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Bringing Out the Best in Us During the Pandemic

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Pablo Vidal-Ribas Belil at the grocery store
Caption: Pablo Vidal-Ribas visiting a supermarket to pick up groceries for four neighbors. Credit: Pablo Vidal-Ribas

Sheltering at home for more than two months has made many of us acutely aware of just how much we miss getting out and interacting with other human beings. For some, the coronavirus disease 2019 (COVID-19) pandemic has also triggered a more selfless need: to be a good neighbor to the most vulnerable among us and help them stay well, both mentally and physically, during this trying time.

The term “good neighbor” definitely applies to Pablo Vidal-Ribas Belil, a postdoctoral fellow at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Though Vidal-Ribas has his hands full caring for his 4-year-old son in their condo, which is located near NIH’s main campus in Bethesda, MD, he wasn’t too busy to notice that some of his neighbors were in need of help.

Vidal-Ribas extended a helping hand to pick up groceries and prescriptions for the older woman downstairs, as well as several more of his elderly neighbors. He and other concerned neighbors also began enlisting more volunteers to join a neighborhood coronavirus task force. There are now up to 30 volunteers and sometimes hold virtual meetings.

To try to reach everyone in the more than 950-unit Parkside Condominium community, the group coordinated its activities with the help of the management office. They also issued flyers and email messages via the neighborhood list serv, offering to assist people at greatest risk for COVID-19, including seniors and those with compromised immune systems or other serious conditions, by shopping for essential items and dropping the items off at their doors.

The personal interest and care of Vidal-Ribas also comes with medical expertise: he’s a clinical psychologist by training. Vidal-Ribas, who is originally from Barcelona, Spain, came to the United States four years ago to work with an NIH lab that specializes in the study of depression and related conditions in young people. Last year, Vidal-Ribas moved to NICHD as a Social and Behavioral Sciences Branch Fellow, where he now works with Stephen Gilman. There, he explores prenatal and early developmental factors that contribute to attempts at suicide later in life.

His expertise as a psychologist has come in handy. Vidal-Ribas has found that many of the individuals requesting help with grocery items or prescriptions also want to talk. So, the team’s efforts go a long way toward providing not only basic necessities, but also much-needed social and emotional support.

In recognition of this need, the group has expanded to offer virtual chats and other community activities, such as physically distanced games, conversations, or story times. One talented young volunteer has even offered to give music concerts remotely by request. Folks know they can call on Vidal-Ribas and some of the most active task force volunteers at any time.

Vidal-Ribas reports that they’ve taken great care to follow the latest guidelines from the Centers for Disease Control and Prevention on how to protect yourself and others from COVID-19 to ensure that those volunteering their time do so safely. He and other volunteers typically buy for multiple neighbors at once while they do their own personal shopping to reduce the number of outings. They then leave the bags with groceries or prescriptions at their neighbors’ doors with no direct contact. As far as he knows, none of his vulnerable neighbors have come down with COVID-19.

Vidal-Ribas says he’s prepared to continue his volunteer outreach for as long as it takes. And, even when the threat of COVID-19 subsides, he’ll keep on lending a hand to his neighbors. It’s one of the ways he stays connected to his community and grounded within himself during this difficult time. By sharing his story, he hopes it will inspire others to do what they can to help others in need to stay safe and well.

Links:

Coronavirus (COVID-19) (NIH)

Social and Behavioral Sciences Branch Fellows (National Institute of Child Health and Human Development/NIH)

Stephen Gilman ((National Institute of Child Health and Human Development/NIH)


COVID-19 Brings Health Disparities Research to the Forefront

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Zoom conversation between Francis Collins and Eliseo Perez-Stable

The coronavirus 2019 (COVD-19) pandemic has brought into sharp focus many of the troubling things that we already knew about health disparities in the United States but have failed to address. With the bright light now shining on this important issue, it is time to talk about the role research can play in reducing the disproportionate burden of COVID-19, as well as improving the health of all people in our great nation. 

In recent weeks, we’ve seen a growing list of disturbing statistics about how blacks, Hispanics, tribal communities, and some other racial, ethnic, and disadvantaged socioeconomic groups are bearing the brunt of COVID-19. One of the latest studies comes from a research team that analyzed county-by-county data gathered about a month ago. Their findings? The 22 percent of U.S. counties that are disproportionately black accounted for 52 percent of our nation’s COVID-19 cases and 58 percent of COVID-19 deaths. In a paper awaiting peer review, the team, led by Emory University, Atlanta, and amfAR, the Foundation for AIDS Research, Washington, DC., noted that neither the size of the county nor whether it was urban or rural mattered [1].

Recently, I had an opportunity to discuss the disparate burden of COVID-19 with Dr. Eliseo Pérez-Stable, Director of NIH’s National Institute on Minority Health and Health Disparities (NIMHD). Besides leading an institute, Dr. Pérez-Stable is a widely recognized researcher who studies various factors that contribute to health disparities. Our conversation took place via videoconferencing, with him linking in from his home in Washington, D.C., and me from my home in nearby Maryland. Here’s a condensed transcript of our chat:

Collins: Eliseo, you and I recently had a chance to have a pretty intense discussion with the Congressional Black Caucus about health disparities and the COVID-19 pandemic. So, could you start off with a little bit about what populations are being hit hardest?

Pérez-Stable: Collecting data about disease incidence and mortality on the basis of race and ethnicity and other important demographic factors, like socioeconomic status, had really been absent in this pandemic until recently.

Part of that I think is entirely understandable. Hospitals were pressed with a surge of very sick patients, and there was a certain amount of fear and panic in the community. So, people were not completing all these forms that usually get turned in to the health departments and then forwarded to the CDC. If you go back in history, similar things happened in the early 1980s with the HIV epidemic. We weren’t collecting data on race and other sociodemographic variables initially. But, with time, we did complete these data and a picture emerged.

With the COVID-19 pandemic, obviously, the outcomes are much faster, with over 60,000 deaths in just a matter of three months. And we started to see reports, initially out of Connecticut, Milwaukee, Chicago, and New Orleans, that African Americans were dying at a disproportionate rate.

Now, the initial—and I think still the most likely—explanation for this higher mortality relates to two factors. The first is a higher rate of co-morbidities. We know that if you have cardiovascular disease, more than mild obesity, or diabetes, you’re more likely to get severe COVID-19 and potentially die from it. So, we could have just said, “Aha! It’s obvious why this population, and others with higher rates of co-morbidities might be expected to have higher rates of severe disease and higher mortality.”

But there is a second factor that relates to getting infected, for which we have much-less clear data. There was recently a map in The Washington Post showing the distribution of the rate of COVID-19 infections in Washington, D.C., by ward. The highest rates are in the wards that are east of the Anacostia River, which are about 90 percent African American. So, there is an appearance of a correlation between the proportion of African Americans in the community and the rate of Covid-19 infection. Now why could that be?

Collins: Yes, what explains that?

Pérez-Stable: Well, I think crowding is part of it, certainly in this neighborhood. A second option would be multiple families living under one roof.

Collins: So, you can’t exactly practice physical distancing very well in that situation.

Pérez-Stable:  Absolutely. You and I can go into our respective rooms, probably have our respective bathrooms, and socially and physically isolate from the rest of the household if need be. Many people can’t do that. They have three generations in one small apartment, all using one bathroom, maybe two bedrooms for six or eight people.

So, we do face different conditions by which one casual infection can lead to much more community transmission. But much information still needs to be ascertained and there does seem to be some regional variance. For example, in Chicago, Milwaukee, and Atlanta, the reports, at least initially, are worse than they are in Connecticut or Florida. Also, New York City, which has been the epicenter of the U.S. for this pandemic, has an increased rate of infections and mortality among Latino-Hispanic populations as well. So, it isn’t isolated to an African-American issue.

Collins: What about access to healthcare?

Pérez-Stable: Again, we can postulate based on a little bit of anecdote and a little bit of data. I’m a general internist by background, and I can see the enormous impact this pandemic has had on healthcare settings.

First, elective ambulatory visits and elective admissions to the hospital have been postponed, delayed, or cancelled. About 90 percent of ambulatory care is occurring through telemedicine or telephone connections, so in-person visits are occurring only for really urgent matters or suspected COVID-19.

If you have health insurance and can use systems, you can probably, through telephone triage with a nurse, get either approval or nonapproval for being tested [for COVID-19], drive to a place, get tested by someone wearing protective equipment, and never actually have to visit with anyone. And you’ll get your result now back as soon as one day, depending on the system. Now, if you’re insured, but don’t really know how to use systems, navigating all these things can be a huge challenge. So, that could be a factor.

People are also afraid to come to clinic, they’re afraid to show up at the emergency room, because they’re afraid to get infected. So, they’re worried about going in, unless they get very sick.  And when they get very sick, they may be coming in with more advanced cases [of COVID-19].

So, telephone triage, advice from clinicians on the phone, is critical. We are seeing some doctors base their decisions on whether a person is able to breathe okay on the phone, able to say a whole sentence without catching their breath. These kinds of basic things that we learned in clinical medicine training are coming into play in a big way now, because we just cannot provide the kind of care, even in the best of circumstances, that people may need.

Of course, uninsured patients will have even more barriers, although everyone in the healthcare system is trying their best to help patients when they need to be helped, rather than depend on insurance triage.

Collins: A big part of trying to keep the disease from spreading has been access to testing so that people, even those with mild symptoms, can find out if they have this virus and, if so, quarantine and enable public health workers to check out their contacts. I’m guessing, from what you said, that testing has been happening a lot less in urban communities that are heavily populated by African Americans and that further propagates the spread of the disease. Am I right?

Pérez-Stable: So far, most testing has been conducted on the basis of symptoms. So, if you have enough symptoms that you may potentially need to be hospitalized, then you get tested. Also, if you’re a healthcare worker who had contact with a COVID-19 patient, you might be tested, or if there’s someone you’ve been very close to that was infected, you may be tested. So, I don’t think so much it’s a matter of disproportionate access to testing by one group or another, as much as that the overall triage and selection criteria for testing have been rather narrow. Up until now, it has not been a simple process to get tested for COVID-19. As we scale up and get better point-of-care tests and much easier access to getting tested, I think you’ll see dissemination across the board.

Collins: It’s interesting we’re talking about this, because this is an area that Congress recently came to NIH and said, “We want you to do something about the testing by encouraging more technology, particularly technology that can be distributed to the point-of-care, and that is out in the community.”

Everyone wants a test that gives you a quick turnaround, an answer within an hour, instead of maybe a day or two. A big part of what NIH is trying to do is to make sure that if we’re going to develop these new testing technologies, they get deployed in places that otherwise might not have much access to testing—maybe by working through the community health centers. So, we’re hoping we might be able to make a contribution there.

Pérez-Stable: The economic factors in this pandemic are also huge. A significant proportion of the population that we’re referring to—the disparity population, the minorities, the poor people—work in service jobs where they’re on the front line. They were the restaurant servers and people in the kitchen, they’re still the bus drivers and the Uber drivers, and those who are working in pharmacies and supermarkets.

On the one hand, they are at higher risk for getting infected because they’re in more contact with people. On the other hand, they’re really dependent on this income to maintain their household. So, if they test positive or get exposed to COVID-19, we really do have a challenge when we ask them to quarantine and not go to work. They’re not in a position where they have sick leave, and they may be putting themselves at risk for being laid off.

Collins: Eliseo, you’ve been studying health disparities pretty much your whole research career. You come from a community where health disparities are a reality, having been born in Cuba and being part of the Latino community. Did you expect that COVID-19 would be this dramatic in the ways in which it has so disproportionately affected certain groups?

Pérez-Stable: I can’t say that I did. My first thought as a physician was to ask: “Is there any reason to think that an infectious agent like COVID-19 would disproportionally infect or impact any population?” My gut answer was “No.” Infectious diseases usually seem to affect all people; sort of equal opportunity invaders. There are some data that would say that influenza and pneumonia are not any worse among African Americans or Latinos than among whites. There are some slight differences in some regions, but not much.

Yet I know this a question that NIH-funded scientists are interested in addressing. We need to make sure that there aren’t any particular susceptibility factors, possibly related to genetics or the lung epithelium, that lead to such different COVID-19 outcomes in different individuals. Clearly, something must be going on, but we don’t know what that is. Maybe one of those factors tracks through race or ethnicity because of what those social constructs represent.

I recently listened to a presentation by Rob Califf, former FDA Commissioner, who spoke about how the pandemic has created a spotlight on our disparities-creating system. I think much of the time this disparities-creating system is in the background; it doesn’t really affect most people’s daily lives. Now, we’re suddenly hit with a bucket of cold water called COVID-19, and we’re saying what is going on and what can we do about it to make a difference. I hope that, once we begin to emerge from this acute crisis, we take the opportunity to address these fundamental issues in our society.

Collins: Indeed. Let’s talk about what you’re doing at NIMHD to support research to try to dig into both the causes of health disparities and the interventions that might help.

Pérez-Stable: Prompted by your motivation, we started talking about how minority health and health disparities research could respond to this pandemic. In the short-term, we thought along the lines of how can we communicate mitigation interventions, such as physical distancing, in a more effective way to our communities? We also asked what we could do to enhance access to healthcare for our populations, both to manage chronic conditions and for diagnosis and treatment of acute COVID-19.

We also considered in the mid- and long-term effects of economic disruption—this surge of unemployment, loss of jobs, loss of insurance, loss of income—on people’s health. Worries include excess use of alcohol and other substances, and worsening of mental and emotional well-being, particularly due to severe depression and chronic mental disorders not being well controlled. Intimate partner violence has already been noted to increase in some countries, including France, Spain, and the United States, that have gone on physical distancing interventions. Similarly, child abuse can be exacerbated under these circumstances. Just think of 24/7 togetherness as a test of how people can hold it together all the time. I think that that can bring out some fragility. So, interventions to address these, that really activate our community networks and community-based organizations, are real strengths. They build on the resilience of the community to highlight how we can get through this difficult period of time.

I feel optimistic that science will bring answers, in the form of both therapies and vaccines. But in the meantime, we have a way to go and we a lot to do.  

Collins: You mentioned the promise of vaccines. The NIH is working intensively on this, particularly through a partnership called ACTIV, Accelerating Covid-19 Therapeutic Interventions and Vaccines. We hope that in several more months, we’ll be in a position to begin testing these vaccines on a large scale, after having some assurances about their safety and efficacy. From our conversation, it sounds like we should be trying to get early access to those vaccines to people at highest risk, including those in communities with the heaviest burden. But how will that be received? There hasn’t always been an easy relationship between researchers, particularly government researchers, and the African-American community.

Pérez-Stable: I think we have learned from our historical experiences that mistrust of the system is real. To try to pretend that it isn’t there is a big mistake. Address these concerns upfront, obtain support from thought leaders in the community, and really work hard to be inclusive. In addition to vaccines, we need participation in any clinical trials that are coming up for therapeutics.

We also need research on how optimally to communicate this with all the different segments of the population. This includes not just explaining what it means to be eligible for vaccine trials or therapeutic trials, but also discussing the consequences of, say, getting tested, whether it be a viral or antibody test. What does the information mean for them?  

Most people just want to know “Am I clear of the virus or not?” That certainly could be part of the answer, but many may require more nuanced responses. Then there’s behavior. If I’m infected and I recover, am I safe to go back out and do things that other people shouldn’t do? We’d love to be able to inform the population about that. But, as you know, we don’t really have the answers to that just yet.

Collins: Good points. How do we make sure, when we’re trying to reach out to populations that have shouldered such a heavy burden, that we’re actually providing information in a fashion that is readily understood?

Pérez-Stable:  One thing to keep in mind is the issue of language. About 5 to 10 percent of U.S. adults don’t speak English well. So, we really have to address the language barrier. I also want to highlight the challenge that some tribal nations are facing. Navajo country has had particular challenges with COVID-19 infections in a setting of minimal medical infrastructure. In fact, there are communities that have to go and get their water for the day at a distant site, so they don’t have modern plumbing. How can we recommend frequent hand washing to someone who doesn’t even have running water at home? These are just a few examples of the diversity of our country that need to be addressed as we deal with this pandemic.

Collins:  Eliseo, you’ve given us a lot to think about in an obviously very serious situation. Anything you’d like to add?

Pérez-Stable:  In analyzing health outcomes, researchers often think about responses related to a metabolic pathway or to a gene or to a response to a particular drug. But as we use the power of science to understand and contain the COVID-19 pandemic, I’d like to re-emphasize the importance of considering race, ethnicity, socioeconomic status, the built environment, the social environment, and systems. Much of the time these factors may only play secondary roles, but, as in all science related to humans, I think they have to be considered. This experience should be a lesson for us to learn more about that.

Collins: Thank you for those wonderful, inspiring words. It was good to have this conversation, Eliseo, because we are the National Institutes of Health, but that has to be health for everybody. With COVID-19, we have an example where that has not turned out to be the case. We need to do everything we can going forward to identify ways to change that.

Reference:

[1] Assessing Differential Impacts of COVID-19 on Black Communities. Millet GA et al. MedRxiv. Preprint posted on May 8, 2020.

Links:

Video: Francis Collins and Eliseo Pérez-Stable on COVID-19 Health Disparities (NIH)

Coronavirus (COVID-19) (NIH)

Director’s Corner (National Institute on Minority Health and Disparities/NIH)

COVID-19 and Racial/Ethnic Disparities. Webb Hooper M, Nápoles AM, Pérez-Stable EJ.JAMA. 2020 May 11.

amfAR Study Shows Disproportionate Impact of COVID-19 on Black Americans, amfAR News Release, May 5, 2020.



A Neuronal Light Show

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Credit: Chen X, Cell, 2019

These colorful lights might look like a video vignette from one of the spectacular evening light shows taking place this holiday season. But they actually aren’t. These lights are illuminating the way to a much fuller understanding of the mammalian brain.

The video features a new research method called BARseq (Barcoded Anatomy Resolved by Sequencing). Created by a team of NIH-funded researchers led by Anthony Zador, Cold Spring Harbor Laboratory, NY, BARseq enables scientists to map in a matter of weeks the location of thousands of neurons in the mouse brain with greater precision than has ever been possible before.

How does it work? With BARseq, researchers generate uniquely identifying RNA barcodes and then tag one to each individual neuron within brain tissue. As reported recently in the journal Cell, those barcodes allow them to keep track of the location of an individual cell amid millions of neurons [1]. This also enables researchers to map the tangled paths of individual neurons from one region of the mouse brain to the next.

The video shows how the researchers read the barcodes. Each twinkling light is a barcoded neuron within a thin slice of mouse brain tissue. The changing colors from frame to frame correspond to one of the four letters, or chemical bases, in RNA (A=purple, G=blue, U=yellow, and C=white). A neuron that flashes blue, purple, yellow, white is tagged with a barcode that reads GAUC, while yellow, white, white, white is UCCC.

By sequencing and reading the barcodes to distinguish among seemingly identical cells, the researchers mapped the connections of more than 3,500 neurons in a mouse’s auditory cortex, a part of the brain involved in hearing. In fact, they report they’re now able to map tens of thousands of individual neurons in a mouse in a matter of weeks.

What makes BARseq even better than the team’s previous mapping approach, called MAPseq, is its ability to read the barcodes at their original location in the brain tissue [2]. As a result, they can produce maps with much finer resolution. It’s also possible to maintain other important information about each mapped neuron’s identity and function, including the expression of its genes.

Zador reports that they’re continuing to use BARseq to produce maps of other essential areas of the mouse brain with more detail than had previously been possible. Ultimately, these maps will provide a firm foundation for better understanding of human thought, consciousness, and decision-making, along with how such mental processes get altered in conditions such as autism spectrum disorder, schizophrenia, and depression.

Here’s wishing everyone a safe and happy holiday season. It’s been a fantastic year in science, and I look forward to bringing you more cool NIH-supported research in 2020!

References:

[1] High-Throughput Mapping of Long-Range Neuronal Projection Using In Situ Sequencing. Chen X, Sun YC, Zhan H, Kebschull JM, Fischer S, Matho K, Huang ZJ, Gillis J, Zador AM. Cell. 2019 Oct 17;179(3):772-786.e19.

[2] High-Throughput Mapping of Single-Neuron Projections by Sequencing of Barcoded RNA. Kebschull JM, Garcia da Silva P, Reid AP, Peikon ID, Albeanu DF, Zador AM. Neuron. 2016 Sep 7;91(5):975-987.

Links:

Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)

Zador Lab (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY)

NIH Support: National Institute of Neurological Disorders and Stroke; National Institute on Drug Abuse; National Cancer Institute


The Amazing Brain: Deep Brain Stimulation

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A composite image of neurostimulation
Credit: Andrew Janson, Butson Lab, University of Utah

August is here, and many folks have plans to enjoy a well-deserved vacation this month. I thought you might enjoy taking a closer look during August at the wonder and beauty of the brain here on my blog, even while giving your own brains a rest from some of the usual work and deadlines.

Some of the best imagery—and best science—comes from the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, a pioneering project aimed at revolutionizing our understanding of the human brain. Recently, the BRAIN Initiative held a “Show Us Your Brain Contest!”, which invited researchers involved in the effort to submit their coolest images. So, throughout this month, I’ve decided to showcase a few of these award-winning visuals.

Let’s start with the first-place winner in the still-image category. What you see above is an artistic rendering of deep brain stimulation (DBS), an approach now under clinical investigation to treat cognitive impairment that can arise after a traumatic brain injury and other conditions.

The vertical lines represent wire leads with a single electrode that has been inserted deep within the brain to reach a region involved in cognition, the central thalamus. The leads are connected to a pacemaker-like device that has been implanted in a patient’s chest (not shown). When prompted by the pacemaker, the leads’ electrode emits electrical impulses that stimulate a network of neuronal fibers (blue-white streaks) involved in arousal, which is an essential component of human consciousness. The hope is that DBS will improve attention and reduce fatigue in people with serious brain injuries that are not treatable by other means.

Andrew Janson, who is a graduate student in Christopher Butson’s NIH-supported lab at the Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, composed this image using a software program called Blender. It’s an open-source, 3D computer graphics program often used to create animated films or video games, but not typically used in biomedical research. That didn’t stop Janson.

With the consent of a woman preparing to undergo experimental DBS treatment for a serious brain injury suffered years before in a car accident, Janson used Blender to transform her clinical brain scans into a 3D representation of her brain and the neurostimulation process. Then, he used a virtual “camera” within Blender to capture the 2D rendering you see here. Janson plans to use such imagery, along with other patient-specific modeling and bioelectric fields simulations, to develop a virtual brain stimulation surgery to predict the activation of specific fiber pathways, depending upon lead location and stimulation settings.

DBS has been used for many years to relieve motor symptoms of certain movement disorders, including Parkinson’s disease and essential tremor. More recent experimental applications include this one for traumatic brain injury, and others for depression, addiction, Alzheimer’s disease, and chronic pain. As the BRAIN Initiative continues to map out the brain’s complex workings in unprecedented detail, it will be exciting to see how such information can lead to even more effective applications of to DBS to help people living with a wide range of neurological conditions.

Links:

Deep Brain Stimulation for Movement Disorders (National Institute of Neurological Disorders and Stroke/NIH)

Video: Deep Brain Stimulation (University of Utah, Salt Lake City)

Deep Brain Stimulation for the Treatment of Parkinson’s Disease and Other Movement Disorders (NINDS/NIH)

Butson Lab (University of Utah)

Show Us Your Brain! (BRAIN Initiative/NIH)

Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)

NIH Support: National Institute of Neurological Disorders and Stroke


Mood-Altering Messenger Goes Nuclear

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Serotonin

Serotonin is best known for its role as a chemical messenger in the brain, helping to regulate mood, appetite, sleep, and many other functions. It exerts these influences by binding to its receptor on the surface of neural cells. But startling new work suggests the impact of serotonin does not end there: the molecule also can enter a cell’s nucleus and directly switch on genes.

While much more study is needed, this is a potentially groundbreaking discovery. Not only could it have implications for managing depression and other mood disorders, it may also open new avenues for treating substance abuse and neurodegenerative diseases.

To understand how serotonin contributes to switching genes on and off, a lesson on epigenetics is helpful. Keep in mind that the DNA instruction book of all cells is essentially the same, yet the chapters of the book are read in very different ways by cells in different parts of the body. Epigenetics refers to chemical marks on DNA itself or on the protein “spools” called histones that package DNA. These marks influence the activity of genes in a particular cell without changing the underlying DNA sequence, switching them on and off or acting as “volume knobs” to turn the activity of particular genes up or down.

The marks include various chemical groups—including acetyl, phosphate, or methyl—which are added at precise locations to those spool-like proteins called histones. The addition of such groups alters the accessibility of the DNA for copying into messenger RNA and producing needed proteins.

In the study reported in Nature, researchers led by Ian Maze and postdoctoral researcher Lorna Farrelly, Icahn School of Medicine at Mount Sinai, New York, followed a hunch that serotonin molecules might also get added to histones [1]. There had been hints that it might be possible. For instance, earlier evidence suggested that inside cells, serotonin could enter the nucleus. There also was evidence that serotonin could attach to proteins outside the nucleus in a process called serotonylation.

These data begged the question: Is serotonylation important in the brain and/or other living tissues that produce serotonin in vivo? After a lot of hard work, the answer now appears to be yes.

These NIH-supported researchers found that serotonylation does indeed occur in the cell nucleus. They also identified a particular enzyme that directly attaches serotonin molecules to histone proteins. With serotonin attached, DNA loosens on its spool, allowing for increased gene expression.

The team found that histone serotonylation takes place in serotonin-producing human neurons derived from induced pluripotent stem cells (iPSCs). They also observed this process occurring in the brains of developing mice.

In fact, the researchers found evidence of those serotonin marks in many parts of the body. They are especially prevalent in the brain and gut, where serotonin also is produced in significant amounts. Those marks consistently correlate with areas of active gene expression.

The serotonin mark often occurs on histones in combination with a second methyl mark. The researchers suggest that this double marking of histones might help to further reinforce an active state of gene expression.

This work demonstrates that serotonin can directly influence gene expression in a manner that’s wholly separate from its previously known role in transmitting chemical messages from one neuron to the next. And, there are likely other surprises in store.

The newly discovered role of serotonin in modifying gene expression may contribute significantly to our understanding of mood disorders and other psychiatric conditions with known links to serotonin signals, suggesting potentially new targets for therapeutic intervention. But for now, this fundamental discovery raises many more intriguing questions than it answers.

Science is full of surprises, and this paper is definitely one of them. Will this kind of histone marking occur with other chemical messengers, such as dopamine and acetylcholine? This unexpected discovery now allows us to track serotonin and perhaps some of the brain’s other chemical messengers to see what they might be doing in the cell nucleus and whether this information might one day help in treating the millions of Americans with mood and behavioral disorders.

Reference:

[1] Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Farrelly LA, Thompson RE, Zhao S, Lepack AE, Lyu Y, Bhanu NV, Zhang B, Loh YE, Ramakrishnan A, Vadodaria KC, Heard KJ, Erikson G, Nakadai T, Bastle RM, Lukasak BJ, Zebroski H 3rd, Alenina N, Bader M, Berton O, Roeder RG, Molina H, Gage FH, Shen L, Garcia BA, Li H, Muir TW, Maze I. Nature. 2019 Mar 13. [Epub ahead of print]

Links:

Any Mood Disorder (National Institute of Mental Health/NIH)

Drugs, Brains, and Behavior: The Science of Addiction (National Institute on Drug Abuse/NIH)

Epigenomics (National Human Genome Research Institute/NIH)

Maze Lab (Icahn School of Medicine at Mount Sinai, New York, NY)

NIH Support: National Institute on Drug Abuse; National Institute of Mental Health; National Institute of General Medical Sciences; National Cancer Institute


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