Posted on by Dr. Francis Collins
You might think nutrient-sensing cells in the human gastrointestinal (GI) tract would have no connection whatsoever to autism spectrum disorder (ASD). But if Diego Bohórquez’s “big idea” is correct, these GI cells, called neuropods, could one day help to provide a direct link into understanding and treating some aspects of autism and other brain disorders.
Bohórquez, a researcher at Duke University, Durham, NC, recently discovered that cells in the intestine, previously known for their hormone-releasing ability, form extensions similar to neurons. He also found that those extensions connect to nerve fibers in the gut, which relay signals to the vagus nerve and onward to the brain. In fact, he found that those signals reach the brain in milliseconds .
Bohórquez has dedicated his lab to studying this direct, high-speed hookup between gut and brain and its impact on nutrient sensing, eating, and other essential behaviors. Now, with support from a 2019 NIH Director’s New Innovator Award, he will also explore the potential for treating autism and other brain disorders with drugs that act on the gut.
Bohórquez became interested in autism and its possible link to the gut-brain connection after a chance encounter with Geraldine Dawson, director of the Duke Center for Autism and Brain Development. Dawson mentioned that autism typically affects multiple organ systems.
With further reading, he discovered that kids with autism frequently cope with GI issues, including bowel inflammation, abdominal pain, constipation, and/or diarrhea . They often also show unusual food-related behaviors, such as being extremely picky eaters. But his curiosity was especially piqued by evidence that certain gut microbes can influence abnormal behaviors in mice that model autism.
With his New Innovator Award, Bohórquez will study neuropods and the gut-brain connection in a mouse model of autism. Using the tools of optogenetics, which make it possible to activate cells with light, he’ll also see whether autism-like symptoms in mice can be altered or alleviated by controlling neuropods in the gut. Those symptoms include anxiety, repetitive behaviors, and lack of interest in interacting with other mice. He’ll also explore changes in the animals’ eating habits.
In another line of study, he will take advantage of intestinal tissue samples collected from people with autism. He’ll use those tissues to grow and then examine miniature intestinal “organoids,” looking for possible evidence that those from people with autism are different from others.
For the millions of people now living with autism, no truly effective drug therapies are available to help to manage the condition and its many behavioral and bodily symptoms. Bohórquez hopes one day to change that with drugs that act safely on the gut. In the meantime, he and his fellow “GASTRONAUTS” look forward to making some important and fascinating discoveries in the relatively uncharted territory where the gut meets the brain.
 A gut-brain neural circuit for nutrient sensory transduction. Kaelberer MM, Buchanan KL, Klein ME, Barth BB, Montoya MM, Shen X, Bohórquez DV. Science. 2018 Sep 21;361(6408).
 Association of maternal report of infant and toddler gastrointestinal symptoms with autism: evidence from a prospective birth cohort. Bresnahan M, Hornig M, Schultz AF, Gunnes N, Hirtz D, Lie KK, Magnus P, Reichborn-Kjennerud T, Roth C, Schjølberg S, Stoltenberg C, Surén P, Susser E, Lipkin WI. JAMA Psychiatry. 2015 May;72(5):466-474.
Autism Spectrum Disorder (National Institute of Mental Health/NIH)
Bohórquez Lab (Duke University, Durham, NC)
Bohórquez Project Information (NIH RePORTER)
NIH Director’s New Innovator Award (Common Fund)
NIH Support: Common Fund; National Institute of Mental Health
Posted on by Dr. Francis Collins
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 . 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.
 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.
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
Posted on by Dr. Francis Collins
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 . 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:
 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.
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
Posted on by Dr. Francis Collins
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 . 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 . 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!
 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.
 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.
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
Posted on by Dr. Francis Collins
Your brain has the capacity to store a lifetime of memories, covering everything from the name of your first pet to your latest computer password. But what does a memory actually look like? Thanks to some very cool neuroscience, you are looking at one.
The physical manifestation of a memory, or engram, consists of clusters of brain cells active when a specific memory was formed. Your brain’s hippocampus plays an important role in storing and retrieving these memories. In this cross-section of a mouse hippocampus, imaged by the lab of NIH-supported neuroscientist Steve Ramirez, at Boston University, cells belonging to an engram are green, while blue indicates those not involved in forming the memory.
When a memory is recalled, the cells within an engram reactivate and turn on, to varying degrees, other neural circuits (e.g., sight, sound, smell, emotions) that were active when that memory was recorded. It’s not clear how these brain-wide connections are made. But it appears that engrams are the gatekeepers that mediate memory.
The story of this research dates back several years, when Ramirez helped develop a system that made it possible to image engrams by tagging cells in the mouse brain with fluorescent dyes. Using an innovative technology developed by other researchers, called optogenetics, Ramirez’s team then discovered it could shine light onto a collection of hippocampal neurons storing a specific memory and reactivate the sensation associated with the memory .
Ramirez has since gone on to show that, at least in mice, optogenetics can be used to trick the brain into creating a false memory . From this work, he has also come to the interesting and somewhat troubling conclusion that the most accurate memories appear to be the ones that are never recalled. The reason: the mammalian brain edits—and slightly changes—memories whenever they are accessed.
All of the above suggested to Ramirez that, given its tremendous plasticity, the brain may possess the power to downplay a traumatic memory or to boost a pleasant recollection. Toward that end, Ramirez’s team is now using its mouse system to explore ways of suppressing one engram while enhancing another .
For Ramirez, though, the ultimate goal is to develop brain-wide maps that chart all of the neural networks involved in recording, storing, and retrieving memories. He recently was awarded an NIH Director’s Transformative Research Award to begin the process. Such maps will be invaluable in determining how stress affects memory, as well as what goes wrong in dementia and other devastating memory disorders.
 Optogenetic stimulation of a hippocampal engram activates fear memory recall. Liu X, Ramirez S, Pang PT, Puryear CB, Govindarajan A, Deisseroth K, Tonegawa S. Nature. 2012 Mar 22;484(7394):381-385.
 Creating a false memory in the hippocampus. Ramirez S, Liu X, Lin PA, Suh J, Pignatelli M, Redondo RL, Ryan TJ, Tonegawa S. Science. 2013 Jul 26;341(6144):387-391.
 Artificially Enhancing and Suppressing Hippocampus-Mediated Memories. Chen BK, Murawski NJ, Cincotta C, McKissick O, Finkelstein A, Hamidi AB, Merfeld E, Doucette E, Grella SL, Shpokayte M, Zaki Y, Fortin A, Ramirez S. Curr Biol. 2019 Jun 3;29(11):1885-1894.
The Ramirez Group (Boston University, MA)
Ramirez Project Information (Common Fund/NIH)
NIH Director’s Early Independence Award (Common Fund)
NIH Director’s Transformative Research Award (Common Fund)
NIH Support: Common Fund
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