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The Amazing Brain: Zooming Through the Globus Pallidus Externa

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The Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative continues to find new ways to visualize neurons interconnecting into the billions of circuits that control our thoughts, feelings, and movements. This video, another winner in the initiative’s “Show Us Your Brain!” contest, offers a beautiful example of how these imaging techniques are getting better all the time.

The video features a millimeter-thick block of fixed tissue from a part of the mouse brain that’s known for its role in controlling voluntary movement. It’s called the globus pallidus externa (GPE). The video takes us inside the 3D landscape of the GPE, zooming in on the many neural cell bodies (yellow) and their arm-like extensions (red) that receive or transmit information. There’s also another class of neural cells called interneurons (blue) that act only within the circuit.

The video comes from the lab of Kwanghun Chung, Massachusetts Institute of Technology, Cambridge, in collaboration with Byungkook Lim’s group at the University of California, San Diego, and showcases a technique called SHIELD [1]. Brain tissue is extremely delicate to work with and prone to damage. SHIELD, developed in the Chung lab, offers a new way around this longstanding problem.

SHIELD uses polyepoxides, which are epoxy resins often used to produce glues. The researchers’ polyepoxide of choice has a flexible backbone and five branches, which bind to proteins and other molecules in place, including DNA and RNA. The molecule’s flexibility allows it to bind in multiple places along a single biomolecule and form supportive cross-links with other nearby molecules.

All of this support renders the tissue and its biological information extremely stable, even when exposed to heat and other harsh conditions. This makes it possible for researchers to label proteins, RNA, and various other biomolecules of interest simultaneously, as you see shown here in this remarkable video. SHIELD even allowed them to trace the many projections of multiple neural cell types and their connections within the GPE at once.

In the future, the team hopes to learn whether differences in the projection patterns of these neurons or in their molecular details may influence Parkinson’s disease and other illnesses that affect motor control. With this imaging advance and others through the BRAIN Initiative, mapping the biocircuitry of the brain just keeps getting better all the time.


[1] Protection of tissue physicochemical properties using polyfunctional crosslinkers. Park YG, Sohn CH, Chen R, McCue M, Yun DH, Drummond GT, Ku T, Evans NB, Oak HC, Trieu W, Choi H, Jin X, Lilascharoen V, Wang J, Truttmann MC, Qi HW, Ploegh HL, Golub TR, Chen SC, Frosch MP, Kulik HJ, Lim BK, Chung K. Nat Biotechnol. 2018 Dec 17.


Brain Basics: Know Your Brain (National Institute of Neurological Disorders and Stroke/NIH)

Chung Lab (Massachusetts Institute of Technology, Cambridge)

Show Us Your Brain! (BRAIN Initiative/NIH)

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

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

Huntington’s Disease: Gene Editing Shows Promise in Mouse Studies

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Cas9 clipping the Huntington's repeatsMy father was a folk song collector, and I grew up listening to the music of Woody Guthrie. On July 14th, folk music enthusiasts will be celebrating the 105th anniversary of Guthrie’s birth in his hometown of Okemah, OK. Besides being renowned for writing “This Land is Your Land” and other folk classics, Guthrie has another more tragic claim to fame: he provided the world with a glimpse at the devastation caused by a rare, inherited neurological disorder called Huntington’s disease.

When Guthrie died from complications of Huntington’s a half-century ago, the disease was untreatable. Sadly, it still is. But years of basic science advances, combined with the promise of innovative gene editing systems such as CRISPR/Cas9, are providing renewed hope that we will someday be able to treat or even cure Huntington’s disease, along with many other inherited disorders.

Snapshots of Life: A Colorful Look Inside the Retina

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Mapping neurons in the retina

Credit: Amy Robinson, Alex Norton, William Silversmith, Jinseop Kim, Kisuk Lee, Aleks Zlasteski, Matt Green, Matthew Balkam, Rachel Prentki, Marissa Sorek, Celia David, Devon Jones, and Doug Bland, Massachusetts Institute of Technology, Cambridge, MA; Sebastian Seung, Princeton University, Princeton, NJ

This eerie scene might bring back memories of the computer-generated alien war machines from Steven Spielberg’s War of the Worlds thriller. But what you’re seeing is a computer-generated depiction of a quite different world—the world inside the retina, the light-sensitive tissue that lines the back of the eye. The stilt-legged “creatures” are actually ganglion nerve cells, and what appears to be their long “noses” are fibers that will eventually converge to form the optic nerve that relays visual signals to the brain. The dense, multi-colored mat near the bottom of the image is a region where the ganglia and other types of retinal cells interact to convey visual information.

What I find particularly interesting about this image is that it was produced through the joint efforts of people who played EyeWire, an internet crowdsourcing game developed in the lab of computational neuroscientist Sebastian Seung, now at Princeton University in New Jersey.  Seung and his colleagues created EyeWire using a series of high-resolution microscopic images of the mouse retina, which were digitized into 3D cubes containing dense skeins of branching nerve fibers. It’s at this point where the crowdsourcing came in. Online gamers—most of whom aren’t scientists— volunteered for a challenge that involved mapping the 3D structure of individual nerve cells within these 3D cubes. Players literally colored-in the interiors of the cells and progressively traced their long extensions across the image to distinguish them from their neighbors. Sounds easy, but the branches are exceedingly thin and difficult to follow.

Watching Neuron Attachments in Real Time

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Bright neon yellow and green blob with many light green fingers dotted with green and red radiating from it.

Caption: A living cortical neuron in a culture dish. Red and green dots reveal synapses—potential communication junctions between neurons.
Credit: Don Arnold, University of Southern California

This glittering web is actually a live nerve cell, or neuron, in which its branches are labeled with glowing probes. Each dot reveals a potential junction between neurons—called a synapse—where chemicals are released allowing the cells to talk to each other. The red dots reveal inhibitory synapses—which silence electrical signals—whereas the green dots show the excitatory synapses that promote electrical signals.

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