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
Posted on by Dr. Francis Collins
Most of us can point to a few unwanted scars on our bodies. Every scar tells a story, but people are spending billions of dollars each year trying to hide or get rid of them . What if there was a way to get the wounds on our skin to heal without scarring in the first place?
In a recent paper in the journal Science, a team of NIH-supported researchers has taken an important step in this direction. Working with mice, the researchers deciphered some of the key chemical and physical signals that cause certain skin cells to form tough, fibrous scars while healing a wound . They also discovered how to reprogram them with a topical treatment and respond to injuries more like fetal skin cells, which can patch up wounds in full, regrowing hair, glands, and accessory structures of the skin, and all without leaving a mark.
Of course, mice are not humans. Follow-up research is underway to replicate these findings in larger mammals with skin that’s tighter and more akin to ours. But if the preclinical data hold up, the researchers say they can test in future human clinical trials the anti-scarring drug used in the latest study, which has been commercially available for two decades to treat blood vessel disorders in the eye.
The work comes from Michael Longaker, Shamik Mascharak, and colleagues, Stanford Medicine, Palo Alto, CA. But, to be more precise, the work began with a research project that Longaker was given back in 1987, while a post doc in the lab of Michael Harrison, University of California, San Francisco.
Harrison, a surgeon then performing groundbreaking prenatal surgery, noticed that babies born after undergoing surgery in the womb healed from their surgeries without any scarring. He asked his postdoc to find out why, and Longaker has been trying to answer that question and understand scar formation ever since.
Longaker and his Stanford colleague Geoffrey Gurtner suspected that the difference between healing inside and outside the womb had something to do with tension. Inside the womb, the skin of the unborn is bathed in fluid and develops in a soft, tension-free state. Outside the womb, human skin is exposed to continuous environmental stresses and must continuously remodel and grow to remain viable, which creates a high level of skin tension.
Following up on Longaker and Gurtner’s suspicion, Mascharak found in a series of mouse experiments that a particular class of fibroblast, a type of cell in skin and other connective tissues, activates a gene called Engrailed-1 during scar formation . To see if mechanical stress played a role in this process, Mascharak and team grew mouse fibroblast cells on either a soft, stress-free gel or on a stiff plastic dish that produced mechanical strain. Importantly, they also tried growing the fibroblasts on the same strain-inducing plastic, but in the presence of a chemical that blocked the mechanical-strain signal.
Their studies showed that fibroblasts grown on the tension-free gel didn’t activate the scar-associated genetic program, unlike fibroblasts growing on the stress-inducing plastic. With the chemical that blocked the cells’ ability to sense the mechanical strain, Engrailed-1 didn’t get switched on either.
They also showed the opposite. When tension was applied to healing surgical incisions in mice, it led to an increase in the number of those fibroblast cells expressing Engrailed-1 and thicker scars.
The researchers went on to make another critical finding. The mechanical stress of a fresh injury turns on a genetic program that leads to scar formation, and that program gets switched on through another protein called Yes-associated protein (YAP). When they blocked this protein with an existing eye drug called verteporfin, skin healed more slowly but without any hint of a scar.
It’s worth noting that scars aren’t just a cosmetic issue. Scars differ from unwounded skin in many ways. They lack hair follicles, glands that produce oil and sweat, and nerves for sensing pain or pressure. Because the fibers that make up scar tissue run parallel to each other instead of being more intricately interwoven, scars also lack the flexibility and strength of healthy skin.
These new findings therefore suggest it may one day be possible to allow wounds to heal without compromising the integrity of the skin. The findings also may have implications for many other medical afflictions that involve scarring, such as liver and lung fibrosis, burns, scleroderma, and scarring of heart tissue after a heart attack. That’s also quite a testament to sticking with a good postdoc project, wherever it may lead. One day, it may even improve public health!
 Human skin wounds: A major and snowballing threat to public health and the economy. Sen CK, Gordillo GM, Roy S, Kirsner R, Lambert L, Hunt TK, Gottrup F, Gurtner GC, Longaker MT. Wound Repair Regen. 2009 Nov-Dec;17(6):763-771.
 Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring.
Mascharak S, desJardins-Park HE, Davitt MF, Griffin M, Borrelli MR, Moore AL, Chen K, Duoto B, Chinta M, Foster DS, Shen AH, Januszyk M, Kwon SH, Wernig G, Wan DC, Lorenz HP, Gurtner GC, Longaker MT. Science. 2021 Apr 23;372(6540):eaba2374.
 Skin fibrosis. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Rinkevich Y, Walmsley GG, Hu MS, Maan ZN, Newman AM, Drukker M, Januszyk M, Krampitz GW, Gurtner GC, Lorenz HP, Weissman IL, Longaker MT. Science. 2015 Apr 17;348(6232):aaa2151.
Skin Health (National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH)
Michael Longaker (Stanford Medicine, Palo Alto, CA)
Geoffrey Gurtner (Stanford Medicine)
NIH Support: National Institute of General Medical Sciences; National Institute of Dental and Craniofacial Research
Posted on by Dr. Francis Collins
Can you identify a familiar pattern in this image’s square grid? Yes, it’s the outline of the periodic table! But instead of organizing chemical elements, this periodic table sorts 46 different types of neurons present in the visual cortex of a mouse brain.
Scientists, led by Hongkui Zeng at the Allen Institute for Brain Science, Seattle, constructed this periodic table by assigning colors to their neuronal discoveries based upon their main cell functions . Cells in pinks, violets, reds, and oranges have inhibitory electrical activity, while those in greens and blues have excitatory electrical activity.
For any given cell, the darker colors indicate dendrites, which receive signals from other neurons. The lighter colors indicate axons, which transmit signals. Examples of electrical properties—the number and intensity of their “spikes”—appear along the edges of the table near the bottom.
To create this visually arresting image, Zeng’s NIH-supported team injected dye-containing probes into neurons. The probes are engineered to carry genes that make certain types of neurons glow bright colors under the microscope.
This allowed the researchers to examine a tiny slice of brain tissue and view each colored neuron’s shape, as well as measure its electrical response. They followed up with computational tools to combine these two characteristics and classify cell types based on their shape and electrical activity. Zeng’s team could then sort the cells into clusters using a computer algorithm to avoid potential human bias from visually interpreting the data.
Why compile such a detailed atlas of neuronal subtypes? Although scientists have been surveying cells since the invention of the microscope centuries ago, there is still no consensus on what a “cell type” is. Large, rich datasets like this atlas contain massive amounts of information to characterize individual cells well beyond their appearance under a microscope, helping to explain factors that make cells similar or dissimilar. Those differences may not be apparent to the naked eye.
Just last year, Allen Institute researchers conducted similar work by categorizing nearly 24,000 cells from the brain’s visual and motor cortex into different types based upon their gene activity . The latest research lines up well with the cell subclasses and types categorized in the previous gene-activity work. As a result, the scientists have more evidence that each of the 46 cell types is actually distinct from the others and likely drives a particular function within the visual cortex.
Publicly available resources, like this database of cell types, fuel much more discovery. Scientists all over the world can look at this table (and soon, more atlases from other parts of the brain) to see where a cell type fits into a region of interest and how it might behave in a range of brain conditions.
 Classification of electrophysiological and morphological neuron types in the mouse visual cortex. N Gouwens NW, et al. Neurosci. 2019 Jul;22(7):1182-1195.
 Shared and distinct transcriptomic cell types across neocortical areas. Tasic B, et al. Nature. 2018 Nov;563(7729):72-78.
Brain Basics: The Life and Death of a Neuron (National Institute of Neurological Disorders and Stroke/NIH)
Cell Types: Overview of the Data (Allen Brain Atlas/Allen Institute for Brain Science, Seattle)
Hongkui Zeng (Allen Institute)
NIH Support: National Institute of Mental Health; Eunice Kennedy Shriver National Institute of Child Health & Human Development