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First Comprehensive Census of Cell Types in Brain Area Controlling Movement

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Credit: SciePro/Shutterstock; BRAIN Initiative Cell Census Network, Nature, 2021

The primary motor cortex is the part of the brain that enables most of our skilled movements, whether it’s walking, texting on our phones, strumming a guitar, or even spiking a volleyball. The region remains a major research focus, and that’s why NIH’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative – Cell Census Network (BICCN) has just unveiled two groundbreaking resources: a complete census of cell types present in the mammalian primary motor cortex, along with the first detailed atlas of the region, located along the back of the frontal lobe in humans (purple stripe above).

This remarkably comprehensive work, detailed in a flagship paper and more than a dozen associated articles published in the journal Nature, promises to vastly expand our understanding of the primary motor cortex and how it works to keep us moving [1]. The papers also represent the collaborative efforts of more than 250 BICCN scientists from around the world, teaming up over many years.

Started in 2013, the BRAIN Initiative is an ambitious project with a range of groundbreaking goals, including the creation of an open-access reference atlas that catalogues all of the brain’s many billions of cells. The primary motor cortex was one of the best places to get started on assembling an atlas because it is known to be well conserved across mammalian species, from mouse to human. There’s also a rich body of work to aid understanding of more precise cell-type information.

Taking advantage of recent technological advances in single-cell analysis, the researchers categorized into different types the millions of neurons and other cells in this brain region. They did so on the basis of morphology, or shape, of the cells, as well as their locations and connections to other cells. The researchers went even further to characterize and sort cells based on: their complex patterns of gene expression, the presence or absence of chemical (or epigenetic) marks on their DNA, the way their chromosomes are packaged into chromatin, and their electrical properties.

The new data and analyses offer compelling evidence that neural cells do indeed fall into distinct types, with a high degree of correspondence across their molecular genetic, anatomical, and physiological features. These findings support the notion that neural cells can be classified into molecularly defined types that are also highly conserved or shared across mammalian species.

So, how many cell types are there? While that’s an obvious question, it doesn’t have an easy answer. The number varies depending upon the method used for sorting them. The researchers report that they have identified about 25 classes of cells, including 16 different neuronal classes and nine non-neuronal classes, each composed of multiple subtypes of cells.

These 25 classes were determined by their genetic profiles, their locations, and other characteristics. They also showed up consistently across species and using different experimental approaches, suggesting that they have important roles in the neural circuitry and function of the motor cortex in mammals.

Still, many precise features of the cells don’t fall neatly into these categories. In fact, by focusing on gene expression within single cells of the motor cortex, the researchers identified more potentially important cell subtypes, which fall into roughly 100 different clusters, or distinct groups. As scientists continue to examine this brain region and others using the latest new methods and approaches, it’s likely that the precise number of recognized cell types will continue to grow and evolve a bit.

This resource will now serve as a springboard for future research into the structure and function of the brain, both within and across species. The datasets already have been organized and made publicly available for scientists around the world.

The atlas also now provides a foundation for more in-depth study of cell types in other parts of the mammalian brain. The BICCN is already engaged in an effort to generate a brain-wide cell atlas in the mouse, and is working to expand coverage in the atlas for other parts of the human brain.

The cell census and atlas of the primary motor cortex are important scientific advances with major implications for medicine. Strokes commonly affect this region of the brain, leading to partial or complete paralysis of the opposite side of the body.

By considering how well cell census information aligns across species, scientists also can make more informed choices about the best models to use for deepening our understanding of brain disorders. Ultimately, these efforts and others underway will help to enable precise targeting of specific cell types and to treat a wide range of brain disorders that affect thinking, memory, mood, and movement.

Reference:

[1] A multimodal cell census and atlas of the mammalian primary motor cortex. BRAIN Initiative Cell Census Network (BICCN). Nature. Oct 6, 2021.

Links:

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

BRAIN Initiative – Cell Census Network (BICCN) (NIH)

NIH Support: National Institute of Mental Health; National Institute of Neurological Disorders and Stroke


The Amazing Brain: Motor Neurons of the Cervical Spine

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Today, you may have opened a jar, done an upper body workout, played a guitar or a piano, texted a friend, or maybe even jotted down a grocery list longhand. All of these “skilled” arm, wrist, and hand movements are made possible by the bundled nerves, or circuits, running through a part of the central nervous system in the neck area called the cervical spine.

This video, which combines sophisticated imaging and computation with animation, shows the density of three types of nerve cells in the mouse cervical spine. There are the V1 interneurons (red), which sit between sensory and motor neurons; motor neurons associated with controlling the movement of the bicep (blue); and motor neurons associated with controlling the tricep (green).

At 4 seconds, the 3D animation morphs to show all the colors and cells intermixed as they are naturally in the cervical spine. At 8 seconds, the animation highlights the density of these three cells types. Notice in the bottom left corner, a light icon appears indicating the different imaging perspectives. What’s unique here is the frontal, or rostral, view of the cervical spine. The cervical spine is typically imaged from a lateral, or side, perspective.

Starting at 16 seconds, the animation highlights the location and density of each of the individual neurons. For the grand finale, viewers zoom off on a brief fly-through of the cervical spine and a flurry of reds, blues, and greens.

The video comes from Jamie Anne Mortel, a research assistant in the lab of Samuel Pfaff, Salk Institute, La Jolla, CA. Mortel is part of a team supported by the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative that’s developing a comprehensive atlas of the circuitry within the cervical spine that controls how mice control their forelimb movements, such as reaching and grasping.

This basic research will provide a better understanding of how the mammalian brain and spinal cord work together to produce movement. More than that, this research may provide valuable clues into better treating paralysis to arms, wrists, and/or hands caused by neurological diseases and spinal cord injuries.

As a part of this project, the Pfaff lab has been busy developing a software tool to take their imaging data from different parts of the cervical spine and present it in 3D. Mortel, who likes to make cute cartoon animations in her spare time, noticed that the software lacked animation capability. So she took the initiative and spent the next three weeks working after hours to produce this video—her first attempt at scientific animation. No doubt she must have been using a lot of wrist and hand movements!

With a positive response from her Salk labmates, Mortel decided to enter her scientific animation debut in the 2021 Show Us BRAINs! Photo and Video Contest. To her great surprise and delight, Mortel won third place in the video competition. Congratulations, and continued success for you and the team in producing this much-needed atlas to define the circuitry underlying skilled arm, wrist, and hand movements.

Links:

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

Spinal Cord Injury Information Page (National Institute of Neurological Disorders and Stroke/NIH)

Samuel Pfaff (Salk Institute, La Jolla, CA)

Show Us Your BRAINs! Photo and Video Contest (Brain Initiative/NIH)

NIH Support: National Institute of Neurological Disorders and Stroke


The Amazing Brain: Tracking Molecular Events with Calling Cards

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In days mostly gone by, it was fashionable in some circles for people to hand out calling cards to mark their arrival at special social events. This genteel human tradition is now being adapted to the lab to allow certain benign viruses to issue their own high-tech calling cards and mark their arrival at precise locations in the genome. These special locations show where there’s activity involving transcription factors, specialized proteins that switch genes on and off and help determine cell fate.

The idea is that myriad, well-placed calling cards can track brain development over time in mice and detect changes in transcription factor activity associated with certain neuropsychiatric disorders. This colorful image, which won first place in this year’s Show Us Your BRAINs! Photo and Video contest, provides a striking display of these calling cards in action in living brain tissue.

The image comes from Allen Yen, a PhD candidate in the lab of Joseph Dougherty, collaborating with the nearby lab of Rob Mitra. Both labs are located in the Washington University School of Medicine, St. Louis.

Yen and colleagues zoomed in on this section of mouse brain tissue under a microscope to capture dozens of detailed images that they then stitched together to create this high-resolution overview. The image shows neural cells (red) and cell nuclei (blue). But focus in on the neural cells (green) concentrated in the brain’s outer cortex (top) and hippocampus (two lobes in the upper center). They’ve been labelled with calling cards that were dropped off by adeno-associated virus [1].

Once dropped off, a calling card doesn’t bear a pretentious name or title. Rather, the calling card, is a small mobile snippet of DNA called a transposon. It gets dropped off with the other essential component of the technology: a specialized enzyme called a transposase, which the researchers fuse to one of many specific transcription factors of interest.

Each time one of these transcription factors of interest binds DNA to help turn a gene on or off, the attached transposase “grabs” a transposon calling card and inserts it into the genome. As a result, it leaves behind a permanent record of the interaction.

What’s also nice is the calling cards are programmed to give away their general locations. That’s because they encode a fluorescent marker (in this image, it’s a green fluorescent protein). In fact, Yen and colleagues could look under a microscope and tell from all the green that their calling card technology was in place and working as intended.
The final step, though, was to find out precisely where in the genome those calling cards had been left. For this, the researchers used next-generation sequencing to produce a cumulative history and map of each and every calling card dropped off in the genome.

These comprehensive maps allow them to identify important DNA-protein binding events well after the fact. This innovative technology also enables scientists to attribute past molecular interactions with observable developmental outcomes in a way that isn’t otherwise possible.

While the Mitra and Dougherty labs continue to improve upon this technology, it’s already readily adaptable to answer many important questions about the brain and brain disorders. In fact, Yen is now applying the technology to study neurodevelopment in mouse models of neuropsychiatric disorders, specifically autism spectrum disorder (ASD) [2]. This calling card technology also is available for any lab to deploy for studying a transcription factor of interest.

This research is supported by the Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative. One of the major goals of BRAIN Initiative is to accelerate the development and application of innovative technologies to gain new understanding of the brain. This award-winning image is certainly a prime example of striving to meet this goal. I’ll look forward to what these calling cards will tell us in the future about ASD and other important neurodevelopmental conditions affecting the brain.

References:

[1] A viral toolkit for recording transcription factor-DNA interactions in live mouse tissues. Cammack AJ, Moudgil A, Chen J, Vasek MJ, Shabsovich M, McCullough K, Yen A, Lagunas T, Maloney SE, He J, Chen X, Hooda M, Wilkinson MN, Miller TM, Mitra RD, Dougherty JD. Proc Natl Acad Sci U S A. 2020 May 5;117(18):10003-10014.

[2] A MYT1L Syndrome mouse model recapitulates patient phenotypes and reveals altered brain development due to disrupted neuronal maturation. Jiayang Chen, Mary E. Lambo, Xia Ge, Joshua T. Dearborn, Yating Liu, Katherine B. McCullough, Raylynn G. Swift, Dora R. Tabachnick, Lucy Tian, Kevin Noguchi, Joel R. Garbow, John N. Constantino. bioRxiv. May 27, 2021.

Links:

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

Autism Spectrum Disorder (National Institute of Mental Health/NIH)

Dougherty Lab (Washington University School of Medicine, St. Louis)

Mitra Lab (Washington University School of Medicine)

Show Us Your BRAINs! Photo and Video Contest (BRAIN Initiative/NIH)

NIH Support: National Institute of Neurological Disorders and Stroke; National Institute of Mental Health; National Center for Advancing Translational Sciences; National Human Genome Research Institute; National Institute of General Medical Sciences


The Amazing Brain: A Sharper Image of the Pyramidal Tract

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Flip the image above upside down, and the shape may remind you of something. If you think it resembles a pyramid, then you and a lot of great neuroscientists are thinking alike. What you are viewing is a colorized, 3D reconstruction of a pyramidal tract, which are bundles of nerve fibers that originate from the brain’s cerebral cortex and relay signals to the brainstem or the spinal cord. These signals control many important activities, including the voluntary movement of our arms, legs, head, and face.

For a while now, it’s been possible to combine a specialized form of magnetic resonance imaging (MRI) with computer modeling tools to produce 3D reconstructions of complicated networks of nerve fibers, such as the pyramidal tract. Still, for technical reasons, the quality of these reconstructions has remained poor in parts of the brain where nerve fibers cross at angles of 40 degrees or less.

The video above demonstrates how adding a sophisticated algorithm, called Orientation Distribution Function (ODF)-Fingerprinting, to such modeling can help overcome this problem when reconstructing a pyramidal tract. It has potential to enhance the reliability of these 3D reconstructions as neurosurgeons begin to use them to plan out their surgeries to help ensure they are carried out with the utmost safety and precision.

In the first second of the video, you see gray, fuzzy images from a diffusion MRI of the pyramidal tract. But, very quickly, a more colorful, detailed 3D reconstruction begins to appear, swiftly filling in from the top down. Colors are used to indicate the primary orientations of the nerve fibers: left to right (red), back to front (green), and top to bottom (blue). The orange, magenta, and other colors represent combinations of these primary directional orientations.

About three seconds into the video, a rough draft of the 3D reconstruction is complete. The top of the pyramidal tract looks pretty good. However, looking lower down, you can see distortions in color and relatively poor resolution of the nerve fibers in the middle of the tract—exactly where the fibers cross each other at angles of less than 40 degrees. So, researchers tapped into the power of their new ODF-Fingerprinting software to improve the image—and, starting about nine seconds into the video, you can see an impressive final result.

The researchers who produced this amazing video are Patryk Filipiak and colleagues in the NIH-supported lab of Steven Baete, Center for Advanced Imaging Innovation and Research, New York University Grossman School of Medicine, New York. The work paired diffusion MRI data from the NIH Human Connectome Project with the ODF-Fingerprinting algorithm, which was created by Baete to incorporate additional MRI imaging data on the shape of nerve fibers to infer their directionality [1].

This innovative approach to imaging recently earned Baete’s team second place in the 2021 “Show Us Your BRAINs” Photo and Video contest, sponsored by the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative. But researchers aren’t stopping there! They are continuing to refine ODF-Fingerprinting, with the aim of modeling the pyramidal tract in even higher resolution for use in devising new and better ways of helping people undergoing neurosurgery.

Reference:

[1] Fingerprinting Orientation Distribution Functions in diffusion MRI detects smaller crossing angles. Baete SH, Cloos MA, Lin YC, Placantonakis DG, Shepherd T, Boada FE. Neuroimage. 2019 Sep;198:231-241.

Links:

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

Human Connectome Project (University of Southern California, Los Angeles)

Steven Baete (Center for Advanced Imaging Innovation and Research, New York University Grossman School of Medicine, New York)

Show Us Your BRAINs! Photo and Video Contest (BRAIN Initiative/NIH)

NIH Support: National Institute of Biomedical Imaging and Bioengineering; National Institute of Neurological Disorders and Stroke; National Cancer Institute


The Amazing Brain: Toward a Wiring Diagram of Connectivity

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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!

Links:

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

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


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