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Discovering the Brain’s Nightly “Rinse Cycle”

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Getting plenty of deep, restful sleep is essential for our physical and mental health. Now comes word of yet another way that sleep is good for us: it triggers rhythmic waves of blood and cerebrospinal fluid (CSF) that appear to function much like a washing machine’s rinse cycle, which may help to clear the brain of toxic waste on a regular basis.

The video above uses functional magnetic resonance imaging (fMRI) to take you inside a person’s brain to see this newly discovered rinse cycle in action. First, you see a wave of blood flow (red, yellow) that’s closely tied to an underlying slow-wave of electrical activity (not visible). As the blood recedes, CSF (blue) increases and then drops back again. Then, the cycle—lasting about 20 seconds—starts over again.

The findings, published recently in the journal Science, are the first to suggest that the brain’s well-known ebb and flow of blood and electrical activity during sleep may also trigger cleansing waves of blood and CSF. While the experiments were conducted in healthy adults, further study of this phenomenon may help explain why poor sleep or loss of sleep has previously been associated with the spread of toxic proteins and worsening memory loss in people with Alzheimer’s disease.

In the new study, Laura Lewis, Boston University, MA, and her colleagues at the Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston. recorded the electrical activity and took fMRI images of the brains of 13 young, healthy adults as they slept. The NIH-funded team also built a computer model to learn more about the fluid dynamics of what goes on in the brain during sleep. And, as it turns out, their sophisticated model predicted exactly what they observed in the brains of living humans: slow waves of electrical activity followed by alternating waves of blood and CSF.

Lewis says her team is now working to come up with even better ways to capture CSF flow in the brain during sleep. Currently, people who volunteer for such experiments have to be able to fall asleep while wearing an electroencephalogram (EEG) cap inside of a noisy MRI machine—no easy feat. The researchers are also recruiting older adults to begin exploring how age-related changes in brain activity during sleep may affect the associated fluid dynamics.

Reference:

[1] Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Fultz NE, Bonmassar G, Setsompop K, Stickgold RA, Rosen BR, Polimeni JR, Lewis LD. Science. 2019 Nov 1;366(6465):628-631.

Links:

Sleep and Memory (National Institute of Mental Health/NIH)

Sleep Deprivation and Deficiency (National Heart, Lung, and Blood Institute/NIH)

Alzheimer’s Disease and Related Dementias (National Institute on Aging/NIH)

NIH Support: National Institute of Mental Health; National Institute of Biomedical Imaging and Bioengineering; National Institute of Neurological Disorders and Stroke


The Perfect Cytoskeletal Storm

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Ever thought about giving cell biology a whirl? If so, I suggest you sit down and take a look at this full-blown cytoskeletal “storm,” which provides a spectacular dynamic view of the choreography of life.

Before a cell divides, it undergoes a process called mitosis that copies its chromosomes and produces two identical nuclei. As part of this process, microtubules, which are structural proteins that help make up the cell’s cytoskeleton, reorganize the newly copied chromosomes into a dense, football-shaped spindle. The position of this mitotic spindle tells the cell where to divide, allowing each daughter cell to contain its own identical set of DNA.

To gain a more detailed view of microtubules in action, researchers designed an experimental system that utilizes an extract of cells from the African clawed frog (Xenopus laevis). As the video begins, a star-like array of microtubules (red) radiate outward in an apparent effort to prepare for cell division. In this configuration, the microtubules continually adjust their lengths with the help of the protein EB-1 (green) at their tips. As the microtubules grow and bump into the walls of a lab-generated, jelly-textured enclosure (dark outline), they buckle—and the whole array then whirls around the center.

Abdullah Bashar Sami, a Ph.D. student in the NIH-supported lab of Jesse “Jay” Gatlin, University of Wyoming, Laramie, shot this movie as a part his basic research to explore the still poorly understood physical forces generated by microtubules. The movie won first place in the 2019 Green Fluorescent Protein Image and Video Contest sponsored by the American Society for Cell Biology. The contest honors the 25th anniversary of the discovery of green fluorescent protein (GFP), which transformed cell biology and earned the 2008 Nobel Prize in Chemistry for three scientists who had been supported by NIH.

Like many movies, the setting was key to this video’s success. The video was shot inside a microfluidic chamber, designed in the Gatlin lab, to study the physics of microtubule assembly just before cells divide. The tiny chamber holds a liquid droplet filled with the cell extract.

When the liquid is exposed to an ultra-thin beam of light, it forms a jelly-textured wall, which traps the molecular contents inside [1]. Then, using time-lapse microscopy, the researchers watch the mechanical behavior of GFP-labeled microtubules [2] to see how they work to position the mitotic spindle. To do this, microtubules act like shapeshifters—scaling to adjust to differences in cell size and geometry.

The Gatlin lab is continuing to use their X. laevis system to ask fundamental questions about microtubule assembly. For many decades, both GFP and this amphibian model have provided cell biologists with important insights into the choreography of life, and, as this work shows, we can expect much more to come!

References:

[1] Microtubule growth rates are sensitive to global and local changes in microtubule plus-end density. Geisterfer ZM, Zhu D, Mitchison T, Oakey J, Gatlin JC. November 20, 2019.

[2] Tau-based fluorescent protein fusions to visualize microtubules. Mooney P, Sulerud T, Pelletier JF, Dilsaver MR, et al. Cytoskeleton (Hoboken). 2017 Jun;74(6):221-232.

Links:

Mitosis (National Human Genome Research Institute/NIH)

Gatlin Lab (University of Wyoming, Laramie)

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

2008 Nobel Prize in Chemistry (Nobel Foundation, Stockholm, Sweden)

NIH Support: National Institute of General Medical Sciences


Why Flies and Humans Freeze When Startled

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When faced with something unexpected and potentially ominous, like a sudden, loud noise or a threat of danger, humans often freeze before we act. This is colloquially referred to as the “deer in the headlights” phenomenon. The movie of fruit flies that you see above may help explain the ancient origins of the “startle response” and other biomechanical aspects of motion.

In this video, which shows a footrace between two flies (Drosophila melanogaster), there are no winners or losers. Their dash across the screen provides a world-class view of the biomechanics of walking in these tiny, 3 millimeter-long insects that just won’t sit still.

The fly at the top zips along at about 25 millimeters per second, the normal walking speed for Drosophila. As a six-legged hexapod, the fly walks with a “tripod gait,” alternating between its stance phase—right fore (RF), left middle (LM), and right hind (RH) —and its swing phase sequence of left fore (LF), right middle (RM), and left hind (LH).

The slowpoke at the bottom of the video clocks in at a mere 15 millimeters per second. This fly’s more-tentative gait isn’t due to an injury or a natural lack of speed. What is causing the delay is the rapid release of the chemical messenger serotonin into its nervous system, which models a startle response.

You may have already heard about serotonin because of its role in regulating mood and appetite in humans. Now, a team led by Richard S. Mann and Clare Howard, Columbia University’s Zuckerman Institute, New York, has discovered that fruit flies naturally release serotonin to turn on neural circuits that downshift and steady the speed of their gait.

As detailed recently in Current Biology [1], serotonin is active under myriad conditions to tell flies to slow things down. For example, serotonin helps flies weather the stress of extreme temperatures, conserve energy during bouts of hunger, and even walk upside down on the ceiling.

But the research team, which was supported by the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, found that serotonin’s most-powerful effect came during an actual startle response, prompted by a sudden, jolting vibration. Scientists suspect the release of serotonin activates motor neurons much like an emergency brake, stiffening and locking up the fly’s leg joints. When the researchers blocked the fly’s release of serotonin, it interrupted their normal startle response.

In years past, such a detailed, high-resolution “action video” of Drosophila, one of the most-popular model organisms in biology, would have been impossible to produce. Fruit flies are tiny and possess extremely high energy.

But a few years ago, the Mann lab developed the approach used in this video to bring the hurried gait of fruit flies into tight focus [2]. Their system combines an optical touch sensor and high-speed video imaging that records the footfalls of all six of a fly’s feet.

Then, using the lab’s unique software program called FlyWalker , the researchers can extract various biomechanical parameters of walking in time and space. These include step length, footprint alignment, and, as the letters in the video show, the natural sequence of a tripod gait.

Drosophila may be a very distant relative of humans. But these ubiquitous insects that sometimes buzz around our fruit bowls contain many fundamental clues into human biology, whether the area of research is genetics, nutrition, biomechanics, or even the underlying biology of the startle response.

Reference:

[1] Serotonergic Modulation of Walking in Drosophila. Howard CE, Chen CL, Tabachnik T, Hormigo R, Ramdya P, Mann RS. Curr Biol. 2019 Nov 22.

[2] Quantification of gait parameters in freely walking wild type and sensory deprived Drosophila melanogaster. Mendes CS, Bartos I, Akay T, Márka S, Mann RS. Elife. 2013 Jan 8;2:e00231.

Links:

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

Mann Lab (Columbia University’s Zuckerman Institute, New York)

MouseWalker Colored Feet (YouTube)

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


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


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