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The Amazing Brain: Where Thoughts Trigger Body Movement

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3D column of red neurons (top) and blue neurons (middle)
Credit: Nicolas Antille, SUNY Downstate Health Sciences University, Brooklyn, NY

You’re looking at a section of a mammalian motor cortex (left), the part of the brain where thoughts trigger our body movements. Part of the section is also shown (right) in higher resolution to help you see the intricate details.

These views are incredibly detailed, and they also can’t be produced on a microscope or any current state-of-the-art imaging device. They were created on a supercomputer. Researchers input vast amounts of data covering the activity of the motor cortex to model this highly detailed and scientifically accurate digital simulation.

The vertical section (left) shows a circuit within a column of motor neurons. The neurons run from the top, where the brain meets the skull, downward to the point that the motor cortex connects with other brain areas.

The various colors represent different layers of the motor cortex, and the bright spots show where motor neurons are firing. Notice the thread-like extensions of the motor neurons, some of which double back to connect cells from one layer with others some distance away. All this back and forth makes it appear as though the surface is unraveling.

This unique imaging was part of this year’s Show Us Your Brain Photo and Video contest, supported by NIH’s Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative. Nicolas Antille, an expert in turning scientific data into accurate and compelling visuals, created the images using a scientific model developed in the lab of Salvador Dura-Bernal, SUNY Downstate Health Sciences University, Brooklyn, NY. In the Dura-Bernal lab, scientists develop software and highly detailed computational models of neural circuits to better understand how they give rise to different brain functions and behavior [1].

Antille’s images make the motor neurons look densely packed, but in life the density would be five times as much. Antille has paused the computer simulation at a resolution that he found scientifically and visually interesting. But the true interconnections among neurons, or circuits, inside a real brain—even a small portion of a real brain—are more complex than the most powerful computers today can fully process.

While Antille is invested in revealing brain circuits as close to reality as possible, he also has the mind of an artist. He works with the subtle interaction of light with these cells to show how many individual neurons form this much larger circuit. Here’s more of his artistry at work. Antille wants to invite us all to ponder—even if only for a few moments—the wondrous beauty of the mammalian brain, including this remarkable place where thoughts trigger movements.

Reference:

[1] NetPyNE, a tool for data-driven multiscale modeling of brain circuits. Dura-Bernal S, Suter BA, Gleeson P, Cantarelli M, Quintana A, Rodriguez F, Kedziora DJ, Chadderdon GL, Kerr CC, Neymotin SA, McDougal RA, Hines M, Shepherd GM, Lytton WW. Elife. 2019 Apr 26;8:e44494.

Links:

Nicolas Antille

Dura-Bernal Lab (State University of New York Downstate, Brooklyn)

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

Show Us Your BRAINs Photo & Video Contest (BRAIN Initiative)

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


The Amazing Brain: Tight-Knit Connections

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colored tracts create a model of the entire brain
Credit: Sahar Ahmad, Ye Wu, and Pew-Thian Yap, The University of North Carolina, Chapel Hill

You’ve likely seen pictures of a human brain showing its smooth, folded outer layer, known as the cerebral cortex. Maybe you’ve also seen diagrams highlighting some of the brain’s major internal, or subcortical, structures.

These familiar representations, however, overlook the brain’s intricate internal wiring that power our thoughts and actions. This wiring consists of tightly bundled neural projections, called fiber tracts, that connect different parts of the brain into an integrated neural communications network.

The actual patterns of these fiber tracts are represented here and serve as the featured attraction in this award-winning image from the 2022 Show Us Your BRAINs Photo and Video contest. The contest is supported by NIH’s Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative.

Let’s take a closer look. At the center of the brain, you see some of the major subcortical structures: hippocampus (orange), amygdala (pink), putamen (magenta), caudate nucleus (purple), and nucleus accumbens (green). The fiber tracts are presented as colorful, yarn-like projections outside of those subcortical and other brain structures. The various colors, like a wiring diagram, distinguish the different fiber tracts and their specific connections.

This award-winning atlas of brain connectivity comes from Sahar Ahmad, Ye Wu, and Pew-Thian Yap, The University of North Carolina, Chapel Hill. The UNC Chapel Hill team produced this image using a non-invasive technique called diffusion MRI tractography. It’s an emerging approach with many new possibilities for neuroscience and the clinic [1]. Ahmad’s team is putting it to work to map the brain’s many neural connections and how they change across the human lifespan.

In fact, the connectivity atlas you see here isn’t from a single human brain. It’s actually a compilation of images of the brains of multiple 30-year-olds. The researchers are using this brain imaging approach to visualize changes in the brain and its fiber tracts as people grow, develop, and mature from infancy into old age.

Sahar says their comparisons of such images show that early in life, many dynamic changes occur in the brain’s fiber tracts. Once a person reaches young adulthood, the connective wiring tends to stabilize until old age, when fiber tracts begin to break down. These and other similarly precise atlases of the human brain promise to reveal fascinating insights into brain organization and the functional dynamics of its architecture, now and in the future.

Reference:

[1] Diffusion MRI fiber tractography of the brain. Jeurissen B, Descoteaux M, Mori S, Leemans A. NMR Biomed. 2019 Apr;32(4):e3785.

Links:

Brain Basics: Know Your Brain (National Institute of Neurological Disorders and Stroke/NIH)

Sahar Ahmad (The University of North Carolina, Chapel Hill)

Ye Wu (The University of North Carolina, Chapel Hill)

Pew-Thian Yap (The University of North Carolina, Chapel Hill)

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

Show Us Your BRAINs Photo & Video Contest (BRAIN Initiative)

NIH Support: BRAIN Initiative; National Institute of Mental Health


The Amazing Brain: Capturing Neurons in Action

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Credit: Andreas Tolias, Baylor College of Medicine, Houston

With today’s powerful imaging tools, neuroscientists can monitor the firing and function of many distinct neurons in our brains, even while we move freely about. They also possess another set of tools to capture remarkable, high-resolution images of the brain’s many thousands of individual neurons, tracing the form of each intricate branch of their tree-like structures.

Most brain imaging approaches don’t capture neural form and function at once. Yet that’s precisely what you’re seeing in this knockout of a movie, another winner in the Show Us Your BRAINs! Photo and Video Contest, supported by NIH’s Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative.

This first-of-its kind look into the mammalian brain produced by Andreas Tolias, Baylor College of Medicine, Houston, and colleagues features about 200 neurons in the visual cortex, which receives and processes visual information. First, you see a colorful, tightly packed network of neurons. Then, those neurons, which were colorized by the researchers in vibrant pinks, reds, blues, and greens, pull apart to reveal their finely detailed patterns and shapes. Throughout the video, you can see neural activity, which appears as flashes of white that resemble lightning bolts.

Making this movie was a multi-step process. First, the Tolias group presented laboratory mice with a series of visual cues, using a functional imaging approach called two-photon calcium imaging to record the electrical activity of individual neurons. While this technique allowed the researchers to pinpoint the precise locations and activity of each individual neuron in the visual cortex, they couldn’t zoom in to see their precise structures.

So, the Baylor team sent the mice to colleagues Nuno da Costa and Clay Reid, Allen Institute for Brain Science, Seattle, who had the needed electron microscopes and technical expertise to zoom in on these structures. Their data allowed collaborator Sebastian Seung’s team, Princeton University, Princeton, NJ, to trace individual neurons in the visual cortex along their circuitous paths. Finally, they used sophisticated machine learning algorithms to carefully align the two imaging datasets and produce this amazing movie.

This research was supported by Intelligence Advanced Research Projects Activity (IARPA), part of the Office of the Director of National Intelligence. The IARPA is one of NIH’s governmental collaborators in the BRAIN Initiative.

Tolias and team already are making use of their imaging data to learn more about the precise ways in which individual neurons and groups of neurons in the mouse visual cortex integrate visual inputs to produce a coherent view of the animals’ surroundings. They’ve also collected an even-larger data set, scaling their approach up to tens of thousands of neurons. Those data are now freely available to other neuroscientists to help advance their work. As researchers make use of these and similar data, this union of neural form and function will surely yield new high-resolution discoveries about the mammalian brain.

Links:

Tolias Lab (Baylor College of Medicine, Houston)

Nuno da Costa (Allen Institute for Brain Science, Seattle)

R. Clay Reid (Allen Institute)

H. Sebastian Seung (Princeton University, Princeton, NJ)

Machine Intelligence from Cortical Networks (MICrONS) Explorer

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

Show Us Your BRAINs Photo & Video Contest (BRAIN Initiative)

NIH Support: BRAIN Initiative; Common Fund


The Amazing Brain: Seeing Two Memories at Once

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Light microscopy. Green at top and bottom with a middle blue layer showing cells.
Credit: Stephanie Grella, Boston University, MA

The NIH’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative is revolutionizing our understanding of the human brain. As described in the initiative’s name, the development of innovative imaging technologies will enable researchers to see the brain in new and increasingly dynamic ways. Each year, the initiative celebrates some standout and especially creative examples of such advances in the “Show Us Your BRAINs! Photo & Video Contest. During most of August, I’ll share some of the most eye-catching developments in our blog series, The Amazing Brain.

In this fascinating image, you’re seeing two stored memories, which scientists call engrams, in the hippocampus region of a mouse’s brain. The engrams show the neural intersection of a good memory (green) and a bad memory (pink). You can also see the nuclei of many neurons (blue), including nearby neurons not involved in the memory formation.

This award-winning image was produced by Stephanie Grella in the lab of NIH-supported neuroscientist Steve Ramirez, Boston University, MA. It’s also not the first time that the blog has featured Grella’s technical artistry. Grella, who will soon launch her own lab at Loyola University, Chicago, previously captured what a single memory looks like.

To capture two memories at once, Grella relied on a technology known as optogenetics. This powerful method allows researchers to genetically engineer neurons and selectively activate them in laboratory mice using blue light. In this case, Grella used a harmless virus to label neurons involved in recording a positive experience with a light-sensitive molecule, known as an opsin. Another molecular label was used to make those same cells appear green when activated.

After any new memory is formed, there’s a period of up to about 24 hours during which the memory is malleable. Then, the memory tends to stabilize. But with each retrieval, the memory can be modified as it restabilizes, a process known as memory reconsolidation.

Grella and team decided to try to use memory reconsolidation to their advantage to neutralize an existing fear. To do this, they placed their mice in an environment that had previously startled them. When a mouse was retrieving a fearful memory (pink), the researchers activated with light associated with the positive memory (green), which for these particular mice consisted of positive interactions with other mice. The aim was to override or disrupt the fearful memory.

As shown by the green all throughout the image, the experiment worked. While the mice still showed some traces of the fearful memory (pink), Grella explained that the specific cells that were the focus of her study shifted to the positive memory (green).

What’s perhaps even more telling is that the evidence suggests the mice didn’t just trade one memory for another. Rather, it appears that activating a positive memory actually suppressed or neutralized the animal’s fearful memory. The hope is that this approach might one day inspire methods to help people overcome negative and unwanted memories, such as those that play a role in post-traumatic stress disorder (PTSD) and other mental health issues.

Links:

Stephanie Grella (Boston University, MA)

Ramirez Group (Boston University)

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

Show Us Your BRAINs Photo & Video Contest (BRAIN Initiative)

NIH Support: BRAIN Initiative; Common Fund


Tackling Complex Scientific Questions Requires a Team Approach

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A group of people are hand in hand in a spiral. Team Science
Credit: Getty Images/melitas

During the COVID-19 pandemic, we have seen unprecedented, rapid scientific collaboration, as experts around the world in discrete, previously disconnected fields, have found ways to collaborate to face a common cause. For example, physicists helped respiratory specialists understand how virus particles could spread in air, leading to improved mitigation strategies. Specialists in cardiovascular science, neuroscience, immunology, and other fields are now working together to understand and address Long COVID. Over the past two years, we have also seen remarkable international sharing of epidemiological data and information on effects of vaccines.

Science is increasingly a team activity, which is true for many fields, not just biomedicine. The professional diversity of research teams reflects the increased complexity of the questions science is called upon to answer. This is especially obvious in the study of the brain, which is the most complex system known to us.

The NIH’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, with the goal of vastly enhancing neuroscience through new technologies, includes research teams with neuroscientists, engineers, mathematicians, physicists, data scientists, ethicists, and more. Nearly half (47 percent) of grant awards have multiple principal investigators.

Besides the BRAIN Initiative, other multi-institute NIH research projects are applying team science to complex research questions, such as those related to neurodevelopment, addiction, and pain. The Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, created a team-based research framework to advance promising pain therapeutics quickly to clinical testing.

In the Adolescent Brain Cognitive Development (ABCD) study, which is led by NIDA in close partnership with NIH’s National Institute on Alcohol Abuse and Alcoholism (NIAAA), and other NIH institutes, 21 research centers are collecting behavioral, biospecimen, and neuroimaging data from 11,878 children from age 10 through their teens. Teams led by experts in adolescent psychiatry, developmental psychology, and pediatrics interview participants and their families. These experts then gather a battery of health metrics from psychological, cognitive, sociocultural, and physical assessments, including collection and analysis of various kinds of biospecimens (blood, saliva). Further, experts in biophysics gather information on the structure and function of participants’ brains every two years.

A similar study of young children in the first decade of life beginning with the prenatal period, the HEALthy Brain and Child Development (HBCD) study, supported by HEAL, NIDA, and several other NIH institutes and centers, is now underway at 25 research sites across the country. A range of scientific specialists, similar to that in the ABCD study, is involved in this effort. In this case, they are aided by experts in obstetric care and in infant neuroimaging.

For both of these studies, teams of data scientists validate and curate all the information generated and make it available to researchers across the world. This makes it possible to investigate complex questions such as human neurodevelopmental diversity and the effects of genes and social experiences and their relation to mental health. More than half of the publications using ABCD data have been authored by non-ABCD investigators taking advantage of the open-access format.

Yet, institutions that conduct and fund science—including NIH—have been slow to support and reward collaboration. Because authorship and funding are so important in tenure and promotion decisions at universities, for example, an individual’s contribution to larger, multi-investigator projects on which they may not be the grantee or lead author on a study publication may carry less weight.

For this reason, early-career scientists may be particularly reluctant to collaborate on team projects. Among the recommendations of a 2015 National Academies of Sciences, Engineering, and Medicine (NASEM) report, Enhancing the Effectiveness of Team Science, was that universities and other institutions should find effective ways to give credit for team-based work to assist promotion and tenure committees.

The strongest teams will be diverse in other respects, not just scientific expertise. Besides more actively fostering productive collaborations across disciplines, NIH is making a more concerted effort to promote racial equity and inclusivity in our research workforce, both through the NIH UNITE Initiative and through Institute-specific initiatives like NIDA’s Racial Equity Initiative.

To promote diversity, inclusivity, and accessibility in research, the BRAIN Initiative recently added a requirement in most of its funding opportunity announcements (FOAs) that has applicants include a Plan for Enhancing Diverse Perspectives (PEDP) in the proposed research. The PEDPs are evaluated and scored during the peer review as part of the holistic considerations used to inform funding decisions. These long-overdue measures will not only ensure that NIH-funded science is more diverse, but they are also important steps toward studying and addressing social determinants of health and the health disparities that exist for so many conditions.

Increasingly, scientific discovery is as much about exploring new connections between different kinds of researchers as it is about finding new relationships among different kinds of scientific databases. The challenges before us are great—ending the COVID pandemic, finding a solution to the addiction and overdose crisis, and so many others—and increased collaboration between scientists will give us the greatest chance to successfully overcome these challenges.

Links:

Nora Volkow’s Blog (National Institute on Drug Abuse/NIH)

Adolescent Brain Cognitive Development Study

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

Racial Equity Initiative (NIDA)

Note: Acting NIH Director Lawrence Tabak 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 13th in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.


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