Posted on by Dr. Francis Collins
For experienced and aspiring shutterbugs alike, sometimes the best photo in the bunch turns out to be a practice shot. That’s also occasionally true in the lab when imaging cells and tissues, and it’s the story behind this spectacular image showing the interface of skin and muscle during mammalian development.
Here you see an area of the mouse forelimb located near a bone called the humerus. This particular sample was labeled for laminin, a protein found in the extracellular matrix (ECM) that undergirds cells and tissues to give them mechanical and biochemical support. Computer algorithms were used to convert the original 2D confocal scan into a 3D image, and colorization was added to bring the different layers of tissue into sharper relief.
Skin tissue (bright red and yellow) is located near the top of the image; blood vessels (paler red, orange, and yellow) are in the middle and branching downward; and muscle (green, blue, and purple) makes up the bottom layer.
The image was created by Sarah Lipp, a graduate student in the NIH-supported tissue engineering lab of Sarah Calve. The team focuses on tissue interfaces to better understand the ECM and help devise strategies to engineer musculoskeletal tissues, such as tendon and cartilage.
In February 2020, Lipp was playing around with some new software tools for tissue imaging. Before zeroing in on her main target—the mouse’s myotendinous junction, where muscle transfers its force to tendon, Lipp snapped this practice shot of skin meeting muscle. After processing the practice shot with a color-projecting macro in an image processing tool called Fiji, she immediately liked what she saw.
So, Lipp tweaked the color a bit more and entered the image in the 2020 BioArt Scientific Image & Video Competition, sponsored by the Federation of American Societies for Experimental Biology, Bethesda, MD. Last December, the grad student received the good news that her practice shot had snagged one of the prestigious contest’s top awards.
But she’s not stopping there. Lipp is continuing to pursue her research interests at the University of Colorado, Boulder, where the Calve lab recently moved from Purdue University, West Lafayette, IN. Here’s wishing her a career filled with more great images—and great science!
Muscle and Bone Diseases (National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH)
Musculoskeletal Extracellular Matrix Laboratory (University of Colorado, Boulder)
BioArt Scientific Image & Video Competition (Federation of American Societies for Experimental Biology, Bethesda, MD)
NIH Support: National Institute of Arthritis and Musculoskeletal and Skin Diseases
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.
 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.
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)
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
Posted on by Dr. Francis Collins
The NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative continues to teach us about the world’s most sophisticated computer: the human brain. This striking image offers a spectacular case in point, thanks to a new tool called Visual Neuronal Dynamics (VND).
VND is not a camera. It is a powerful software program that can display, animate, and analyze models of neurons and their connections, or networks, using 3D graphics. What you’re seeing in this colorful image is a strip of mouse primary visual cortex, the area in the brain where incoming sensory information gets processed into vision.
This strip contains more than 230,000 neurons of 17 different cell types. Long and spindly excitatory neurons that point upward (purple, blue, red, orange) are intermingled with short and stubby inhibitory neurons (green, cyan, magenta). Slicing through the neuronal landscape is a neuropixels probe (silver): a tiny flexible silicon detector that can record brain activity in awake animals .
Developed by Emad Tajkhorshid and his team at University of Illinois at Urbana-Champaign, along with Anton Arkhipov of the Allen Institute, Seattle, VND represents a scientific milestone for neuroscience: using an adept software tool to see and analyze massive neuronal datasets on a computer. What’s also nice is the computer doesn’t have to be a fancy one, and VND’s instructions, or code, are publicly available for anyone to use.
VND is the neuroscience-adapted cousin of Visual Molecular Dynamics (VMD), a popular molecular biology visualization tool to see life up close in 3D, also developed by Tajkhorshid’s group . By modeling and visualizing neurons and their connections, VND helps neuroscientists understand at their desktops how neural networks are organized and what happens when they are manipulated. Those visualizations then lay the groundwork for follow-up lab studies to validate the data and build upon them.
Through the Allen Institute, the NIH BRAIN Initiative is compiling a comprehensive whole-brain atlas of cell types in the mouse, and Arkhipov’s work integrates these data into computer models. In May 2020, his group published comprehensive models of the mouse primary visual cortex .
Arkhipov and team are now working to understand how the primary visual cortex’s physical structure (the cell shapes and connections within its complicated circuits) determines its outputs. For example, how do specific connections determine network activity? Or, how fast do cells fire under different conditions?
Ultimately, such computational research may help us understand how brain injuries or disease affect the structure and function of these neural networks. VND should also propel understanding of many other areas of the brain, for which the data are accumulating rapidly, to answer similar questions that still remain mysterious to scientists.
In the meantime, VND is also creating some award-winning art. The image above was the second-place photo in the 2021 “Show us Your BRAINs!” Photo and Video Contest sponsored by the NIH BRAIN Initiative.
 Fully integrated silicon probes for high-density recording of neural activity. Jun JJ, Steinmetz NA, Siegle JH, Denman DJ, Bauza M, Barbarits B, Lee AK, Anastassiou CA, Andrei A, Aydın Ç, Barbic M, Blanche TJ, Bonin V, Couto J, Dutta B, Gratiy SL, Gutnisky DA, Häusser M, Karsh B, Ledochowitsch P, Lopez CM, Mitelut C, Musa S, Okun M, Pachitariu M, Putzeys J, Rich PD, Rossant C, Sun WL, Svoboda K, Carandini M, Harris KD, Koch C, O’Keefe J, Harris TD. Nature. 2017 Nov 8;551(7679):232-236.
 VMD: visual molecular dynamics. Humphrey W, Dalke A, Schulten K. J Mol Graph. 1996 Feb;14(1):33-8, 27-8.
 Systematic integration of structural and functional data into multi-scale models of mouse primary visual cortex. Billeh YN, Cai B, Gratiy SL, Dai K, Iyer R, Gouwens NW, Abbasi-Asl R, Jia X, Siegle JH, Olsen SR, Koch C, Mihalas S, Arkhipov A. Neuron. 2020 May 6;106(3):388-403.e18
Models of the Mouse Primary Visual Cortex (Allen Institute, Seattle)
Visual Neuronal Dynamics (NIH Center for Macromolecular Modeling and Bioinformatics, University of Illinois at Urbana-Champaign)
Tajkhorshid Lab (University of Illinois at Urbana-Champaign)
Arkhipov Lab (Allen Institute)
Show Us Your BRAINs! Photo & Video Contest (BRAIN Initiative/NIH)
NIH Support: National Institute of Neurological Disorders and Stroke
Posted on by Dr. Francis Collins
It’s summertime and, thanks to the gift of COVID-19 vaccines, many folks are getting the chance to take a break. So, I think it’s also time that my blog readers finally get a break from what’s been nearly 18 months of non-stop coverage of COVID-19 research. And I can’t think of a more enjoyable way to do that than by taking a look at just a few of the many spectacular images and insights that researchers have derived about the amazing brain.
The Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, which is an NIH-led project aimed at revolutionizing our understanding of the human brain, happens to have generated some of the coolest—and most informative—imagery now available in neuroscience. So, throughout the month of August, I’ll share some of the entries from the initiative’s latest Show Us Your BRAINs! Photo and Video Contest.
With nearly 100 billion neurons and 100 trillion connections, the human brain remains one of the greatest mysteries in science. Among the many ways in which neuroscientists are using imaging to solve these mysteries is by developing more detailed maps of connectivity within the brain.
For example, the image featured above from the contest shows a dense weave of neurons in the anterior cingulate cortex, which is the part of the brain involved in learning, memory, and some motor control. In this fluorescence micrograph of tissue from a mouse, each neuron has been labeled with green fluorescent protein, enabling you to see how it connects to other neurons through arm-like projections called axons and dendrites.
The various connections, or circuits, within the brain process and relay distinct types of sensory information. In fact, a single neuron can form a thousand or more of these connections. Among the biggest challenges in biomedicine today is deciphering how these circuits work, and how they can misfire to cause potentially debilitating neurological conditions, including Alzheimer’s disease, Parkinson’s disease, autism, epilepsy, schizophrenia, depression, and traumatic brain injury.
This image was produced by Nicholas Foster and Lei Gao in the NIH-supported lab of Hong Wei Dong, University of California, Los Angeles. The Dong Lab is busy cataloging cell types and helping to assemble a wiring diagram of the connectivity in the mammalian brain—just one of the BRAIN Initiative’s many audacious goals. Stay tuned for more throughout the month of August!
Dong Lab (University of California, Los Angeles)
Show Us Your BRAINs! Photo and Video Contest (BRAIN Initiative/NIH)
NIH Support: National Institute of Mental Health
Posted on by Dr. Francis Collins
The human small intestine, though modest in diameter and folded compactly to fit into the abdomen, is anything but small. It measures on average about 20 feet from end to end and plays a big role in the gastrointestinal tract, breaking down food and drink from the stomach to absorb the water and nutrients.
Also anything but small is the total surface area of the organ’s inner lining, where millions of U-shaped folds in the mucosal tissue triple the available space to absorb the water and nutrients that keep our bodies nourished. If these folds, packed with finger-like absorptive cells called villi, were flattened out, they would be the size of a tennis court!
That’s what makes this this microscopic image so interesting. It shows in cross section the symmetrical pattern of the villi (its cells outlined by yellow) that pack these folds. Each cell’s nucleus contains DNA (teal), and the villi themselves are fringed by thousands of tiny bristles, called microvilli (magenta), which are too small to see individually here. Collectively, microvilli make up an absorptive surface, called the brush border, where digested nutrients in the fluid passing through the intestine can enter cells via transport channels.
Amy Engevik, a researcher at the Medical University of South Carolina, Charleston, took this snapshot to show what a healthy intestinal cellular landscape looks like in a young mouse. The Engevik lab studies the dynamic movement of ions, water, and proteins in the intestine—a process that goes wrong in humans born with a rare disorder called microvillus inclusion disease (MVID).
MVID causes chronic gastrointestinal problems in newborn babies, due to defects in a protein that transports various cellular components. Because they cannot properly absorb nutrition from food, these tiny patients require intravenous feeding almost immediately, which carries a high risk for sepsis and intestinal injury.
Engevik and her team study this disease using a mouse model that replicates many of the characteristics of the disorder in humans . Interestingly, when Engevik gets together with her family, she isn’t the only one talking about MVID and villi. Her two sisters, Mindy and Kristen, also study the basic science of gastrointestinal disorders! Instead of sibling rivalry, though, this close alliance has strengthened the quality of her research, says Amy, who is the middle child.
Beyond advancing science and nurturing sisterhood in science, Engevik’s work also captured the fancy of the judges for the Federation of American Societies for Experimental Biology’s annual BioArt Scientific Image and Video Competition. Her image was one of 10 winners announced in December 2020.
Because multiple models are useful for understanding fundamentals of diseases like MVID, Engevik has also developed a large-animal model (pig) that has many features of the human disease . She hopes that her efforts will help to improve our understanding of MVID and other digestive diseases, as well as lead to new, potentially life-saving treatments for babies suffering from MVID.
 Loss of MYO5B Leads to reductions in Na+ absorption with maintenance of CFTR-dependent Cl- secretion in enterocytes. Engevik AC, Kaji I, Engevik MA, Meyer AR, Weis VG, Goldstein A, Hess MW, Müller T, Koepsell H, Dudeja PK, Tyska M, Huber LA, Shub MD, Ameen N, Goldenring JR. Gastroenterology. 2018 Dec;155(6):1883-1897.e10.
 Editing myosin VB gene to create porcine model of microvillus inclusion disease, with microvillus-lined inclusions and alterations in sodium transporters. Engevik AC, Coutts AW, Kaji I, Rodriguez P, Ongaratto F, Saqui-Salces M, Medida RL, Meyer AR, Kolobova E, Engevik MA, Williams JA, Shub MD, Carlson DF, Melkamu T, Goldenring JR. Gastroenterology. 2020 Jun;158(8):2236-2249.e9.
Microvillus inclusion disease (Genetic and Rare Diseases Center/NIH)
Digestive Diseases (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Amy Engevik (Medical University of South Carolina, Charleston)
Podcast: A Tale of Three Sisters featuring Drs. Mindy, Amy, and Kristen Engevik (The Immunology Podcast, April 29, 2021)
BioArt Scientific Image and Video Competition (Federation of American Societies for Experimental Biology, Bethesda, MD)
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases