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How Our Brains Replay Memories

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Retrieving a Memory
Caption: Encoding and replaying learned memory. Left panel shows the timed sequence of neurons firing in a part of a person’s brain involved in memory as it encodes the random pair of words, “crow” and “jeep.” Colors are assigned to different neurons to differentiate their firing within the sequence. Right panel shows a highly similar timed sequence of those same neurons firing just before a person given the word “jeep,” recalled and said the correct answer “crow.” Credit: Vaz AP, Science, 2020.

Note to my blog readers: the whole world is now facing a major threat from the COVID-19 pandemic. We at NIH are doing everything we can to apply the best and most powerful science to the development of diagnostics, therapeutics, and vaccines, while also implementing public health measures to protect our staff and the patients in our hospital. This crisis is expected to span many weeks, and I will occasionally report on COVID-19 in this blog format. Meanwhile, science continues to progress on many other fronts—and so I will continue to try to bring you stories across a wide range of topics. Perhaps everyone can use a little break now and then from the coronavirus news? Today’s blog takes you into the intricacies of memory.

When recalling the name of an acquaintance, you might replay an earlier introduction, trying to remember the correct combination of first and last names. (Was it Scott James? Or James Scott?) Now, neuroscientists have found that in the split second before you come up with the right answer, your brain’s neurons fire in the same order as when you first learned the information [1].

This new insight into memory retrieval comes from recording the electrical activity of thousands of neurons in the brains of six people during memory tests of random word pairs, such as “jeep” and “crow.” While similar firing patterns had been described before in mice, the new study is the first to confirm that the human brain stores memories in specific sequences of neural activity that can be replayed again and again.

The new study, published in the journal Science, is the latest insight from neurosurgeon and researcher Kareem Zaghloul at NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Zaghloul’s team has for years been involved in an NIH Clinical Center study for patients with drug-resistant epilepsy whose seizures cannot be controlled with drugs.

As part of this work, his surgical team often temporarily places a 4 millimeter-by-4 millimeter array of tiny electrodes on the surface of the brains of the study’s participants. They do this in an effort to pinpoint brain tissues that may be the source of their seizures before performing surgery to remove them. With a patient’s informed consent to take part in additional research, the procedure also has led to a series of insights into what happens in the human brain when we make and later retrieve new memories.

Here’s how it works: The researchers record electrical currents as participants are asked to learn random word pairs presented to them on a computer screen, such as “cake” and “fox,” or “lime” and “camel.” After a period of rest, their brain activity is again recorded as they are given a word and asked to recall the matching word.

Last year, the researchers reported that the split second before a person got the right answer, tiny ripples of electrical activity appeared in two specific areas of the brain [2]. The team also had shown that, when a person correctly recalled a word pair, the brain showed patterns of activity that corresponded to those formed when he or she first learned to make a word association.

The new work takes this a step further. As study participants learned a word pair, the researchers noticed not only the initial rippling wave of electricity, but also that particular neurons in the brain’s cerebral cortex fired repeatedly in a sequential order. In fact, with each new word pair, the researchers observed unique firing patterns among the active neurons.

If the order of neuronal firing was essential for storing new memories, the researchers reasoned that the same would be true for correctly retrieving the information. And, indeed, that’s what they were able to show. For example, when individuals were shown “cake” for a second time, they replayed a very similar firing pattern to the one recorded initially for this word just milliseconds before correctly recalling the paired word “fox.”

The researchers then calculated the average sequence similarity between the firing patterns of learning and retrieval. They found that as a person recalled a word, those patterns gradually became more similar. Just before a correct answer was given, the recorded neurons locked onto the right firing sequence. That didn’t happen when a person gave an incorrect answer.

Further analysis confirmed that the exact order of neural firing was specific to each word pair. The findings show that our memories are encoded as unique sequences that must be replayed for accurate retrieval, though we still don’t understand the molecular mechanisms that undergird this.

Zaghloul reports that there’s still more to learn about how these processes are influenced by other factors such as our attention. It’s not yet known whether the brain replays sequences similarly when retrieving longer-term memories. Along with these intriguing insights into normal learning and memory, the researchers think this line of research will yield important clues as to what changes in people who suffer from memory disorders, with potentially important implications for developing the next generation of treatments.

Reference:

[1] Replay of cortical spiking sequences during human memory retrieval. Vaz AP, Wittig JH Jr, Inati SK, Zaghloul KA. Science. 2020 Mar 6;367(6482):1131-1134.

[2] Coupled ripple oscillations between the medial temporal lobe and neocortex retrieve human memory. Vaz AP, Inati SK, Brunel N, Zaghloul KA. Science. 2019 Mar 1;363(6430):975-978.

Links:

Epilepsy Information Page (National Institute of Neurological Disorders and Stroke/NIH)

Brain Basics (NINDS)

Zaghloul Lab (NINDS)

NIH Support: National Institute of Neurological Disorders and Stroke; National Institute of General Medical Sciences


Largest-Ever Genetic Study of Autism Yields New Insights

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Baby and DNA Strands

Anyone who’s spent time with people affected by autism spectrum disorder (ASD) can tell you that it’s a very complex puzzle. The wide variability seen among individuals with this group of developmental brain disorders, which can disrupt communication, behavior control, and social skills, has also posed a huge challenge for researchers trying to identify underlying genetic and environmental factors. So, it’s no surprise that there’s been considerable interest in the recent findings of the largest-ever genetic study of ASD.

In a landmark study that analyzed the DNA of more than 35,000 people from around the world, the NIH-funded international Autism Sequencing Consortium (ASC) identified variants in 102 genes associated with increased risk of developing ASD, up from 65 identified previously. Of the 102 genes, 60 had not been previously linked to ASD and 53 appeared to be primarily connected to ASD as opposed to other types of intellectual disability or developmental delay. It is expected that this newfound genetic knowledge will serve to improve understanding of the complex biological mechanisms involved in ASD, ultimately paving the way for new approaches to diagnosis and treatment.

The study reported in the journal Cell was led by Joseph Buxbaum, Icahn School of Medicine at Mount Sinai, New York; Stephan Sanders, University of California, San Francisco; Kathryn Roeder, Carnegie Mellon University, Pittsburgh, PA; and Mark Daly, Massachusetts General Hospital, Boston, MA and the Broad Institute of MIT and Harvard, Cambridge, MA. These researchers and their teams faced what might seem like a rather daunting task.

While common genetic variants collectively are known to contribute substantially to ASD, rare variants have been recognized individually as more major contributors to a person’s risk of developing ASD. The challenge was how to find such rare variants—whether inherited or newly arising.

To do so, the researchers needed to analyze a enormous amount of DNA data. Fortunately, they and their ASC colleagues already had assembled a vast trove of data. Over the last decade, the ASC had collected DNA samples with full consent from thousands of people with and without ASD, including unaffected siblings and parents. All were aggregated with other studies, and, at the time of this investigation, they had gathered 35,584 unique samples. Those included more than 21,000 family-based samples and almost 12,000 samples from people diagnosed with ASD.

In search of rare genetic alterations, they sequenced whole exomes, the approximately 1.5 percent of the genome that codes for proteins. Their search produced a list of 102 ASD-associated genes, including 30 that had never been implicated in any developmental brain disorder previously.

But that was just the beginning. Next, the ASC team dug deeper into this list. The researchers knew from previous work that up to half of people with ASD also have an intellectual disability or developmental delay. Many of the associated genes overlap, meaning they play roles in both outcomes. So, in one set of analyses, the team compared the list to the results of another genetic study of people diagnosed with developmental delays, including problems with learning or gross motor skills such as delayed walking.

The detailed comparison allowed them to discern genes that are more associated with features of ASD, as opposed to those that are more specific to these developmental delays. It turns out that 49 of the 102 autism-associated genes were altered more often in people with developmental delay than in those diagnosed with ASD. The other 53 were altered more often in ASD, suggesting that they may be more closely linked to this condition’s unique features.

Further study also showed that people who carried alterations in genes found predominantly in ASD also had better intellectual function. They also were more likely to have learned to walk without a developmental delay.

The 102 new genes fell primarily into one of two categories. Many play a role in the brain’s neural connections. The rest are involved primarily in switching other genes on and off in brain development. Interestingly, they are expressed both in excitatory neurons, which are active in sending signals in the brain, and in inhibitory neurons that squelch such activity. Many of these genes are also commonly expressed in the brain’s cerebral cortex, the outermost part of the brain that is responsible for many complex behaviors.

Overall, these findings underscore that ASD truly does exist on a spectrum. Indeed, there are many molecular paths to this disorder. The ASC researchers continue to collect samples, so we can expect this list of 102 genes will continue to expand in the future.

With these gene discoveries in hand, the researchers will now also turn their attention to unravelling additional details about how these genes function in the brain. The hope is that this growing list of genes will converge on a smaller number of important molecular pathways, pointing the way to new and more precise ways of treating ASD in all its complexity.

Reference:

[1] Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Satterstrom FK, Kosmicki JA, Wang J, Breen MS, De Rubeis S, An JY, Peng M, Collins R, Grove J, Klei L, Stevens C, Reichert J, Mulhern MS, Artomov M, Gerges S, Sheppard B, Xu X, Bhaduri A, Norman U, Brand H, Schwartz G, Nguyen R, Guerrero EE, Dias C; Autism Sequencing Consortium; iPSYCH-Broad Consortium, Betancur C, Cook EH, Gallagher L, Gill M, Sutcliffe JS, Thurm A, Zwick ME, Børglum AD, State MW, Cicek AE, Talkowski ME, Cutler DJ, Devlin B, Sanders SJ, Roeder K, Daly MJ, Buxbaum JD.Cell. 2020 Jan 23. {Epub ahead of print]

Links:

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

Joseph Buxbaum (Icahn School of Medicine at Mount Sinai, New York)

Sanders Lab (University of California, San Francisco)

Kathryn Roeder (Carnegie Mellon University, Pittsburgh, PA)

Mark Daly (Broad Institute of MIT and Harvard, Cambridge, MA)

Autism Sequencing Consortium (Emory University, Atlanta)

NIH Support: National Institute Mental Health; National Human Genome Research Institute


A Real-Time Look at Value-Based Decision Making

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All of us make many decisions every day. For most things, such as which jacket to wear or where to grab a cup of coffee, there’s usually no right answer, so we often decide using values rooted in our past experiences. Now, neuroscientists have identified the part of the mammalian brain that stores information essential to such value-based decision making.

Researchers zeroed in on this particular brain region, known as the retrosplenial cortex (RSC), by analyzing movies—including the clip shown about 32 seconds into this video—that captured in real time what goes on in the brains of mice as they make decisions. Each white circle is a neuron, and the flickers of light reflect their activity: the brighter the light, the more active the neuron at that point in time.

All told, the NIH-funded team, led by Ryoma Hattori and Takaki Komiyama, University of California at San Diego, La Jolla, made recordings of more than 45,000 neurons across six regions of the mouse brain [1]. Neural activity isn’t usually visible. But, in this case, researchers used mice that had been genetically engineered so that their neurons, when activated, expressed a protein that glowed.

Their system was also set up to encourage the mice to make value-based decisions, including choosing between two drinking tubes, each with a different probability of delivering water. During this decision-making process, the RSC proved to be the region of the brain where neurons persistently lit up, reflecting how the mouse evaluated one option over the other.

The new discovery, described in the journal Cell, comes as something of a surprise to neuroscientists because the RSC hadn’t previously been implicated in value-based decisions. To gather additional evidence, the researchers turned to optogenetics, a technique that enabled them to use light to inactivate neurons in the RSC’s of living animals. These studies confirmed that, with the RSC turned off, the mice couldn’t retrieve value information based on past experience.

The researchers note that the RSC is heavily interconnected with other key brain regions, including those involved in learning, memory, and controlling movement. This indicates that the RSC may be well situated to serve as a hub for storing value information, allowing it to be accessed and acted upon when it is needed.

The findings are yet another amazing example of how advances coming out of the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative are revolutionizing our understanding of the brain. In the future, the team hopes to learn more about how the RSC stores this information and sends it to other parts of the brain. They note that it will also be important to explore how activity in this brain area may be altered in schizophrenia, dementia, substance abuse, and other conditions that may affect decision-making abilities. It will also be interesting to see how this develops during childhood and adolescence.

Reference:

[1] Area-Specificity and Plasticity of History-Dependent Value Coding During Learning. Hattori R, Danskin B, Babic Z, Mlynaryk N, Komiyama T. Cell. 2019 Jun 13;177(7):1858-1872.e15.

Links:

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

Komiyama Lab (UCSD, La Jolla)

NIH Support: National Institute of Neurological Disorders and Stroke; National Eye Institute; National Institute on Deafness and Other Communication Disorders


Seeing the Cytoskeleton in a Whole New Light

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It’s been 25 years since researchers coaxed a bacterium to synthesize an unusual jellyfish protein that fluoresced bright green when irradiated with blue light. Within months, another group had also fused this small green fluorescent protein (GFP) to larger proteins to make their whereabouts inside the cell come to light—like never before.

To mark the anniversary of this Nobel Prize-winning work and show off the rainbow of color that is now being used to illuminate the inner workings of the cell, the American Society for Cell Biology (ASCB) recently held its Green Fluorescent Protein Image and Video Contest. Over the next few months, my blog will feature some of the most eye-catching entries—starting with this video that will remind those who grew up in the 1980s of those plasma balls that, when touched, light up with a simulated bolt of colorful lightning.

This video, which took third place in the ASCB contest, shows the cytoskeleton of a frequently studied human breast cancer cell line. The cytoskeleton is made from protein structures called microtubules, made visible by fluorescently tagging a protein called doublecortin (orange). Filaments of another protein called actin (purple) are seen here as the fine meshwork in the cell periphery.

The cytoskeleton plays an important role in giving cells shape and structure. But it also allows a cell to move and divide. Indeed, the motion in this video shows that the complex network of cytoskeletal components is constantly being organized and reorganized in ways that researchers are still working hard to understand.

Jeffrey van Haren, Erasmus University Medical Center, Rotterdam, the Netherlands, shot this video using the tools of fluorescence microscopy when he was a postdoctoral researcher in the NIH-funded lab of Torsten Wittman, University of California, San Francisco.

All good movies have unusual plot twists, and that’s truly the case here. Though the researchers are using a breast cancer cell line, their primary interest is in the doublecortin protein, which is normally found in association with microtubules in the developing brain. In fact, in people with mutations in the gene that encodes this protein, neurons fail to migrate properly during development. The resulting condition, called lissencephaly, leads to epilepsy, cognitive disability, and other neurological problems.

Cancer cells don’t usually express doublecortin. But, in some of their initial studies, the Wittman team thought it would be much easier to visualize and study doublecortin in the cancer cells. And so, the researchers tagged doublecortin with an orange fluorescent protein, engineered its expression in the breast cancer cells, and van Haren started taking pictures.

This movie and others helped lead to the intriguing discovery that doublecortin binds to microtubules in some places and not others [1]. It appears to do so based on the ability to recognize and bind to certain microtubule geometries. The researchers have since moved on to studies in cultured neurons.

This video is certainly a good example of the illuminating power of fluorescent proteins: enabling us to see cells and their cytoskeletons as incredibly dynamic, constantly moving entities. And, if you’d like to see much more where this came from, consider visiting van Haren’s Twitter gallery of microtubule videos here:

Reference:

[1] Doublecortin is excluded from growing microtubule ends and recognizes the GDP-microtubule lattice. Ettinger A, van Haren J, Ribeiro SA, Wittmann T. Curr Biol. 2016 Jun 20;26(12):1549-1555.

Links:

Lissencephaly Information Page (National Institute of Neurological Disorders and Stroke/NIH)

Wittman Lab (University of California, San Francisco)

Green Fluorescent Protein Image and Video Contest (American Society for Cell Biology, Bethesda, MD)

NIH Support: National Institute of General Medical Sciences


A Neuronal Light Show

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Credit: Chen X, Cell, 2019

These colorful lights might look like a video vignette from one of the spectacular evening light shows taking place this holiday season. But they actually aren’t. These lights are illuminating the way to a much fuller understanding of the mammalian brain.

The video features a new research method called BARseq (Barcoded Anatomy Resolved by Sequencing). Created by a team of NIH-funded researchers led by Anthony Zador, Cold Spring Harbor Laboratory, NY, BARseq enables scientists to map in a matter of weeks the location of thousands of neurons in the mouse brain with greater precision than has ever been possible before.

How does it work? With BARseq, researchers generate uniquely identifying RNA barcodes and then tag one to each individual neuron within brain tissue. As reported recently in the journal Cell, those barcodes allow them to keep track of the location of an individual cell amid millions of neurons [1]. This also enables researchers to map the tangled paths of individual neurons from one region of the mouse brain to the next.

The video shows how the researchers read the barcodes. Each twinkling light is a barcoded neuron within a thin slice of mouse brain tissue. The changing colors from frame to frame correspond to one of the four letters, or chemical bases, in RNA (A=purple, G=blue, U=yellow, and C=white). A neuron that flashes blue, purple, yellow, white is tagged with a barcode that reads GAUC, while yellow, white, white, white is UCCC.

By sequencing and reading the barcodes to distinguish among seemingly identical cells, the researchers mapped the connections of more than 3,500 neurons in a mouse’s auditory cortex, a part of the brain involved in hearing. In fact, they report they’re now able to map tens of thousands of individual neurons in a mouse in a matter of weeks.

What makes BARseq even better than the team’s previous mapping approach, called MAPseq, is its ability to read the barcodes at their original location in the brain tissue [2]. As a result, they can produce maps with much finer resolution. It’s also possible to maintain other important information about each mapped neuron’s identity and function, including the expression of its genes.

Zador reports that they’re continuing to use BARseq to produce maps of other essential areas of the mouse brain with more detail than had previously been possible. Ultimately, these maps will provide a firm foundation for better understanding of human thought, consciousness, and decision-making, along with how such mental processes get altered in conditions such as autism spectrum disorder, schizophrenia, and depression.

Here’s wishing everyone a safe and happy holiday season. It’s been a fantastic year in science, and I look forward to bringing you more cool NIH-supported research in 2020!

References:

[1] High-Throughput Mapping of Long-Range Neuronal Projection Using In Situ Sequencing. Chen X, Sun YC, Zhan H, Kebschull JM, Fischer S, Matho K, Huang ZJ, Gillis J, Zador AM. Cell. 2019 Oct 17;179(3):772-786.e19.

[2] High-Throughput Mapping of Single-Neuron Projections by Sequencing of Barcoded RNA. Kebschull JM, Garcia da Silva P, Reid AP, Peikon ID, Albeanu DF, Zador AM. Neuron. 2016 Sep 7;91(5):975-987.

Links:

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

Zador Lab (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY)

NIH Support: National Institute of Neurological Disorders and Stroke; National Institute on Drug Abuse; National Cancer Institute


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