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Mammalian Brain Like You’ve Never Seen It Before

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Credit: Gao et. al, Science

Researchers are making amazing progress in developing new imaging approaches. And they are now using one of their latest creations, called ExLLSM, to provide us with jaw-dropping views of a wide range of biological systems, including the incredibly complex neural networks within the mammalian brain.

In this video, ExLLSM takes us on a super-resolution, 3D voyage through a tiny sample (0.0030 inches thick) from the part of the mouse brain that processes sensation, the primary somatosensory cortex. The video zooms in and out of densely packed pyramidal neurons (large yellow cell bodies), each of which has about 7,000 synapses, or connections. You can also see presynapses (cyan), the part of the neuron that sends chemical signals; and postsynapes (magenta), the part of the neuron that receives chemical signals.

At 1:45, the video zooms in on dendritic spines, which are mushroom-like nubs on the neuronal branches (yellow). These structures, located on the tips of dendrites, receive incoming signals that are turned into electrical impulses. While dendritic spines have been imaged in black and white with electron microscopy, they’ve never been presented before on such a vast, colorful scale.

The video comes from a paper, published recently in the journal Science [1], from the labs of Ed Boyden, Massachusetts Institute of Technology, Cambridge, and the Nobel Prize-winning Eric Betzig, Janelia Research Campus of the Howard Hughes Medical Institute, Ashburn, VA. Like many collaborations, this one comes with a little story.

Four years ago, the Boyden lab developed expansion microscopy (ExM). The technique involves infusing cells with a hydrogel, made from a chemical used in disposable diapers. The hydrogel expands molecules within the cell away from each other, usually by about 4.5 times, but still locks them into place for remarkable imaging clarity. It makes structures visible by light microscopy that are normally below the resolution limit.

Though the expansion technique has worked well with a small number of cells under a standard light microscope, it hasn’t been as successful—until now—at imaging thicker tissue samples. That’s because thicker tissue is harder to illuminate, and flooding the specimen with light often bleaches out the fluorescent markers that scientists use to label proteins. The signal just fades away.

For Boyden, that was a problem that needed to be solved. Because his lab’s goal is to trace the inner workings of the brain in unprecedented detail, Boyden wants to image entire neural circuits in relatively thick swaths of tissue, not just look at individual cells in isolation.

After some discussion, Boyden’s team concluded that the best solution might be to swap out the light source for the standard microscope with a relatively new imaging tool developed in the Betzig lab. It’s called lattice light-sheet microscopy (LLSM), and the tool generates extremely thin sheets of light that illuminate tissue only in a very tightly defined plane, dramatically reducing light-related bleaching of fluorescent markers in the tissue sample. This allows LLSM to extend its range of image acquisition and quickly deliver stunningly vivid pictures.

Telephone calls were made, and the Betzig lab soon welcomed Ruixuan Gao, Shoh Asano, and colleagues from the Boyden lab to try their hand at combining the two techniques. As the video above shows, ExLLSM has proved to be a perfect technological match. In addition to the movie above, the team has used ExLLSM to provide unprecedented views of a range of samples—from human kidney to neuron bundles in the brain of the fruit fly.

Not only is ExLLSM super-resolution, it’s also super-fast. In fact, the team imaged the entire fruit fly brain in 2 1/2 days—an effort that would take years using an electron microscope.

ExLLSM will likely never supplant the power of electron microscopy or standard fluorescent light microscopy. Still, this new combo imaging approach shows much promise as a complementary tool for biological exploration. The more innovative imaging approaches that researchers have in their toolbox, the better for our ongoing efforts to unlock the mysteries of the brain and other complex biological systems. And yes, those systems are all complex. This is life we’re talking about!


[1] Cortical column and whole-brain imaging with molecular contrast and nanoscale resolution. Gao R, Asano SM, Upadhyayula S, Pisarev I, Milkie DE, Liu TL, Singh V, Graves A, Huynh GH, Zhao Y, Bogovic J, Colonell J, Ott CM, Zugates C, Tappan S, Rodriguez A, Mosaliganti KR, Sheu SH, Pasolli HA, Pang S, Xu CS, Megason SG, Hess H, Lippincott-Schwartz J, Hantman A, Rubin GM, Kirchhausen T, Saalfeld S, Aso Y, Boyden ES, Betzig E. Science. 2019 Jan 18;363(6424).


Video: Expansion Microscopy Explained (YouTube)

Video: Lattice Light-Sheet Microscopy (YouTube)

How to Rapidly Image Entire Brains at Nanoscale Resolution, Howard Hughes Medical Institute, January 17, 2019.

Synthetic Neurobiology Group (Massachusetts Institute of Technology, Cambridge)

Eric Betzig (Janelia Reseach Campus, Ashburn, VA)

NIH Support: National Institute of Neurological Disorders and Stroke; National Human Genome Research Institute; National Institute on Drug Abuse; National Institute of Mental Health; National Institute of Biomedical Imaging and Bioengineering

Mapping the Brain’s Memory Bank

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There’s a lot of groundbreaking research now underway to map the organization and internal wiring of the brain’s hippocampus, essential for memory, emotion, and spatial processing. This colorful video depicting a mouse hippocampus offers a perfect case in point.

The video presents the most detailed 3D atlas of the hippocampus ever produced, highlighting its five previously defined zones: dentate gyrus, CA1, CA2, CA3, and subiculum. The various colors within those zones represent areas with newly discovered and distinctive patterns of gene expression, revealing previously hidden layers of structural organization.

For instance, the subiculum, which sends messages from the hippocampus to other parts of the brain, includes several subregions. The subregions include the three marked in red, yellow, and blue at about 23 seconds into the video.

How’d the researchers do it? In the new study, published in Nature Neuroscience, the researchers started with the Allen Mouse Brain Atlas, a rich, publicly accessible 3D atlas of gene expression in the mouse brain. The team, led by Hong-Wei Dong, University of Southern California, Los Angeles, drilled down into the data to pull up 258 genes that are differentially expressed in the hippocampus and might be helpful for mapping purposes.

Some of those 258 genes were generally expressed only in previously defined portions of the hippocampus. Others were “turned on” only in discrete portions of known hippocampal domains, leading the researchers to define 20 distinct subregions that hadn’t been recognized before.

Combining these data, sophisticated analytical tools, and plenty of hard work, the team assembled this detailed atlas, together with connectivity data, to create a detailed wiring diagram. It includes about 200 signaling pathways that show how all those subregions network together and with other portions of the brain.

What’s really interesting is that the data also showed that these components of the hippocampus contribute to three relatively independent brain-wide communication networks. While much more study is needed, those three networks appear to relate to distinct functions of the hippocampus, including spatial navigation, social behaviors, and metabolism.

This more-detailed view of the hippocampus is just the latest from the NIH-funded Mouse Connectome Project. The ongoing project aims to create a complete connectivity atlas for the entire mouse brain.

The Mouse Connectome Project isn’t just for those with an interest in mice. Indeed, because the mouse and human brain are similarly organized, studies in the smaller mouse brain can help to provide a template for making sense of the larger and more complex human brain, with its tens of billions of interconnected neurons.

Ultimately, the hope is that this understanding of healthy brain connections will provide clues for better treating the brain’s abnormal connections and/or disconnections. They are involved in numerous neurological conditions, including Alzheimer’s disease, Parkinson’s disease, and autism spectrum disorder.


[1] Integration of gene expression and brain-wide connectivity reveals the multiscale organization of mouse hippocampal networks. Bienkowski MS, Bowman I, Song MY, Gou L, Ard T, Cotter K, Zhu M, Benavidez NL, Yamashita S, Abu-Jaber J, Azam S, Lo D, Foster NN, Hintiryan H, Dong HW. Nat Neurosci. 2018 Nov;21(11):1628-1643.

Mouse Connectome Project (University of Southern California, Los Angeles)

Human Connectome Project (USC)

Allen Brain Map (Allen Institute, Seattle)

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

NIH Support: National Institute of Mental Health; National Cancer Institute

Taking Microfluidics to New Lengths

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Fiber Microfluidics

Caption: Microfluidic fiber sorting a solution containing either live or dead cells. The type of cell being imaged and the real time voltage (30v) is displayed at bottom. It is easy to imagine how this could be used to sort a mixture of live and dead cells. Credit: Yuan et al., PNAS

Microfluidics—the manipulation of fluids on a microscopic scale— has made it possible to produce “lab-on-a-chip” devices that detect, for instance, the presence of Ebola virus in a single drop of blood. Now, researchers hope to apply the precision of microfluidics to a much broader range of biomedical problems. Their secret? Move the microlab from chips to fibers.

To do this, an NIH-funded team builds microscopic channels into individual synthetic polymer fibers reaching 525 feet, or nearly two football fields long! As shown in this video, the team has already used such fibers to sort live cells from dead ones about 100 times faster than current methods, relying only on natural differences in the cells’ electrical properties. With further design and development, the new, fiber-based systems hold great promise for, among other things, improving kidney dialysis and detecting metastatic cancer cells in a patient’s bloodstream.

Watching Cancer Cells Play Ball

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Credit: Ning Wang, University of Illinois at Urbana-Champaign

As tumor cells divide and grow, they push, pull, and squeeze one another. While scientists have suspected those mechanical stresses may play important roles in cancer, it’s been tough to figure out how. That’s in large part because there hadn’t been a good way to measure those forces within a tissue. Now, there is.

As described in Nature Communications, an NIH-funded research team has developed a technique for measuring those subtle mechanical forces in cancer and also during development [1]. Their ingenious approach is called the elastic round microgel (ERMG) method. It relies on round elastic microspheres—similar to miniature basketballs, only filled with fluorescent nanoparticles in place of air. In the time-lapse video above, you see growing and dividing melanoma cancer cells as they squeeze and spin one of those cell-sized “balls” over the course of 24 hours.

First Day in the Life of Nine Amazing Creatures

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Credit: Tessa Montague, Harvard University, and Zuzka Vavrušová, University of California, San Francisco

Each summer for the last 125 years, students from around the country have traveled to the Marine Biological Laboratory (MBL), Woods Hole, MA, for an intensive course in embryology. While visiting this peaceful and scenic village on Cape Cod, they’re exposed to a dizzying array of organisms and state-of-the-art techniques to study their development.

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