neural circuitry
Most Detailed 3D Reconstruction of Human Brain Tissue Ever Produced Yields Surprising Insights
Posted on by Dr. Monica M. Bertagnolli
The NIH Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative has expanded scientists’ understanding of the human brain in recent years, offering fascinating insights into the ways that individual cells and complex neural circuits interact dynamically to enable us to think, feel, and act. But neuroscientists still have much more to learn about how our brains are put together at the most fundamental, subcellular level.
As a step in that direction, in a new study supported in part by the NIH BRAIN Initiative and reported in the journal Science, researchers have created the most detailed nanoscale resolution map ever produced of a cubic millimeter of brain tissue, about the size of half a grain of rice.
Despite its small size, this fragment of healthy brain contained about 57,000 cells of various types, 230 millimeters of blood vessels, 150 million neural connections, or synapses, and the protective myelin that insulates neurons. To capture it all in vivid detail, the researchers relied on electron microscopy to amass an impressive 1,400 terabytes of imaging data. For perspective, one terabyte of data is enough to store 100,000 photos on your smartphone.
While there are many more details yet to analyze given the sheer quantity of data, this impressively detailed subcellular map has already revealed multiple brain structures that have never been seen before. This includes a class of triangular neurons in deep brain layers being described for the first time. The map also revealed axons, the long extensions of nerve cells that carry electrical impulses, with as many as 50 synapses and other unusual structures, including axons arranged into extensive spiraling patterns that now warrant further study.
The findings come from a team led by Jeff W. Lichtman, Harvard University, Cambridge, MA, and Viren Jain, Google Research, Mountain View, CA. They recognized that fully understanding the human brain requires knowledge of its most basic construction. While the imaging technologies needed to produce this kind of map were available, there were other barriers, including a limited availability of healthy and high-quality human brain tissue samples for study.
Most biopsies of the brain are done to examine or take out abnormal growths of cells or tissues, making them unsuitable for understanding the normal makeup of the brain. In this case, the researchers were able to obtain a tiny sample from the brain tissue removed and destined for disposal during the normal course of surgery for a patient with epilepsy. The researchers first stained the preserved sample to make the cells easier to trace individually before slicing it into 5,000 thin layers for microscopic imaging.
To put those slices back together into a complete 3D reconstruction, the researchers relied on artificial intelligence (AI) models. Because the dataset is too large for any one group to fully analyze, they’ve made it all freely available to the research community in an online resource. They’ve also provided tools for its further analysis and proofreading.
While there is plenty still left to uncover, the findings offer proof-of-principle that it’s possible to visualize the brain at this very detailed level. This is crucial groundwork for new research now supported by the BRAIN Initiative Connectivity Across Scales (BRAIN CONNECTS) program. BRAIN CONNECTS will develop and scale up tools to produce an equally detailed map of a complete mouse brain, which is about 1,000 times larger than the human brain fragment. The researchers now hope their 3D map and others like it will be put to work to understand both normal and disordered brain function more fully.
Reference:
[1] Shapson-Coe A, et al. A petavoxel fragment of human cerebral cortex reconstructed at nanoscale resolution. Science. DOI: 10.1126/science.adk4858 (2024).
NIH Support: NIH BRAIN Initiative, National Institute of Mental Health
Experiencing the Neural Symphony Underlying Memory through a Blend of Science and Art
Posted on by John Ngai, PhD, NIH BRAIN Initiative
Ever wonder how you’re able to remember life events that happened days, months, or even years ago? You have your hippocampus to thank. This essential area in the brain relies on intense and highly synchronized patterns of activity that aren’t found anywhere else in the brain. They’re called “sharp-wave ripples.”
These dynamic ripples have been likened to the brain version of an instant replay, appearing most commonly during rest after a notable experience. And, now, the top video winner in this year’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative’s annual Show Us Your BRAINs! Photo and Video Contest allows you to witness the “chatter” that those ripples set off in other neurons. The details of this chatter determine just how durable a particular memory is in ways neuroscientists are still working hard to understand.
Neuroscientist Saman Abbaspoor in the lab of Kari Hoffman at Vanderbilt University, Nashville, in collaboration with Tyler Sloan from the Montreal-based Quorumetrix Studio, sets the stage in the winning video by showing an electrode or probe implanted in the brain that can reach the hippocampus. This device allows the Hoffman team to wirelessly record neural activity in different layers of the hippocampus as the animal either rests or moves freely about.
In the scenes that follow, neurons (blue, cyan, and yellow) flash on and off. The colors highlight the fact that this brain area and the neurons within it aren’t all the same. Various types of neurons are found in the brain area’s different layers, some of which spark the activity you see, while others dampen it.
Hoffman explains that the specific shapes of individual cells pictured are realistic but also symbolic. While they didn’t trace the individual branches of neurons in the brain in their studies, they relied on information from previous anatomical studies, overlaying their intricate forms with flashing bursts of activity that come straight from their recorded data.
Sloan then added yet another layer of artistry to the experience with what he refers to as sonification, or the use of music to convey information about the dynamic and coordinated bursts of activity in those cells. At five seconds in, you hear the subtle flutter of a sharp-wave ripple. With each burst of active neural chatter that follows, you hear the dramatic plink of piano keys.
Together, their winning video creates a unique sensory experience that helps to explain what goes on during memory formation and recall in a way that words alone can’t adequately describe. Through their ongoing studies, Hoffman reports that they’ll continue delving even deeper into understanding these intricate dynamics and their implications for learning and memory. Ultimately, they also want to explore how brain ripples, and the neural chatter they set off, might be enhanced to make memory formation and recall even stronger.
References:
S Abbaspoor & KL Hoffman. State-dependent circuit dynamics of superficial and deep CA1 pyramidal cells in macaques. BioRxiv DOI: 10.1101/2023.12.06.570369 (2023). Please note that this article is a pre-print and has not been peer-reviewed.
NIH Support: The NIH BRAIN Initiative
This article was updated on Dec. 15, 2023 to reflect better the collaboration on the project among Abbaspoor, Hoffman and Sloan.
How the Brain Differentiates the ‘Click,’ ‘Crack,’ or ‘Thud’ of Everyday Tasks
Posted on by Lawrence Tabak, D.D.S., Ph.D.
If you’ve been staying up late to watch the World Series, you probably spent those nine innings hoping for superstars Bryce Harper or José Altuve to square up a fastball and send it sailing out of the yard. Long-time baseball fans like me can distinguish immediately the loud crack of a home-run swing from the dull thud of a weak grounder.
Our brains have such a fascinating ability to discern “right” sounds from “wrong” ones in just an instant. This applies not only in baseball, but in the things that we do throughout the day, whether it’s hitting the right note on a musical instrument or pushing the car door just enough to click it shut without slamming.
Now, an NIH-funded team of neuroscientists has discovered what happens in the brain when one hears an expected or “right” sound versus a “wrong” one after completing a task. It turns out that the mammalian brain is remarkably good at predicting both when a sound should happen and what it ideally ought to sound like. Any notable mismatch between that expectation and the feedback, and the hearing center of the brain reacts.
It may seem intuitive that humans and other animals have this auditory ability, but researchers didn’t know how neurons in the brain’s auditory cortex, where sound is processed, make these snap judgements to learn complex tasks. In the study published in the journal Current Biology, David Schneider, New York University, New York, set out to understand how this familiar experience really works.
To do it, Schneider and colleagues, including postdoctoral fellow Nicholas Audette, looked to mice. They are a lot easier to study in the lab than humans and, while their brains aren’t miniature versions of our own, our sensory systems share many fundamental similarities because we are both mammals.
Of course, mice don’t go around hitting home runs or opening and closing doors. So, the researchers’ first step was training the animals to complete a task akin to closing the car door. To do it, they trained the animals to push a lever with their paws in just the right way to receive a reward. They also played a distinctive tone each time the lever reached that perfect position.
After making thousands of attempts and hearing the associated sound, the mice knew just what to do—and what it should sound like when they did it right. Their studies showed that, when the researchers removed the sound, played the wrong sound, or played the correct sound at the wrong time, the mice took notice and adjusted their actions, just as you might do if you pushed a car door shut and the resulting click wasn’t right.
To find out how neurons in the auditory cortex responded to produce the observed behaviors, Schneider’s team also recorded brain activity. Intriguingly, they found that auditory neurons hardly responded when a mouse pushed the lever and heard the sound they’d learned to expect. It was only when something about the sound was “off” that their auditory neurons suddenly crackled with activity.
As the researchers explained, it seems from these studies that the mammalian auditory cortex responds not to the sounds themselves but to how those sounds match up to, or violate, expectations. When the researchers canceled the sound altogether, as might happen if you didn’t push a car door hard enough to produce the familiar click shut, activity within a select group of auditory neurons spiked right as they should have heard the sound.
Schneider’s team notes that the same brain areas and circuitry that predict and process self-generated sounds in everyday tasks also play a role in conditions such as schizophrenia, in which people may hear voices or other sounds that aren’t there. The team hopes their studies will help to explain what goes wrong—and perhaps how to help—in schizophrenia and other neural disorders. Perhaps they’ll also learn more about what goes through the healthy brain when anticipating the satisfying click of a closed door or the loud crack of a World Series home run.
Reference:
[1] Precise movement-based predictions in the mouse auditory cortex. Audette NJ, Zhou WX, Chioma A, Schneider DM. Curr Biology. 2022 Oct 24.
Links:
How Do We Hear? (National Institute on Deafness and Other Communication Disorders/NIH)
Schizophrenia (National Institute of Mental Health/NIH)
David Schneider (New York University, New York)
NIH Support: National Institute of Mental Health; National Institute on Deafness and Other Communication Disorders
Creative Minds: Reprogramming the Brain
Posted on by Dr. Francis Collins
Caption: Neuronal circuits in the mouse retina. Cone photoreceptors (red) enable color vision; bipolar neurons (magenta) relay information further along the circuit; and a subtype of bipolar neuron (green) helps process signals sensed by other photoreceptors in dim light.
Credit: Brian Liu and Melanie Samuel, Baylor College of Medicine, Houston.
When most people think of reprogramming something, they probably think of writing code for a computer or typing commands into their smartphone. Melanie Samuel thinks of brain circuits, the networks of interconnected neurons that allow different parts of the brain to work together in processing information.
Samuel, a researcher at Baylor College of Medicine, Houston, wants to learn to reprogram the connections, or synapses, of brain circuits that function less well in aging and disease and limit our memory and ability to learn. She has received a 2016 NIH Director’s New Innovator Award to decipher the molecular cues that encourage the repair of damaged synapses or enable neurons to form new connections with other neurons. Because extensive synapse loss is central to most degenerative brain diseases, Samuel’s reprogramming efforts could help point the way to preventing or correcting wiring defects before they advance to serious and potentially irreversible cognitive problems.
LabTV: Curious About the Nervous System
Posted on by Dr. Francis Collins
As a child growing up in Croatia, Maja Petkovic dreamed of a future in archeology, medicine, law, and then architecture. But, as she explains in today’s LabTV video, after taking a class in molecular biology, it was love at first sight.
Her passion for biological research landed her in Paris at the Université Denis Diderot, where she pursued a Ph.D. in neuroscience. Now she’s continuing her studies in the United States, working as a Howard Hughes Medical Institute postdoctoral researcher in the NIH-supported lab of Lily and Yuh Nung Jan at the University of California, San Francisco.
Petkovic’s work in the Jan Lab is focused on the basic mechanisms underlying the formation of neural connections and on understanding what happens when those connections go awry. A thorough understanding of neural circuitry has important medical implications, of course, but Petkovic is equally driven by the desire to understand “how stuff works.”
