schizophrenia
This Is Why NIH Invests in Global Health Research
Posted on by Roger I. Glass, M.D., Ph.D., Fogarty International Center
Efforts over the past few years to end the COVID-19 pandemic clearly reveal how global health impacts individual wellbeing and national security. At NIH, the Fogarty International Center helps the other institutes become engaged with global health research, which investigates the dual burden of infectious disease and non-communicable disease.
Global health research also encompasses data science, economics, genetics, climate change science, and many other disciplines. For more than 50 years, Fogarty has been building partnerships among institutions in the U.S. and abroad, while training the next generation of scientists focused on universal health needs.
America’s investment in Fogarty has paid rich dividends
During the pandemic, in particular, we’ve seen researchers trained by our programs make scientific discoveries that contributed to international security. Take Jessica Manning, a former Fogarty fellow who now conducts malaria research in Phnom Penh, Cambodia. Her team at the Ministry of Health sequenced the viral strain of SARS-CoV-2, the cause of COVID-19, infecting the first Cambodian patient and documented early the spread of this novel coronavirus outside of China.
Similarly, Christian Happi, director of the African Centre of Excellence for the Genomics of Infectious Disease, Ede, Nigeria, sequenced the first SARS-CoV-2 genome in Africa. Happi was able to do it by adapting the sequencing and analytical pipelines that he’d created back when he was a Fogarty grantee studying Ebola.
In Botswana, Sikhulile Moyo leveraged the skills he’d acquired while supported by a Fogarty HIV research training grant with Max Essex, Harvard School of Public Health, Cambridge, MA, to track COVID-19 mutations for his country’s Ministry of Health. Last November, he alerted the world of a new Omicron variant. Within six weeks, Omicron became the dominant global strain, challenging the ability of COVID vaccines to control its spread. In the Dominican Republic, William Duke, a national commission member, used what he’d learned as a Fogarty trainee to help create a national COVID-19 intervention plan to prevent and control the disease.
Fogarty’s fostering of global health leaders is one way we advance scientific expertise while ensuring our nation’s biosecurity. Another is by finding effective ways to study abroad the same health conditions that affect our own population.
Research conducted in Colombia, for example, may provide clues for preventing Alzheimer’s disease in the U.S. Fogarty support brought together neuroscientists Kenneth Kosik, University of California, Santa Barbara, and Francisco Lopera, University of Antioquia, Colombia, to study members of the largest-known family with an early-onset, rapidly progressive form of the disease. Over the years, Kosik and Lopera have trained local scientists, explored gene therapy targets, investigated biomarkers to monitor disease progression, and conducted drug trials in search of a cure for Alzheimer’s.
Researchers in other fields also discover unique opportunities to investigate populations with high rates of disease. Siana Nkya, a Fogarty grantee based in Tanzania, has devoted her career to studying the genetic determinants of sickle cell disease, which affects many people around the world, including in the U.S. We hope that US-African partnerships might develop improved, affordable treatments and a cure for all patients with this devastating disease. Similarly, people in the U.S. have access to state-of-the-art HIV treatment studies in places around the globe where incidence rates are higher.
Fogarty has supported many milestone achievements in HIV research over the years. Among them is a study that took place in nine countries. The research, led by Myron Cohen of the University of North Carolina at Chapel Hill, established that antiretroviral therapy can prevent sexual transmission of HIV-1 among couples in which one person is infected and the other is not. In fact, this research informs current HIV treatment recommendations worldwide, including in the U.S.
Americans will also undoubtedly benefit from projects funded by Fogarty’s Global Brain and Nervous System Disorders Research across the Lifespan program. For example, psychologist Tatiana Balachova, University of Oklahoma, Oklahoma City, has designed an intervention for women in Russia to prevent fetal alcohol spectrum disorders. In another project in South Africa, Sandra and Joseph Jacobson, Wayne State University, Detroit, conducted the first-ever prospective longitudinal study of the syndrome. Findings from both projects are ripe for translation within an American context.
Other examples of Global Brain program investigations with broad implications in our own country include studying early psychosis in China; capacity building for schizophrenia research in Macedonia; exploring family consequences from the Zika virus in Brazil; and studying dementia and related health and social challenges in Lebanon.
These are just a few examples of Fogarty’s work and its unique mission. What is most remarkable about Fogarty is that just under 90 percent of our grants are co-funded by at least one other NIH institute, center, or office. Collaboration, both within borders and across them, is Fogarty’s formula for success.
Links:
Fogarty International Center (NIH)
Overview of Brain Disorders: Research Across the Lifespan (Fogarty)
Former Fogarty Scholar Dr Jessica Manning Helps Cambodia Respond to COVID (Fogarty)
Christian Happi: Former Fogarty Grantee Leads COVID-19 Genomics Work in Africa (Fogarty)
Sikhulile Moyo: Fogarty Fellow Recognized for Omicron Discovery (Fogarty)
William Duke: Former Fogarty HIV Trainee Helps Lead Dominican Republic’s COVID Response (Fogarty)
Kenneth Kosic and Francisco Lopera: NIH Support Spurs Alzheimer’s Research in Colombia (Fogarty)
Former Fogarty fellow Siana Nkya Tackles Sickle Cell Disease in Tanzania (Fogarty)
Tatiana Balachova: Researchers Tackle Fetal Alcohol Syndrome in Russia (Fogarty)
Sandra and Joseph Jacobson: Fetal Alcohol Exposure Research Supported by NIAAA in South Africa, Ukraine and Russia Improves Prevention, Outcomes (Fogarty)
Note: Dr. Lawrence Tabak, who performs the duties of the NIH Director, has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 22nd in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.
How the Brain Differentiates the ‘Click,’ ‘Crack,’ or ‘Thud’ of Everyday Tasks
Posted on by Lawrence Tabak, D.D.S., Ph.D.
If you’ve been staying up late to watch the World Series, you probably spent those nine innings hoping for superstars Bryce Harper or José Altuve to square up a fastball and send it sailing out of the yard. Long-time baseball fans like me can distinguish immediately the loud crack of a home-run swing from the dull thud of a weak grounder.
Our brains have such a fascinating ability to discern “right” sounds from “wrong” ones in just an instant. This applies not only in baseball, but in the things that we do throughout the day, whether it’s hitting the right note on a musical instrument or pushing the car door just enough to click it shut without slamming.
Now, an NIH-funded team of neuroscientists has discovered what happens in the brain when one hears an expected or “right” sound versus a “wrong” one after completing a task. It turns out that the mammalian brain is remarkably good at predicting both when a sound should happen and what it ideally ought to sound like. Any notable mismatch between that expectation and the feedback, and the hearing center of the brain reacts.
It may seem intuitive that humans and other animals have this auditory ability, but researchers didn’t know how neurons in the brain’s auditory cortex, where sound is processed, make these snap judgements to learn complex tasks. In the study published in the journal Current Biology, David Schneider, New York University, New York, set out to understand how this familiar experience really works.
To do it, Schneider and colleagues, including postdoctoral fellow Nicholas Audette, looked to mice. They are a lot easier to study in the lab than humans and, while their brains aren’t miniature versions of our own, our sensory systems share many fundamental similarities because we are both mammals.
Of course, mice don’t go around hitting home runs or opening and closing doors. So, the researchers’ first step was training the animals to complete a task akin to closing the car door. To do it, they trained the animals to push a lever with their paws in just the right way to receive a reward. They also played a distinctive tone each time the lever reached that perfect position.
After making thousands of attempts and hearing the associated sound, the mice knew just what to do—and what it should sound like when they did it right. Their studies showed that, when the researchers removed the sound, played the wrong sound, or played the correct sound at the wrong time, the mice took notice and adjusted their actions, just as you might do if you pushed a car door shut and the resulting click wasn’t right.
To find out how neurons in the auditory cortex responded to produce the observed behaviors, Schneider’s team also recorded brain activity. Intriguingly, they found that auditory neurons hardly responded when a mouse pushed the lever and heard the sound they’d learned to expect. It was only when something about the sound was “off” that their auditory neurons suddenly crackled with activity.
As the researchers explained, it seems from these studies that the mammalian auditory cortex responds not to the sounds themselves but to how those sounds match up to, or violate, expectations. When the researchers canceled the sound altogether, as might happen if you didn’t push a car door hard enough to produce the familiar click shut, activity within a select group of auditory neurons spiked right as they should have heard the sound.
Schneider’s team notes that the same brain areas and circuitry that predict and process self-generated sounds in everyday tasks also play a role in conditions such as schizophrenia, in which people may hear voices or other sounds that aren’t there. The team hopes their studies will help to explain what goes wrong—and perhaps how to help—in schizophrenia and other neural disorders. Perhaps they’ll also learn more about what goes through the healthy brain when anticipating the satisfying click of a closed door or the loud crack of a World Series home run.
Reference:
[1] Precise movement-based predictions in the mouse auditory cortex. Audette NJ, Zhou WX, Chioma A, Schneider DM. Curr Biology. 2022 Oct 24.
Links:
How Do We Hear? (National Institute on Deafness and Other Communication Disorders/NIH)
Schizophrenia (National Institute of Mental Health/NIH)
David Schneider (New York University, New York)
NIH Support: National Institute of Mental Health; National Institute on Deafness and Other Communication Disorders
Groundbreaking Study Maps Key Brain Circuit
Posted on by Dr. Francis Collins
Biologists have long wondered how neurons from different regions of the brain actually interconnect into integrated neural networks, or circuits. A classic example is a complex master circuit projecting across several regions of the vertebrate brain called the basal ganglia. It’s involved in many fundamental brain processes, such as controlling movement, thought, and emotion.
In a paper published recently in the journal Nature, an NIH-supported team working in mice has created a wiring diagram, or connectivity map, of a key component of this master circuit that controls voluntary movement. This groundbreaking map will guide the way for future studies of the basal ganglia’s direct connections with the thalamus, which is a hub for information going to and from the spinal cord, as well as its links to the motor cortex in the front of the brain, which controls voluntary movements.
This 3D animation drawn from the paper’s findings captures the biological beauty of these intricate connections. It starts out zooming around four of the six horizontal layers of the motor cortex. At about 6 seconds in, the video focuses on nerve cell projections from the thalamus (blue) connecting to cortex nerve cells that provide input to the basal ganglia (green). It also shows connections to the cortex nerve cells that input to the thalamus (red).
At about 25 seconds, the video scans back to provide a quick close-up of the cell bodies (green and red bulges). It then zooms out to show the broader distribution of nerve cells within the cortex layers and the branched fringes of corticothalamic nerve cells (red) at the top edge of the cortex.
The video comes from scientific animator Jim Stanis, University of Southern California Mark and Mary Stevens Neuroimaging and Informatics Institute, Los Angeles. He collaborated with Nick Foster, lead author on the Nature paper and a research scientist in the NIH-supported lab of Hong-Wei Dong at the University of California, Los Angeles.
The two worked together to bring to life hundreds of microscopic images of this circuit, known by the unusually long, hyphenated name: the cortico-basal ganglia-thalamic loop. It consists of a series of subcircuits that feed into a larger signaling loop.
The subcircuits in the loop make it possible to connect thinking with movement, helping the brain learn useful sequences of motor activity. The looped subcircuits also allow the brain to perform very complex tasks such as achieving goals (completing a marathon) and adapting to changing circumstances (running uphill or downhill).
Although scientists had long assumed the cortico-basal ganglia-thalamic loop existed and formed a tight, closed loop, they had no real proof. This new research, funded through NIH’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, provides that proof showing anatomically that the nerve cells physically connect, as highlighted in this video. The research also provides electrical proof through tests that show stimulating individual segments activate the others.
Detailed maps of neural circuits are in high demand. That’s what makes results like these so exciting to see. Researchers can now better navigate this key circuit not only in mice but other vertebrates, including humans. Indeed, the cortico-basal ganglia-thalamic loop may be involved in a number of neurological and neuropsychiatric conditions, including Huntington’s disease, Parkinson’s disease, schizophrenia, and addiction. In the meantime, Stanis, Foster, and colleagues have left us with a very cool video to watch.
Reference:
[1] The mouse cortico-basal ganglia-thalamic network. Foster NN, Barry J, Korobkova L, Garcia L, Gao L, Becerra M, Sherafat Y, Peng B, Li X, Choi JH, Gou L, Zingg B, Azam S, Lo D, Khanjani N, Zhang B, Stanis J, Bowman I, Cotter K, Cao C, Yamashita S, Tugangui A, Li A, Jiang T, Jia X, Feng Z, Aquino S, Mun HS, Zhu M, Santarelli A, Benavidez NL, Song M, Dan G, Fayzullina M, Ustrell S, Boesen T, Johnson DL, Xu H, Bienkowski MS, Yang XW, Gong H, Levine MS, Wickersham I, Luo Q, Hahn JD, Lim BK, Zhang LI, Cepeda C, Hintiryan H, Dong HW. Nature. 2021;598(7879):188-194.
Links:
Brain Basics: Know Your Brain (National Institute of Neurological Disorders and Stroke/NIH)
Dong Lab (University of California, Los Angeles)
Mark and Mary Stevens Neuroimaging and Informatics Institute (University of Southern California, Los Angeles)
The Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)
NIH Support: Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Deafness and Other Communication Disorders; National Institute of Mental Health
New Technology Opens Evolutionary Window into Brain Development
Posted on by Dr. Francis Collins
One of the great mysteries in biology is how we humans ended up with such large, complex brains. In search of clues, researchers have spent years studying the protein-coding genes activated during neurodevelopment. But some answers may also be hiding in non-coding regions of the human genome, where sequences called regulatory elements increase or decrease the activity of genes.
A fascinating example involves a type of regulatory element called a human accelerated region (HAR). Although “human” is part of this element’s name, it turns out that the genomes of all vertebrates—not just humans—contain the DNA segments now designated as HARs.
In most organisms, HARs show a relatively low rate of mutation, which means these regulatory elements have been highly conserved across species throughout evolutionary time [1]. The big exception is Homo sapiens, in which HARs have exhibited a much higher rate of mutations.
The accelerated rate of HARs mutations observed in humans suggest that, over the course of very long periods of time, these genomic changes might have provided our species with some sort of evolutionary advantage. What might that be? Many have speculated the advantage might involve the brain because HARs are often associated with genes involved in neurodevelopment. Now, in a paper published in the journal Neuron, an NIH-supported team confirms that’s indeed the case [2].
In the new work, researchers found that about half of the HARs in the human genome influence the activity, or expression, of protein-coding genes in neural cells and tissues during the brain’s development [3]. The researchers say their study—the most comprehensive to date of the 3,171 HARs in the human genome—firmly establishes that this type of regulatory element helps to drive patterns of neurodevelopmental gene activity specific to humans.
Yet to be determined is precisely how HARs affect the development of the human brain. The quest to uncover these details will no doubt shed new light on fundamental questions about the brain, its billions of neurons, and their trillions of interconnections. For example, why does human neural development span decades, longer than the life spans of most primates and other mammals? Answering such questions could also reveal new clues into a range of cognitive and behavioral disorders. In fact, early research has already made tentative links between HARs and neurodevelopmental conditions such as autism spectrum disorder and schizophrenia [3].
The latest work was led by Kelly Girskis, Andrew Stergachis, and Ellen DeGennaro, all of whom were in the lab of Christopher Walsh while working on the project. An NIH grantee, Walsh is director of the Allen Discovery Center for Brain Evolution at Boston Children’s Hospital and Harvard Medical School, which is supported by the Paul G. Allen Foundation Frontiers Group, and is an Investigator of the Howard Hughes Medical Institute.
Though HARs have been studied since 2006, one of the big challenges in systematically assessing them has been technological. The average length of a HAR is about 269 bases of DNA, but current technologies for assessing function can only easily analyze DNA molecules that span 150 bases or less.
Ryan Doan, who was then in the Walsh Lab, and his colleagues solved the problem by creating a new machine called CaptureMPRA. (MPRA is short for “massively parallel reporter assays.”) This technological advance cleverly barcodes HARs and, more importantly, makes it possible to analyze HARs up to about 500 bases in length.
Using CaptureMPRA technology in tandem with cell culture studies, researchers rolled up their sleeves and conducted comprehensive, full-sequence analyses of more than 3,000 HARs. In their initial studies, primarily in neural cells, they found nearly half of human HARs are active to drive gene expression in cell culture. Of those, 42 percent proved to have increased ability to enhance gene expression compared to their orthologues, or counterparts, in chimpanzees.
Next, the team integrated these data with an existing epigenetic dataset derived from developing human brain cells, as well as additional datasets generated from sorted brain cell types. They found that many HARs appeared to have the ability to increase the activity of protein-coding genes, while a smaller—but very significant—subset of the HARs appeared to be enhancing gene expression specifically in neural progenitor cells, which are responsible for making various neural cell types.
The data suggest that as the human HAR sequences mutated and diverged from other mammals, they increased their ability to enhance or sometimes suppress the activity of certain genes in neural cells. To illustrate this point, the researchers focused on two HARs that appear to interact specifically with a gene referred to as R17. This gene can have highly variable gene expression patterns not only in different human cell types, but also in cells from other vertebrates and non-vertebrates.
In the human cerebral cortex, the outermost part of the brain that’s responsible for complex behaviors, R17 is expressed only in neural progenitor cells and only at specific time points. The researchers found that R17 slows the progression of neural progenitor cells through the cell cycle. That might seem strange, given the billions of neurons that need to be made in the cortex. But it’s consistent with the biology. In the human, it takes more than 130 days for the cortex to complete development, compared to about seven days in the mouse.
Clearly, to learn more about how the human brain evolved, researchers will need to look for clues in many parts of the genome at once, including its non-coding regions. To help researchers navigate this challenging terrain, the Walsh team has created an online resource displaying their comprehensive HAR data. It will appear soon, under the name HAR Hub, on the University of California Santa Cruz Genome Browser.
References:
[1] An RNA gene expressed during cortical development evolved rapidly in humans. Pollard KS, Salama SR, Lambert N, Lambot MA, Coppens S, Pedersen JS, Katzman S, King B, Onodera C, Siepel A, Kern AD, Dehay C, Igel H, Ares M Jr, Vanderhaeghen P, Haussler D. Nature. 2006 Sep 14;443(7108):167-72.
[2] Rewiring of human neurodevelopmental gene regulatory programs by human accelerated regions. Girskis KM, Stergachis AB, DeGennaro EM, Doan RN, Qian X, Johnson MB, Wang PP, Sejourne GM, Nagy MA, Pollina EA, Sousa AMM, Shin T, Kenny CJ, Scotellaro JL, Debo BM, Gonzalez DM, Rento LM, Yeh RC, Song JHT, Beaudin M, Fan J, Kharchenko PV, Sestan N, Greenberg ME, Walsh CA. Neuron. 2021 Aug 25:S0896-6273(21)00580-8.
[3] Mutations in human accelerated regions disrupt cognition and social behavior. Doan RN, Bae BI, Cubelos B, Chang C, Hossain AA, Al-Saad S, Mukaddes NM, Oner O, Al-Saffar M, Balkhy S, Gascon GG; Homozygosity Mapping Consortium for Autism, Nieto M, Walsh CA. Cell. 2016 Oct 6;167(2):341-354.
Links:
Christopher Walsh Laboratory (Boston Children’s Hospital and Harvard Medical School)
The Paul G. Allen Foundation Frontiers Group (Seattle)
NIH Support: National Institute of Neurological Disorders and Stroke; National Institute of Mental Health; National Institute of General Medical Sciences; National Cancer Institute
A Real-Time Look at Value-Based Decision Making
Posted on by Dr. Francis Collins
All of us make many decisions every day. For most things, such as which jacket to wear or where to grab a cup of coffee, there’s usually no right answer, so we often decide using values rooted in our past experiences. Now, neuroscientists have identified the part of the mammalian brain that stores information essential to such value-based decision making.
Researchers zeroed in on this particular brain region, known as the retrosplenial cortex (RSC), by analyzing movies—including the clip shown about 32 seconds into this video—that captured in real time what goes on in the brains of mice as they make decisions. Each white circle is a neuron, and the flickers of light reflect their activity: the brighter the light, the more active the neuron at that point in time.
All told, the NIH-funded team, led by Ryoma Hattori and Takaki Komiyama, University of California at San Diego, La Jolla, made recordings of more than 45,000 neurons across six regions of the mouse brain [1]. Neural activity isn’t usually visible. But, in this case, researchers used mice that had been genetically engineered so that their neurons, when activated, expressed a protein that glowed.
Their system was also set up to encourage the mice to make value-based decisions, including choosing between two drinking tubes, each with a different probability of delivering water. During this decision-making process, the RSC proved to be the region of the brain where neurons persistently lit up, reflecting how the mouse evaluated one option over the other.
The new discovery, described in the journal Cell, comes as something of a surprise to neuroscientists because the RSC hadn’t previously been implicated in value-based decisions. To gather additional evidence, the researchers turned to optogenetics, a technique that enabled them to use light to inactivate neurons in the RSC’s of living animals. These studies confirmed that, with the RSC turned off, the mice couldn’t retrieve value information based on past experience.
The researchers note that the RSC is heavily interconnected with other key brain regions, including those involved in learning, memory, and controlling movement. This indicates that the RSC may be well situated to serve as a hub for storing value information, allowing it to be accessed and acted upon when it is needed.
The findings are yet another amazing example of how advances coming out of the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative are revolutionizing our understanding of the brain. In the future, the team hopes to learn more about how the RSC stores this information and sends it to other parts of the brain. They note that it will also be important to explore how activity in this brain area may be altered in schizophrenia, dementia, substance abuse, and other conditions that may affect decision-making abilities. It will also be interesting to see how this develops during childhood and adolescence.
Reference:
[1] Area-Specificity and Plasticity of History-Dependent Value Coding During Learning. Hattori R, Danskin B, Babic Z, Mlynaryk N, Komiyama T. Cell. 2019 Jun 13;177(7):1858-1872.e15.
Links:
Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)
Komiyama Lab (UCSD, La Jolla)
NIH Support: National Institute of Neurological Disorders and Stroke; National Eye Institute; National Institute on Deafness and Other Communication Disorders
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