Solving a biological puzzle: How stress causes gray hair

Scientists uncover link between the nervous system and stem cells that regenerate pigment

January 22, 2020

Science Daily/Harvard University

Scientists have found evidence to support long-standing anecdotes that stress causes hair graying. Researchers found that in mice, the type of nerve involved in the fight-or-flight response causes permanent damage to the pigment-regenerating stem cells in the hair follicle. The findings advance knowledge of how stress impacts the body, and are a first step toward blocking its negative effects.

When Marie Antoinette was captured during the French Revolution, her hair reportedly turned white overnight. In more recent history, John McCain experienced severe injuries as a prisoner of war during the Vietnam War -- and lost color in his hair.

For a long time, anecdotes have connected stressful experiences with the phenomenon of hair graying. Now, for the first time, Harvard University scientists have discovered exactly how the process plays out: stress activates nerves that are part of the fight-or-flight response, which in turn cause permanent damage to pigment-regenerating stem cells in hair follicles.

The study, published in Nature, advances scientists' knowledge of how stress can impact the body.

"Everyone has an anecdote to share about how stress affects their body, particularly in their skin and hair -- the only tissues we can see from the outside," said senior author Ya-Chieh Hsu, the Alvin and Esta Star Associate Professor of Stem Cell and Regenerative Biology at Harvard. "We wanted to understand if this connection is true, and if so, how stress leads to changes in diverse tissues. Hair pigmentation is such an accessible and tractable system to start with -- and besides, we were genuinely curious to see if stress indeed leads to hair graying. "

Narrowing down the culprit

Because stress affects the whole body, researchers first had to narrow down which body system was responsible for connecting stress to hair color. The team first hypothesized that stress causes an immune attack on pigment-producing cells. However, when mice lacking immune cells still showed hair graying, researchers turned to the hormone cortisol. But once more, it was a dead end.

"Stress always elevates levels of the hormone cortisol in the body, so we thought that cortisol might play a role," Hsu said. "But surprisingly, when we removed the adrenal gland from the mice so that they couldn't produce cortisol-like hormones, their hair still turned gray under stress."

After systematically eliminating different possibilities, researchers honed in on the sympathetic nerve system, which is responsible for the body's fight-or-flight response.

Sympathetic nerves branch out into each hair follicle on the skin. The researchers found that stress causes these nerves to release the chemical norepinephrine, which gets taken up by nearby pigment-regenerating stem cells.

Permanent damage

In the hair follicle, certain stem cells act as a reservoir of pigment-producing cells. When hair regenerates, some of the stem cells convert into pigment-producing cells that color the hair.

Researchers found that the norepinephrine from sympathetic nerves causes the stem cells to activate excessively. The stem cells all convert into pigment-producing cells, prematurely depleting the reservoir.

"When we started to study this, I expected that stress was bad for the body -- but the detrimental impact of stress that we discovered was beyond what I imagined," Hsu said. "After just a few days, all of the pigment-regenerating stem cells were lost. Once they're gone, you can't regenerate pigment anymore. The damage is permanent."

The finding underscores the negative side effects of an otherwise protective evolutionary response, the researchers said.

"Acute stress, particularly the fight-or-flight response, has been traditionally viewed to be beneficial for an animal's survival. But in this case, acute stress causes permanent depletion of stem cells," said postdoctoral fellow Bing Zhang, the lead author of the study.

Answering a fundamental question

To connect stress with hair graying, the researchers started with a whole-body response and progressively zoomed into individual organ systems, cell-to-cell interaction and, eventually, all the way down to molecular dynamics. The process required a variety of research tools along the way, including methods to manipulate organs, nerves, and cell receptors.

"To go from the highest level to the smallest detail, we collaborated with many scientists across a wide range of disciplines, using a combination of different approaches to solve a very fundamental biological question," Zhang said.

The collaborators included Isaac Chiu, assistant professor of immunology at Harvard Medical School who studies the interplay between nervous and immune systems.

"We know that peripheral neurons powerfully regulate organ function, blood vessels, and immunity, but less is known about how they regulate stem cells," Chiu said.

"With this study, we now know that neurons can control stem cells and their function, and can explain how they interact at the cellular and molecular level to link stress with hair graying."

The findings can help illuminate the broader effects of stress on various organs and tissues. This understanding will pave the way for new studies that seek to modify or block the damaging effects of stress.

"By understanding precisely how stress affects stem cells that regenerate pigment, we've laid the groundwork for understanding how stress affects other tissues and organs in the body," Hsu said. "Understanding how our tissues change under stress is the first critical step towards eventual treatment that can halt or revert the detrimental impact of stress. We still have a lot to learn in this area."

https://www.sciencedaily.com/releases/2020/01/200122135313.htm

Rich rewards: Scientists reveal ADHD medication's effect on the brain

Researchers scan the brain to uncover how medication for ADHD affects the brain's reward system

January 17, 2020

Science Daily/Okinawa Institute of Science and Technology (OIST) Graduate University

Researchers have identified how certain areas of the human brain respond to methylphenidate -- a stimulant drug which is used to treat symptoms of ADHD. The work may help researchers understand the precise mechanism of the drug and ultimately develop more targeted medicines for the condition.

Attention-deficit hyperactivity disorder (ADHD) is a neurobiological disorder characterized by symptoms of hyperactivity, inattention and impulsivity. People with the condition are often prescribed a stimulant drug called methylphenidate, which treats these symptoms. However, scientists do not fully understand how the drug works.

Now, researchers at the Okinawa Institute of Science and Technology Graduate University (OIST) have identified how certain areas of the human brain respond to methylphenidate. The work may help researchers understand the precise mechanism of the drug and ultimately develop more targeted medicines for the condition.

Previous research suggests that people with ADHD have different brain responses when anticipating and receiving rewards, compared to individuals without ADHD. Scientists at OIST have proposed that in those with ADHD, neurons in the brain release less dopamine -- a 'feel-good' neurotransmitter involved in reward-motivated behavior -- when a reward is expected, with dopamine neurons firing more when a reward is given.

"In practice, what this means is that children, or even young adults, with ADHD may have difficulty engaging in behavior that doesn't result in an immediate positive outcome. For example, children may struggle to focus on schoolwork, as it may not be rewarding at the time, even though it could ultimately lead to better grades. Instead, they get distracted by external stimuli that are novel and interesting, such as a classmate talking or traffic noises," said Dr Emi Furukawa, first author of the study and a researcher in the OIST Human Developmental Neurobiology Unit, led by Professor Gail Tripp.

Scientists believe that methylphenidate helps people with ADHD maintain focus by influencing dopamine availability in the brain. Therefore, Dr Furukawa and her colleagues set out to examine how the drug affects a brain region called the ventral striatum, which is a vital component of the reward system and where dopamine is predominantly released.

"We wanted to take a look at how methylphenidate affects the ventral striatum's responses to reward cues and delivery," said Furukawa.

The study, which was recently published in the journal Neuropharmacology, was jointly conducted with scientists at D'Or Institute for Research and Education (IDOR) in Rio de Janeiro, Brazil. The collaboration allowed the researchers to combine expertise across multiple disciplines and provided access to IDOR's functional magnetic resonance imaging (fMRI) facility.

Delving into the brain

The researchers used fMRI to measure brain activity in young adults with and without ADHD as they played a computer game that simulated a slot machine. The researchers scanned individuals in the ADHD group on two separate occasions -- once when they took methylphenidate and another time when they took a placebo pill. Each time the reels of the slot machine spun, the computer also showed one of two cues, either the Japanese character み (mi) or そ (so). While familiarizing themselves with the game before being scanned, the participants quickly learned that when the slot machine showed み, they often won money, but when the slot machine showed そ, they didn't. The symbol み therefore acted as a reward-predicting cue, whereas そ acted as a non-reward-predicting cue.

The researchers found that when individuals with ADHD took the placebo, neuronal activity in the ventral striatum was similar in response to both the reward predicting and non-reward predicting cue. However, when they took methylphenidate, activity in the ventral striatum increased only in response to the reward cue, showing that they were now able to more easily discriminate between the two cues.

The researchers also explored how neuronal activity in the striatum correlated with neuronal activity in the medial prefrontal cortex -- a brain region involved in decision-making that receives information from the outside world and communicates with many parts of the brain, including the striatum.

When the individuals with ADHD took placebo instead of methylphenidate, neuronal activity in the striatum correlated strongly with activity in the prefrontal cortex at the exact moment the reward was delivered, and the participants received money from the slot machine game. Therefore, the researchers believe that in people with ADHD, the striatum and the prefrontal cortex communicate more actively, which may underline their increased sensitivity to rewarding external stimuli. In participants who took methylphenidate, this correlation was low, as it was in people without ADHD.

The results implicate a second neurotransmitter, norepinephrine, in the therapeutic effects of methylphenidate. Norepinephrine is released by a subset of neurons common in the prefrontal cortex. Researchers speculate that methylphenidate might boost levels of norepinephrine in the prefrontal cortex, which in turn regulates dopamine firing in the striatum when rewards are delivered.

"It's becoming clear to us that the mechanism by which methylphenidate modulates the reward response is very complex," said Furukawa.

Tailoring New Therapies for ADHD

Despite the complexity, the scientists believe that further research could elucidate methylphenidate's mechanism of action, which could benefit millions of people worldwide.

Pinning down how methylphenidate works may help scientists develop better therapies for ADHD, said Furukawa. "Methylphenidate is effective but has some side effects, so some people are hesitant to take the medication or give it to their children," she explained. "If we can understand what part of the mechanism results in therapeutic effects, we could potentially develop drugs that are more targeted."

Furukawa also hopes that understanding how methylphenidate impacts the brain could help with behavioral interventions. For example, by keeping in mind the difference in brain responses when children with ADHD anticipate and receive rewards, parents and teachers could instead help children with ADHD stay focused by praising them frequently and reducing the amount of distracting stimuli in the environment.

https://www.sciencedaily.com/releases/2020/01/200117100257.htm

The night gardeners: Immune cells rewire, repair brain while we sleep

October 21, 2019

Science Daily/University of Rochester Medical Center

Science tells us that a lot of good things happen in our brains while we sleep -- learning and memories are consolidated and waste is removed, among other things. New research shows for the first time that important immune cells called microglia -- which play an important role in reorganizing the connections between nerve cells, fighting infections, and repairing damage -- are also primarily active while we sleep.

The findings, which were conducted in mice and appear in the journal Nature Neuroscience, have implications for brain plasticity, diseases like autism spectrum disorders, schizophrenia, and dementia, which arise when the brain's networks are not maintained properly, and the ability of the brain to fight off infection and repair the damage following a stroke or other traumatic injury.

"It has largely been assumed that the dynamic movement of microglial processes is not sensitive to the behavioral state of the animal," said Ania Majewska, Ph.D., a professor in the University of Rochester Medical Center's (URMC) Del Monte Institute for Neuroscience and lead author of the study. "This research shows that the signals in our brain that modulate the sleep and awake state also act as a switch that turns the immune system off and on."

Microglia serve as the brain's first responders, patrolling the brain and spinal cord and springing into action to stamp out infections or gobble up debris from dead cell tissue. It is only recently that Majewska and others have shown that these cells also play an important role in plasticity, the ongoing process by which the complex networks and connections between neurons are wired and rewired during development and to support learning, memory, cognition, and motor function.

In previous studies, Majewska's lab has shown how microglia interact with synapses, the juncture where the axons of one neuron connects and communicates with its neighbors. The microglia help maintain the health and function of the synapses and prune connections between nerve cells when they are no longer necessary for brain function.

The current study points to the role of norepinephrine, a neurotransmitter that signals arousal and stress in the central nervous system. This chemical is present in low levels in the brain while we sleep, but when production ramps up it arouses our nerve cells, causing us to wake up and become alert. The study showed that norepinephrine also acts on a specific receptor, the beta2 adrenergic receptor, which is expressed at high levels in microglia. When this chemical is present in the brain, the microglia slip into a sort of hibernation.

The study, which employed an advanced imaging technology that allows researchers to observe activity in the living brain, showed that when mice were exposed to high levels of norepinephrine, the microglia became inactive and were unable to respond to local injuries and pulled back from their role in rewiring brain networks.

"This work suggests that the enhanced remodeling of neural circuits and repair of lesions during sleep may be mediated in part by the ability of microglia to dynamically interact with the brain," said Rianne Stowell, Ph.D. a postdoctoral associate at URMC and first author of the paper. "Altogether, this research also shows that microglia are exquisitely sensitive to signals that modulate brain function and that microglial dynamics and functions are modulated by the behavioral state of the animal."

The research reinforces to the important relationship between sleep and brain health and could help explain the established relationship between sleep disturbances and the onset of neurodegenerative conditions like Alzheimer's and Parkinson's.

https://www.sciencedaily.com/releases/2019/10/191021111835.htm