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Groundbreaking Study Maps Key Brain Circuit

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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


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