Summary: A new study reveals how specific brain cells in the hippocampus and entorhinal cortex encode time and experiences, helping us form memories and predict future outcomes.

These neurons fire in patterns reflecting the order of events, even replaying them after the experience is over. This discovery provides insight into how the brain integrates “what” and “when” information to form lasting memories.

Key Facts:

Neurons in the hippocampus and entorhinal cortex store time-related patterns.

The brain replays event sequences during rest, aiding memory formation.

This finding can inform memory-enhancing neuro-prosthetic devices.

Source: UCLA

A landmark study led by UCLA Health has begun to unravel one of the fundamental mysteries in neuroscience – how the human brain encodes and makes sense of the flow of time and experiences.

The study, published in the journal Nature, directly recorded the activity of individual neurons in humans and found specific types of brain cells fired in a way that mostly mirrored the order and structure of a person’s experience.

They found the brain retains these unique firing patterns after the experience is concluded and can rapidly replay them while at rest. Furthermore, the brain is also able to utilize these learned patterns to ready itself for future stimuli following that experience.

These findings provide the first empirical evidence regarding how specific brain cells integrate “what” and “when” information to extract and retain representations of experiences through time.

The study’s senior author, Dr. Itzhak Fried, said the results could serve in the development of neuro-prosthetic devices to enhance memory and other cognitive functions as well as have implications in artificial intelligence’s understanding of cognition in the human brain.

“Recognizing patterns from experiences over time is crucial for the human brain to form memory, predict potential future outcomes and guide behaviors,” said Fried, director of epilepsy surgery at UCLA Health and professor of neurosurgery, psychiatry and biobehavioral sciences at the David Geffen School of Medicine at UCLA.

“But how this process is carried out in the brain at the cellular level had remained unknown – until now.”

Previous research, including by Dr. Fried, used brain recordings and neuroimaging to understand how the brain processes spatial navigation, showing in animal and human models that two regions of the brain – the hippocampus and the entorhinal cortex – played key roles. The two brain regions, both important in memory functions, work to interact to create a “cognitive map.”

The hippocampal neurons act as “place cells” that show when an animal is at a specific location, similar to an ‘X’ on a map, while the entorhinal neurons act as “grid cells” to provide a metric of spatial distance. These cells found first in rodents were later found in humans by Fried’s group.

Further studies have found similar neural actions work to represent non-spatial experiences such as time, sound frequency and characteristics of objects. A seminal finding by Fried and his colleagues was that of “concept cells” in human hippocampus and entorhinal cortex that responds to particular individuals, places or distinct objects and appear to be fundamental to our ability for memory.

To examine the brain processing of events in time, the UCLA study recruited 17 participants with intractable epilepsy who had been previously had depth electrodes implanted in their brains for clinical treatment.

Researchers recorded the neural activity of the participants as they underwent a complex procedure that involved behavioral tasks, pattern recognition and image sequencing.

Participants first underwent an initial screening section during which approximately 120 images of people, animals, objects and landmarks were repeatedly shown to them on a computer over about 40 minutes.

The participants were instructed to perform various tasks such as determining whether the image showed a person or not. The images, of things like famous actors, musicians and places, were selected partly based on each participant’s preferences.

Following this, the participants underwent a three-phase experiment in which they would perform behavioral tasks in response to images that were arbitrarily displayed on different locations of a pyramid-shaped graph. Six images were selected for each participant.

In the first phase, images were displayed in a pseudo-random order. The next phase had the order of images determined by the location on the pyramid graph. The final phase was identical to the first phase.

While watching these images, the participants were asked to perform various behavioral tasks that were unrelated to the positioning of the images on the pyramid graph.

These tasks included determining whether the image showed a male or female or whether a given image was mirrored compared to the previous phase.

In their analyses, Fried and his colleagues found the hippocampal-entorhinal neurons gradually began to modify and closely align their activity to the sequencing of images on the pyramid graphs.

These patterns were formed naturally and without direct instruction to the participants, according to Fried. Additionally, the neuronal patterns reflected the probability of upcoming stimuli and retained the encoded patterns even after the task was completed.

Lead author of the study was Pawel Tacikowski with co-authors Guldamla Kalendar and Davide Ciliberti.

“This study shows us for the first time how the brain uses analogous mechanisms to represent what are seemingly very different types of information: space and time,” Fried said. “We have demonstrated at the neuronal level how these representations of object trajectories in time are incorporated by the human hippocampal-entorhinal system.”

About this neuroscience and time perception research news

Author: Will Houston

Source: UCLA

Contact: Will Houston – UCLA

Image: The image is credited to Neuroscience News

Original Research: The findings will appear in Nature

Segment Transcript

IRA FLATOW: This is Science Friday. I’m Ira Flatow. There’s been a growing body of research that connects what happens in our gut to what happens in our brain. Our gut contains a huge bundle of nerves, one major one, the vagus, leading right up to our gray matter. The gut microbiome is, to me, one of the most interesting frontiers of medicine. You’ll know that if you listen to this program.

And recent research builds on this field showing a clear distinction between the microbiomes of people who are resilient to stress and those who are not. Joining me to talk about this work published in the Journal Nature Mental Health, is the lead author of the study, Dr. Aparna Church, co-director of UCLA’s Goodman Luskin Microbiome Center, based in Los Angeles. Dr. Church, welcome to Science Friday.

ARPANA CHURCH: Thank you for having me on here.

IRA FLATOW: How did you get involved in this?

ARPANA CHURCH: So I was actually– my path to poop was actually from the top versus top down versus bottom up.

IRA FLATOW: Very nice. Very nicely put.

ARPANA CHURCH: So I am actually a psychologist with neuroscience expertise. And I started in the psychology world. And when I came to UCLA, started working in the Division of Digestive Diseases and just realizing like we’re just so interconnected. As a medical field, we are so siloed. And we tend to– for example, if you have a cardiac condition, you go to a cardiologist. If you have a lung condition, you go to a pulmonologist. We’re just so siloed.

But that’s not the way everything works. And as I said, I started from the brain down and realizing that brain was this computer system, this hard drive that controlled all these other organs really was how it started. And then looking at how everything is interconnected. And then being a psychologist, realizing like when people started to talk about mental health and started to use phrases like, I feel sick to my stomach. My head hurts. And just realizing how everything was just interconnected. And so it just seemed like a natural path for me to look at the whole body as a system.

And I don’t just only look at the whole body as a system, but I also look at the environment, because fortunately or unfortunately, we don’t live in bubbles. We’re interconnected to each other. We’re connected to what’s happening in our environment. That’s why I kind of got into this.

IRA FLATOW: Let’s talk about what you found in the study. Tell us.

ARPANA CHURCH: Sure. So, I mean, I think it’s important, first of all, for us to talk about stress. When you think about stress, it’s an inevitable part of life. So studying how we handle stress can really help us understand how to prevent developing diseases. If you think about it, 77% of Americans report physical symptoms caused by stress. And 33% of Americans report that they’re living with extreme stress. So that accounts for over $300 billion that are lost annually in stress related health care costs or even missed work.

And if you think about it, stress is linked to the onset and progression of disease. It can be mental health illnesses like anxiety, depression, or even physical health, issues like obesity, irritable bowel syndrome, cardiovascular disease. In fact, if you think about stress, it’s almost equal to smoking five cigarettes per day.

IRA FLATOW: Is that right?

ARPANA CHURCH: And also think about stress, it’s not just when you’re an adult. It can happen in any form. It can happen any point in the life span from infant to adulthood. Think about a child that’s left in the crib crying. That’s stressful. Think about kids going to school. That’s stressful, making friends, being bullied. That’s all stressful. And then you’re an adult. Economic hardships, and then all the way into old age, you lose a loved one, death of a spouse or a family member.

So stress is just part of our life. It’s inevitable. So for this study, that’s what really was the impetus of looking at the study. I really wanted to know what it was about stress and why is it, because we all experience stress? Every one of us, in some form or another experiences stress. So why is it that some people who experience stress do really poorly? And what is it about those resilient individuals, those individuals who have this grit.

What is it about them that who, despite experiencing stress, are really highly resilient. And so that really was the question. And honestly, in medicine and in research, we’re always looking at the negative, we’re always looking at disease. So I really wanted to flip the script and say like, what is it about the people that do really well? How about studying those individuals and maybe that might give us some insight?

IRA FLATOW: And you went by looking into people’s guts to find the answer.

ARPANA CHURCH: We actually– we did a lot of things. So we had 116 adult individuals. And we gave them a whole bunch of questionnaires and physical and psychological exams. So we measured things like anxiety, depression. We also measured resilience. And the way we measured resilience was using something known as the Connor Davidson Resilience Scale, which is basically this 10-item scale that measures things like positive acceptance of change, tolerance of negative affect, tenacity, the ability to recover after stressful events.

| there are really five factors of resilience. One is personal competence, trust in one’s instincts, positive acceptance of change, sense of control, spiritual influences. And we also measured cognitive functioning. Then we also put them in the MRI scanner and we basically looked at not only their brain structure, but also the connectivity of different brain regions. So how one brain region is connected to another. And then we collected their stool in order to look at their microbiome abundance and function.

IRA FLATOW: That was a great windup. Here’s the pitch. What did you find that was different in one person or one kind of stress handler than another?

ARPANA CHURCH: Yeah, so the highly resilient individuals, the ones that did really well with stress, if you looked at the brain, we found that there were brain features or brain signatures, features and functions that were related to improved emotional regulation and cognition. So what that means is if you think about the brakes in your car, right, if you tap the brakes a little bit, your car stops, great working brakes. But you’re in in a near car collision and your brakes are not working that well, and you’re jamming down your brakes and you’re pressing really hard, that basically shows that those brakes are not working that great. So that’s the same thing.

So those cognitive, those control regions of the brain were working really well. They were able to modulate like these emotional or these hyperarousal regions in the brain. And then we also saw that at the gut level, there were these metabolites and these transcriptomes that were linked to reduced inflammation and also were related to better gut barrier integrity. We also saw that these individuals were very extroverted, they were very mindful. And this was really interesting. I was blown away with this, but they were also kinder and non-judgmental.

IRA FLATOW: We could all use some of that now.

ARPANA CHURCH: Oh my god, I mean, it says something. I talk about this, just being very easygoing and grateful and accepting really means something. So maybe not being that reactive or my God, I can’t believe somebody did that to me or maybe just like, OK

IRA FLATOW: Well, my question is the chicken or the egg? I mean, are they kinder because of what’s going on in their guts or is that influenced the other way?

ARPANA CHURCH: People always ask this question, whether they’re talking about whether it’s the brain that’s messed up or if it’s the microbiome that’s messed up, or is it our personalities that need adjusting. Who knows. This chicken and egg question always comes up in science. And to be honest, we don’t really know whether it’s the chicken or egg. And I like to say, does it really matter? That the important thing to remember is that because everything is connected, we can stop the cycle and we can influence. Because if you think about it, everything is connected. It’s bi-directional. It’s like the cyclical loop.

So what I like to say, who cares what comes first or after? The point is that we can break the cycle and intervene and change things. That’s what we really need to be asking is, can we change it? And how can we change it?

IRA FLATOW: Well that’s– you anticipated my next exact question. Can we change it? And how can we change it? I mean, from what you’ve learned in your study, you found biological markers. You found regions in the brain that act differently, regions in the gut that act differently. How do you use that knowledge?

ARPANA CHURCH: It’s very exciting because your brain is very malleable. Your microbiome is very malleable. And guess what, even your personalities are very malleable. So I love this kind of integrated, what I call whole person or systems biology work because it shows that we can come up with these multi-modal, these multi-pronged interventions that are designed to provide targeted support, whether we’re talking about– at the brain level.

So it could be more resilience training, it could be stress reduction. But even at the behavioral level, think about, OK, maybe teaching people to be more grateful, more easygoing, getting along with people, being more extroverted, maybe not being so as neurotic. Just those kinds of things, being more mindful and non-judgmental.

And then at the microbiome level, people always talk about my God, how can I change my microbiome. And I always tell people, guess what, the microbiome is the easiest thing to change. You can do things today that will change your microbiome within 24 hours, even by tomorrow. So I know when people think about changing the microbiome, they talk about, fecal microbiome transplants or taking crapsules. And I’m like, let’s not even go there. Let’s just talk about easy things, things that we know that work.

So we can talk about probiotics or prebiotics that can change your microbiome, but even something easier than that, your diet, it’s the most accessible, easiest thing to change your diet. And I like to tell people, think about when you’re stressed. Some of us, either eat a lot and we tend to go for those high calorie foods or some of us, just don’t eat, like we go into this kind of I don’t feel like eating, I’m too stressed.

But really just targeting your diet and eating a healthy diet, a diet that’s balanced, that’s diverse, that’s rich in fiber fermented foods, I think that that’s the easiest way to do it. And I always talk about eating diets rich in diverse fruits and vegetables and I call them ABCs, always be counting. And I don’t mean counting calories. I mean counting at least 30 different vegetables and fruits per week.

IRA FLATOW: Wow.

ARPANA CHURCH: Really help maintain your healthy microbiome. If there’s anything that you take away from today, take that away. ABCs always be counting, 30 different fruits and vegetables per week.

IRA FLATOW: Wow, that’s not the American diet. But I want to know.

ARPANA CHURCH: But people always say that, that’s so hard. How can I do 30? Oh my god, I can’t do that. You’re crazy. I have a hard time just getting two vegetables per week. And I tell people, it’s really easy once you start counting. Let me give you an example, if you end up having a bowl of soup or a bowl of stew, think about what you’re putting in that stew, right.

You’re putting tomatoes, onions, garlic, maybe some kind of herb, maybe some kind of spice, like turmeric or pepper, that’s already five or six right there. You add some carrots, maybe. That’s seven. That’s seven already in one meal. So 30 per week, that’s easy.

IRA FLATOW: Wow. You mentioned the term very quickly that I have to go back. I have to replay the tape in my mind. You talked about when we were talking about changing your gut health and you talked about probiotics and crapsules, crapsules. I think I know what that is. But you have to tell me.

ARPANA CHURCH: It’s just a made up word.

IRA FLATOW: I love it.

ARPANA CHURCH: So there’s something known as fecal microbiome transplant, where you basically taking the microbiome of somebody else and you’re ingesting it, whether you’re ingesting it through a capsule. There have been stories of people like making milkshakes. I mean, this I know is disgusting, but people have talked about making milkshakes and having it that way or even put it up through your colon.

So those are ways that you can have these microbial transplants. But if you’ve heard stories of people who have tried to do these kinds of things, it’s not only first of all, it’s not regulated. It’s very risky. It can be very complicated. But secondly, whatever that other person ends like has, you will end up getting that. So you might end up treating one thing, but then you might end up getting for example, like say, for example, I decided to take my husband’s poop and somehow ingest it, whether it’s through a capsule or whatever.

If he has acne, I will end up getting acne.

IRA FLATOW: No.

ARPANA CHURCH: If he has depression, I will end up getting depression. So it’s really very

IRA FLATOW: Unintended consequences.

ARPANA CHURCH: Yes, unintended. And it’s not regulated, and it’s just very complicated. So I really– I really think they’re crap. They’re crapsules. I really don’t advise.

IRA FLATOW: So you don’t recommend a fecal microbiome transplant from the stress resilient people into people who might need it because there’s unintended consequences of that.

ARPANA CHURCH: Unintended, and I just don’t think the research is there. I think if we really need to be doing more research, maybe we need to be doing more research on creating targeted probiotics or even prebiotics or synbiotics. So, for example, like we could take the microbial markers from this study looking at the bacteria or the metabolites that are impacted and creating a supplement from that and then testing that to see if that works. That to me, is safer. It’s more regulated.

IRA FLATOW: Is that on the horizon, you think, to do that?

ARPANA CHURCH: This is where the whole motive of the Goodman Luskin Microbiome center is to be able to develop these targeted either brain or gut microbiome targeted treatments. That’s the whole point of the center, is that we do these large studies and we find these signatures. And then. OK, so people are then. OK, now what? OK, fine. Great, you found this signature. How does this help me?

Sure we can give them interim solutions like, hey maybe change your diet. But I think these kind of tested and engineered supplements are definitely on the horizon. In fact, we have one clinical trial that we’re doing right now based upon a patented probiotic blend that actually came out of a study from the lab.

IRA FLATOW: Interesting. I mean, I hear you saying that we are really so connected to our poop, aren’t we? Yeah, more than people realize.

ARPANA CHURCH: Yes.

IRA FLATOW: Well, there you have it. This has been highly fascinating, Dr. Church. This is– I think I’m certainly a better person for learning about poop and the microbiome and all the things you brought with you to share with us today. Thank you for taking time to be with us today.

ARPANA CHURCH: Thank you for having me.

IRA FLATOW: Dr. Arpana Church, co-director of UCLA’s Goodman Luskin Microbiome center, based in Los Angeles.

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Neurologists have long wondered how the human brain processes time. Now, a recent study by UCLA Health has shed new light on how the brain encodes and interprets the flow of time and human experience. It provides the first solid proof of how brain cells combine details about “what” and “when” experiences that help to store memories over time.

Published in Nature, the study examined brain cells and discovered that specific neurons fired off in ways that reflected the participants’ experiences. The researchers found that the brain holds and remembers these firing patterns and can relay them when the individual rests, preparing the brain for similar experiences in the future.

The study’s lead author, Dr. Itzhak Fried, said these findings could help create brain implants to improve memory and other mental functions. They also help artificial intelligence better understand how the human brain works.

“Recognizing patterns from experiences over time is crucial for the human brain to form memory, predict potential future outcomes, and guide behaviors,” said Fried, director of epilepsy surgery at UCLA Health and professor of neurosurgery, psychiatry, and biobehavioral sciences at the David Geffen School of Medicine at UCLA in a press release.

“But how this process is carried out in the brain at the cellular level had remained unknown – until now.”

Dr. Fried’s earlier research used brain scans and recordings to understand how the brain helps us navigate space. This research showed that two areas, the hippocampus and entorhinal cortex, play critical roles. These areas help create a “mental map” of the world. The hippocampus has “place cells” that light up when you are in a specific spot, like marking an ‘X’ on a map. The entorhinal cortex has “grid cells” that measure distances between places. These cells were first discovered in rodents, but Dr. Fried’s team later found them in humans.

The Hippocampus is a complex brain structure deep into the temporal lobe. Studies have shown that specific region within the brain can also be affected by a variety of neurological and psychiatric disorders. But why research the hippocampus as the area of the brain connected to time and experiences?

Additional research has shown that the brain uses similar processes to understand experiences that aren’t related to physical space, like time, sound, and the features of objects. Fried and his team made a fundamental discovery by identifying “concept cells” in parts of the brain called the hippocampus and entorhinal cortex. These cells react to specific people, places, or unique objects and are crucial for remembering things.

The researchers at UCLA enlisted 17 individuals with intractable epilepsy who had previously had depth electrodes implanted in their brains for clinical treatment.

The study involved showing participants a series of images, such as famous people, animals, and landmarks, and asking them to perform tasks like identifying whether an image was of a person. Later, participants viewed smaller images arranged in specific sequences on a pyramid-shaped graph. While doing unrelated tasks, their brain activity was monitored.

The researchers found that specific brain cells in the hippocampus gradually aligned their activity to the sequence of images, even though the participants weren’t told to focus on the order. These brain patterns remained after the tasks, showing how the brain naturally encodes sequences of events.

“This study shows us for the first time how the brain uses analogous mechanisms to represent what are seemingly very different types of information: space and time,” Fried said.

“We have demonstrated at the neuronal level how these representations of object trajectories in time are incorporated by the human hippocampal-entorhinal system.”

Chrissy Newton is a PR professional and founder of VOCAB Communications. She currently appears on The Discovery Channel and Max and hosts the Rebelliously Curious podcast, which can be found on The Debrief’s YouTube Channel on all audio podcast streaming platforms. Follow her on X: @ChrissyNewton and at chrissynewton.com.

Summary: Researchers have identified changes in brain connectivity before and after puberty that may explain why some children with chromosome 22q11.2 deletion syndrome are more susceptible to autism and schizophrenia. Using brain imaging in both mice and humans, the study found that brain regions involved in social behavior were hyperconnected in childhood but under-connected after puberty.

These shifts appear linked to changes in synaptic structure, particularly a sharp loss of dendritic spines after puberty. Inhibiting a key protein, GSK3-beta, partially restored connectivity in mice, highlighting a potential therapeutic target for neurodevelopmental disorders.

Key Facts:

Connectivity Flip: Brain regions in 22q deletion were overconnected before puberty, under-connected after.

Brain regions in 22q deletion were overconnected before puberty, under-connected after. Synaptic Link: Post-pubertal drop in dendritic spines correlated with disrupted social behaviors.

Post-pubertal drop in dendritic spines correlated with disrupted social behaviors. Targetable Pathway: Inhibiting GSK3-beta restored connectivity and spine density in mice.

Source: UCLA

Changes in brain connectivity before and after puberty may explain why some children with a rare genetic disorder have higher risk of developing autism or schizophrenia, according to a UCLA Health study.

Developmental psychiatric disorders like autism and schizophrenia are associated with changes in brain functional connectivity. However, the complexity of these conditions make it difficult to understand the underlying biological causes.

By studying genetically defined brain disorders, researchers at UCLA Health and collaborators have shed light on possible mechanisms. “

The protein GSK3-beta, which is involved in synapse regulation, may play a role in the connectivity changes. Credit: Neuroscience News

The UCLA study examined a particular genetic condition called chromosome 22q11.2 deletion syndrome — caused by missing DNA on chromosome 22 — which is associated with higher risk of developing neuropsychiatric conditions such as autism and schizophrenia.

But the underlying biological basis of this association has not been well understood.

In the study recently published in the journal Science Advances, researchers used functional brain imaging in both mice and humans to investigate potential mechanisms driving the connection between the genetic mutation and development of neuropsychiatric conditions.

Functional brain imaging showed the brain regions in both humans and genetically modified mice were hyperconnected before puberty before switching to being under-connected after puberty, particularly in brain regions tied to social skills and autism.

Co-senior author Carrie Bearden, Professor at the UCLA Health Semel Institute and the UCLA Brain Research Institute, said changes at the synapse level appear to explain the sudden shift in connectivity and associated effects on social behavior

“Differences in functional connectivity observed on MRI are commonly found in psychiatric disorders, but we don’t have a good understanding of why. It was really valuable to study this phenomenon across species,” Bearden said.

Using mice that were genetically modified to mimic chromosome 22q11.2 deletion syndrome, Bearden and her colleagues at the Italian Institute of Technology found younger mice had a larger density of dendritic spines — small protrusions on brain cells used to communicate with other neurons via synapses — during childhood compared to wild-type (normal) mice.

After the mice reached the equivalent of puberty, the number of dendritic spines sharply decreased compared to wild-type mice.

The protein GSK3-beta, which is involved in synapse regulation, may play a role in the connectivity changes.

Bearden and her collaborators used a drug to inhibit GSK3-beta, which worked to temporarily restore brain activity and dendritic spine density in the mice, possibly by regulating the removal of dendritic spines.

Brain imaging of humans with the condition also found the brain regions affected by the connectivity changes had enriched genes related to GSK3-beta. Further, the brain connectivity changes were related to social behavior in humans, suggesting that the altered wiring contributes to autism traits.

These findings, Bearden said, suggests that synaptic dysfunction drives the changes in brain activity and could be a target to prevent or reduce symptoms caused by chromosome 22q11.2 deletion syndrome.

“These findings strongly suggest that over-weeding of synapses during development may contribute to the behavioral challenges we see,” Bearden said.

The study was co-led by Alessandro Gozzi of the Istituto Italiano di Tecnologia in Rovereto, Italy.

About this autism research news

Author: Will Houston

Source: UCLA

Contact: Will Houston – UCLA

Image: The image is credited to Neuroscience News

Original Research: Open access.

“Synaptic-dependent developmental dysconnectivity in 22q11.2 deletion syndrome” by Carrie Bearden et al. Science Advances

Abstract

Synaptic-dependent developmental dysconnectivity in 22q11.2 deletion syndrome

Chromosome 22q11.2 deletion increases the risk of neuropsychiatric disorders like autism and schizophrenia. Disruption of large-scale functional connectivity in 22q11 deletion syndrome (22q11DS) has been widely reported, but the biological factors driving these changes remain unclear.

We used a cross-species design to uncover the developmental trajectory and neural underpinnings of brain dysconnectivity in 22q11DS. In LgDel mice, a model for 22q11DS, we found age-specific patterns of brain dysconnectivity, with widespread fMRI hyperconnectivity in juvenile mice reconfiguring to hippocampal hypoconnectivity over puberty.

These changes correlated with developmental alterations in dendritic spine density, and both were transiently normalized by GSK3β inhibition, suggesting a synaptic origin for this phenomenon.

Notably, analogous pubertal hyperconnectivity-to-hypoconnectivity reconfiguration occurs in human 22q11DS, affecting cortical regions enriched for GSK3β-associated synaptic genes and autism-relevant transcripts. This dysconnectivity also predicts age-dependent social alterations in 22q11DS individuals.

These results suggest that synaptic mechanisms underlie developmental brain dysconnectivity in 22q11DS.

Fluorescent image of a developing human hippocampus. [Oier Pastor-Alonso/UCSF]

An international research team has provided an unprecedented look at how gene regulation evolves during human brain development, showing how the 3D structure of chromatin—DNA and proteins—plays a critical role. Using single-cell profiling and multimodal imaging techniques, the team headed by Chongyuan Luo, PhD, at the University of California, Los Angeles (UCLA), and Mercedes Paredes, MD, PhD, at UC San Francisco (UCSF), created the first map of DNA modification in the hippocampus (HPC) and prefrontal cortex (PFC)—two regions of the brain critical to learning, memory, and emotional regulation. These areas are also frequently involved in disorders such as autism and schizophrenia. The study offers new insights into how early brain development may shape lifelong mental health.

“Neuropsychiatric disorders, even those emerging in adulthood, often stem from genetic factors disrupting early brain development,” said Luo, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “Our map offers a baseline to compare against genetic studies of diseased-affected brains and pinpoint when and where molecular changes occur.”

The researchers hope their data resource, which they’ve made publicly available through an online platform, will prove to be a valuable tool that scientists can use to connect genetic variants associated with such conditions to the genes, cells and developmental periods that are most sensitive to their effects.

Luo, Paredes and collaborating scientists at the Salk Institute, UC San Diego, and Seoul National University, report on their studies in Nature, in a paper titled “Temporally distinct 3D multi-omic dynamics in the developing human brain.” In their paper they concluded, “Our data provide multimodal resources for studying gene regulatory dynamics in brain development and demonstrate that single-cell three-dimensional multi-omics is a powerful approach for dissecting neuropsychiatric risk loci.”

The adult human brain contains hundreds of cell types that exhibit what the authors described as “an extraordinary diversity of molecular, morphological, anatomic and functional characteristics.” And while the human hippocampus and prefrontal cortex play critical roles in learning and cognition, they continued, “the dynamic molecular characteristics of their development remain enigmatic.”

To produce their map the research team used a cutting-edge sequencing approach Luo developed and scaled with support from the UCLA Broad Stem Cell Research Center Flow Cytometry Core, called single nucleus methyl-seq and chromatin conformation capture (snm3C-seq).

This technique enables researchers to simultaneously analyze two epigenetic mechanisms that control gene expression on a single-cell basis: chemical changes to DNA known as methylation, and chromatin conformation, the 3D structure of how chromosomes are tightly folded to fit into nuclei.

Figuring out how these two regulatory elements act on genes that affect development is a critical step to understanding how errors in this process lead to neuropsychiatric conditions. Yet, as the researchers pointed out, to date, “the dynamic trajectory of DNA methylation and chromatin conformation changes have not been characterized with single-cell resolution in prenatal human brain tissues and compared to those of postnatal development using infant and adult samples.”

For their newly reported study, the research team analyzed more than 53,000 brain cells from donors spanning mid-gestation to adulthood, revealing significant changes in gene regulation during critical developmental windows. In capturing such a broad spectrum of developmental phases, the researchers were able to assemble a remarkably comprehensive picture of the massive genetic rewiring that occurs during critical timepoints in human brain development.

“The vast majority of disease-causing variants we’ve identified are located between genes on the chromosome, so it’s challenging to know which genes they regulate,” said Luo, who is also an assistant professor of human genetics at the David Geffen School of Medicine at UCLA. “By studying how DNA is folded inside of individual cells, we can see where genetic variants connect with certain genes, which can help us pinpoint the cell types and developmental periods most vulnerable to these conditions.”

For example, autism spectrum disorder is commonly diagnosed in children aged two and over. However, if researchers can gain a better understanding of the genetic risk of autism and how it impacts development, they can potentially develop intervention strategies to help alleviate the symptoms of autism, like communication challenges, while the brain is developing.

One of the most dynamic periods comes around the midpoint of pregnancy. At this time, neural stem cells called radial glia, which have produced billions of neurons during the first and second trimesters, stop producing neurons and begin generating glial cells, which support and protect neurons. At the same time, the newly formed neurons mature, gaining the characteristics they need to fulfill specific functions and forming the synaptic connections that enable them to communicate.

This stage of development has been overlooked in previous studies, the researchers suggest, due to the limited availability of brain tissue from this period. They commented “Together, the findings of our imaging analysis of the mid-gestational HPC demonstrated spatially distinct chromatin conformation signatures that marked transitions from neural progenitors to mature neurons,” they wrote. “Our study underscores the dynamic shifts from progenitors to neuronal and glial populations in the second and third trimesters to the neonatal period, highlighting the importance of using primary brain specimens in studies of perinatal development.”

Paredes, an associate professor of neurology at UCSF, added, “Our study tackles the complex relationship between DNA organization and gene expression in developing human brain at ages typically not interrogated: the third trimester and infancy. The connections we’ve identified across different cell types through this work could untangle the current challenges in identifying meaningful genetic risk factors for neurodevelopmental and neuropsychiatric conditions.” The authors added, “The pervasive remodeling of the neuronal methylome and chromatin conformation during perinatal development suggests that the human brain is particularly vulnerable to genetic and environmental perturbations that affect these developmental stages…This work provides a data resource to understand the genetic and epigenetic mechanisms of brain diseases.”

The findings also have implications for improving stem cell-based models, such as brain organoids, which are used to study brain development and diseases. The new map offers a benchmark for scientists to ensure these models accurately replicate human brain development.

“Growing a healthy human brain is a tremendous feat,” said co-author Joseph Ecker, PhD, professor at the Salk Institute and Howard Hughes Medical Institute investigator. “Our study establishes an important database that captures key epigenetic changes that occur during brain development, in turn bringing us closer to understanding where and when failures arise in this development that can lead to neurodevelopmental disorders like autism.”