinic and Policlinic for Psychosomatic Medicine and Psychotherapy at University Hospital Bonn. Information about the study is available at http://www.SocialPhobiaResearch.de [site in GERMAN — go to ‘Kontact’ to send them a message’. “Those who take part will help to research social phobia. This is the basis of better diagnosis and treatment procedures in the future,” says Stefanie Rambau.

Although the link between serotonin and depression and anxiety has been thoroughly documented, researchers are still unsure about the driver of the cause-effect process. Is it a decrease in serotonin the cause of these issues, or do depression and anxiety cause a decrease in serotonin?

To make things even more interesting, a 2015 study found that anxiety was correlated to more serotonin production, not less. Not only did socially anxious people produce more serotonin, but they also pumped more of it back, probably to compensate for the extra production. Together, these two studies paint an interesting picture of how serotonin and its transporters affect anxiety and related issues. There’s still much work to be done.

Journal Reference: Andreas J. Forstner, Stefanie Rambau, Nina Friedrich, Kerstin U. Ludwig, Anne C. Böhmer, Elisabeth Mangold, Anna Maaser, Timo Hess, Alexandra Kleiman, Antje Bittner, Markus M. Nöthen, Jessica Becker, Franziska Geiser, Johannes Schumacher, Rupert Conrad — Further evidence for genetic variation at the serotonin transporter gene SLC6A4 contributing toward anxiety. Psychiatric Genetics, 2017; 1 DOI: 10.1097/YPG.0000000000000171

 

scratching

Scratching makes Itching Worse: the Molecular Mechanism behind the Itch

Seems like your mom was right all along: scratching does, in fact, makes the itching worse. This was the conclusion reached by a group of researchers at Washington University School of Medicine in St. Louis after the scientists studied the molecular and neural pathways that cause and relieve itching. The findings suggest that scratching releases serotonin – a key neurotransmitter involved in controlling pain and depression – which actually intensifies the itching sensation. The researchers believe that now that they’re armed with this new found knowledge, they might be able to break the vicious itch-scratch-more itching cycle and develop working treatments for those suffering from chronic itching.

Scratching causes more itching

scratching

Credit: honeymarkproducts.com

For decades, researchers have known that there’s a well established relationship between pain and itching. When you scratch an insect bite or wound the immediate response is pain, a sensation which is transmitted through the spinal chord to the brain and which temporarily replaces the feeling of itchiness. This is intuitive, yet now researchers have proven that this temporary relief is followed by a more itch intensive relapse caused by pain-inducing serotonin.

“The problem is that when the brain gets those pain signals, it responds by producing the neurotransmitter serotonin to help control that pain,” said Zhou-Feng Chen, PhD, director of Washington University’s Center for the Study of Itch. “But as serotonin spreads from the brain into the spinal cord, we found the chemical can ‘jump the tracks,’ moving from pain-sensing neurons to nerve cells that influence itch intensity.”

A vicious cycle: Scratching an itch causes minor pain, which prompts the brain to release serotonin. But serotonin also reacts with receptors on neurons that carry itch signals to the brain, making itching worse. Credit: WASHINGTON UNIVERSITY CENTER FOR THE STUDY OF ITCH

A vicious cycle: Scratching an itch causes minor pain, which prompts the brain to release serotonin. But serotonin also reacts with receptors on neurons that carry itch signals to the brain, making itching worse. Credit: WASHINGTON UNIVERSITY CENTER FOR THE STUDY OF ITCH

Chen and colleagues bred a strain of mice that lacked the ability to produce serotonin, then injected them with a substance that caused itching on parts of their skin. The researchers found that the engineered mice were less prone to scratch as their normal, serotonin-producing littermates. When the genetically altered mice were injected with serotonin, they scratched as mice would be expected to in response to compounds designed to induce itching.

[ALSO READ] The key to patience lies with serotonin

“So this fits very well with the idea that itch and pain signals are transmitted through different but related pathways,” said Chen, a professor of anesthesiology, of psychiatry and of developmental biology. “Scratching can relieve itch by creating minor pain. But when the body responds to pain signals, that response actually can make itching worse.”

Blocking itch receptors

itchy skin

By this point, the researchers had proven there was a clear relationship between serotonin and more itching, yet they wanted to refine the mechanism. The nerve cells in the spinal cord that specifically transmit the itch are called GRPR neurons. Whenever you scratch your skin, these neurons activate and communicate with brain neurons and Chen and team decided to isolate the receptor used by serotonin.

The team injected mice with a substance that causes itching, along with compounds that activated various serotonin receptors on nerve cells. Ultimately, they learned that a receptor known as 5HT1A was the key to activating the itch-specific GRPR neurons in the spinal cord. When a compound that blocked the receptor was given, the mice scratched less. This final insight is of the greatest importance since it offers a way to break the itch-scratch cycle. Blocking serotonin altogether is a bad idea – it’s key to our mental functioning. Blocking a specific receptor involved in itch and pain relay in the spinal chord is much more feasible, however.

“We always have wondered why this vicious itch-pain cycle occurs,” Chen said. “Our findings suggest that the events happen in this order. First, you scratch, and that causes a sensation of pain. Then you make more serotonin to control the pain. But serotonin does more than only inhibit pain. Our new finding shows that it also makes itch worse by activating GRPR neurons through 5HT1A receptors.”

Until ‘smart’ anti-scratch pills hit the market, though, you better stay clear of scratching. It will only make it worse – listen to your mom!

Sci reference: Zhao ZQ, Liu XY, Jeffry J, Karunarathne WKA, Li JL, Munanairi A, Zhou XY, Li H, Sun YG, Wan L, Wu ZY, Kim S, Huo FQ, Mo P, Barry DM, Zhang CK, Kim JY, Gautam N, Renner KJ, Li YQ, Chen ZF. Descending control of itch transmission by the serotonergic system via 5-HT1A-facilitated GRP-GRPR signaling. Neuron. vol. 84 (4), Nov. 19, 2014. Published online Oct. 30, 2014. http://dx.doi.org/10.1016/j.neuron.2014.10.003

(A) The picture on the left shows serotonin neurons in red. The middle picture shows neurons expressing light sensitive proteins in green. The picture on the right is an overlay of the previous two pictures, showing in orange light sensitive proteins selectively expressed in serotonin neurons. (B) Blue light illumination, 500 microsecond pulse, shown in blue line, induced spontaneous action potentials in the serotonin neuron for approximately 10 seconds. The yellow light illumination, 500 microsecond pulse, shown in yellow line, stopped spontaneous action potentials.

The key to patience lies within serotonin

Image: Flickr Creative Commons

Image: Flickr Creative Commons

Either when someone’s late for a date or you need to queue in line, our patience becomes tested. Some people handle the waiting better than others, leading us to the idea that patience is a virtue that differs from person to person. But what is it exactly that helps us remain patient, and why do some people remain unfazed even when faced with hours, days even of waiting? The answer might lie in serotonin – one of the most widespread neutransmitter believed to influence a variety of psychological and other body functions. An imbalance in serotonin levels, for instance, has been linked with depression.

The finding came after Japanese researchers at the  Neural Computation Unit at the Okinawa Institute of Science and Technology Graduate University used a new technique called optogenetics, where they use light to simulate specific neurons with precise timing.

Serotonin: rewarding patience

Serotonin is involved in a wide array of bodily and cognitive functions. Of the approximately 40 million brain cells, most are influenced either directly or indirectly by serotonin. This includes brain cells related to mood, sexual desire and function, appetite, sleep, memory and learning, temperature regulation, and some social behavior. In classic neuroscience, serotonin was believe to signal punishment and inhibit behaviors, however the opposite might be the case. Serotonin enriching drugs have been shown effective at treating depression, while previous optogenetic stimulation studies have shown that it’s linked with rewards. Also, research conducted by the same Japanese researchers found that inhibiting serotonin neurons causes impulsive behavior.

[ALSO READ] Scientists find brain region that helps you make up your mind

The mice who saw the light

Figure 1. Control of serotonin neural activity by light. (A) The picture on the left shows serotonin neurons in red. The middle picture shows neurons expressing light sensitive proteins in green. The picture on the right is an overlay of the previous two pictures, showing in orange light sensitive proteins selectively expressed in serotonin neurons.  (B) Blue light illumination, 500 microsecond pulse, shown in blue line, induced spontaneous action potentials in the serotonin neuron for approximately 10 seconds. The yellow light illumination, 500 microsecond pulse, shown in yellow line, stopped spontaneous action potentials.

(A) The picture on the left shows serotonin neurons in red. The middle picture shows neurons expressing light sensitive proteins in green. The picture on the right is an overlay of the previous two pictures, showing in orange light sensitive proteins selectively expressed in serotonin neurons.
(B) Blue light illumination, 500 microsecond pulse, shown in blue line, induced spontaneous action potentials in the serotonin neuron for approximately 10 seconds. The yellow light illumination, 500 microsecond pulse, shown in yellow line, stopped spontaneous action potentials. (fig. 1) Image: OIS

The researchers genetically engineered mice so that they produced light-activated molecules only in neurons that produce serotonin (fig. 1), then inserted an optical fiber in the backs of each brain. Five such mice were trained to performed a reward-delayed task, meaning they would receive a tasty treat if they waited at a hole. The game came in various stages; the mouse had to wait for 3 seconds, 6 seconds, 9 seconds or … infinity. The last stage meant that the mouse would never receive a reward – the ultimate patience test. To be sure the mice were actually patiently waiting, each mouse was trained to hold its nose in the hole while waiting for the reward. The researchers call this posture a ‘nose poke’.  Ok, let’s move further.

No prior signal was released that would notify the mice how long the waiting would be, and the waiting periods themselves were shuffled at random.

Figure 2. Effect of serotonin activation on waiting for delayed reward  The mouse easily could wait for 3 and 6 seconds to receive delayed food. When the duration was 9 seconds, the failure in waiting significantly increased. When serotonin neurons were activated with light stimulation during the 9-second delay, the number of reward wait failures significantly decreased.

Figure 2. Effect of serotonin activation on waiting for delayed reward
The mouse easily could wait for 3 and 6 seconds to receive delayed food. When the duration was 9 seconds, the failure in waiting significantly increased. When serotonin neurons were activated with light stimulation during the 9-second delay, the number of reward wait failures significantly decreased.

In half of the trials, researchers stimulated serotonin neurons by shining a light through the optical fiber while the mice were waiting. The mice had no problem waiting for 3 or 6 seconds to receive the food, but from 9 seconds onward the rodents became fed up – and it wasn’t food. When serotonin neurons were stimulated with the light, the researchers found that the failure rate over 9 seconds significantly decreased (fig. 2).

Figure 3. Effect of serotonin activation on waiting time during reward omission  In the 25% of trials, a food pellet was not presented no matter how long the mice waited. Without serotonin neuron stimulation, the mice waited 12 seconds on average. The waiting time was significantly extended to about 17.5 seconds on average with the stimulation of serotonin neurons.

Figure 3. Effect of serotonin activation on waiting time during reward omission
In the 25% of trials, a food pellet was not presented no matter how long the mice waited. Without serotonin neuron stimulation, the mice waited 12 seconds on average. The waiting time was significantly extended to about 17.5 seconds on average with the stimulation of serotonin neurons.

In 25% of the trials, the researchers really messed with the mice’s heads – the food wasn’t rewarded no matter how long they had to wait. During these trials, mice with no serotonin stimulation waited on average 12.0 seconds, while those with serotonin neuron optical stimulation waited on average 17.5 seconds (fig. 3). For control purposes, the researchers were careful to shine light in serotonin neurons at different timing when the mouse did not have its nose poked in the food hole. They found that these mice behaved the same as in unstimulated cases. This suggests that serotonin doesn’t inhibit motor functions and, at the same time, that serotonin neurons promotes patience for delayed rewards.

“Our previous studies have shown that serotonin levels increase when waiting for delayed rewards. We have also shown that inhibiting serotonin neurons leads to an inability to wait for a long time,” explained Drs. Kayoko Miyazaki and Katsuhiko Miyazaki. “By using light to stimulate neurons at specific times, this study has proven serotonin’s role in patience during delayed reward waiting, underlining serotonin’s much greater role than previously thought.”

 

By further exploring the effect of serotonin, the researchers hope to decipher the neuronal network behind mental disorders and behaviors involving serotonin. Findings appeared in the journal Current Biology.

Bacteria can make you happier AND smarter

Mycobacterium vaccae is a type of bacteria that naturally leaves in soil and has been in the attention of researchers for a while now, due to the fact that it decreases anxiety. Recent studies sugest that in fact, it also stimulates neuron growth and thus intelligence and the ability to learn.

smart-mouseDorothy Matthews and Susan Jenks from The Sage Colleges in Troy, New York believed this bacteria could have a beneficial impact on neurons too, and injected the bacteria in mice which, at first, led to a significantly increased serotonin production. However, researchers were interested in a more indirect effect.

“Since serotonin plays a role in learning we wondered if live M. vaccae could improve learning in mice.”

In order to assess this assumption, they took two groups and injected only one of them with the bacteria, and then tested them in a maze. The difference was easy to notice.

“We found that mice that were fed live M. vaccae navigated the maze twice as fast and with less demonstrated anxiety behaviors as control mice.”

The mice were then tested after the bacteria was removed from their organisms. When they were tested immediatly afterward, they still did better than their counterparts, but not as good as the first time. Three weeks later, they were tested again. The results were still slightly better, but not statistically relevant. This seems to suggest that the boost to learning is of temporary nature, but applied to humans with a greater cognitive capacity, the results might be more spectacular.

“This research suggests that M. vaccae may play a role in anxiety and learning in mammals. It is interesting to speculate that creating learning environments in schools that include time in the outdoors where M. vaccae is present may decrease anxiety and improve the ability to learn new tasks.”