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The researchers in this laboratory spend their days eavesdropping on neurons’ electrical chatter
4 min read
For Brain Awareness Week 2022, we dropped in on five Allen Institute teams working to understand the brain. Get a glimpse into their workdays.
Brian Lee, Ph.D., arrives in the lab after a meeting to find five slices of human brain tissue waiting on the lab bench. The dish, containing the tiny pieces of tissue floating in a special liquid known as artificial cerebrospinal fluid, had just been dropped off by Lee’s colleague on the tissue processing team.
Just an hour prior, the piece of brain had arrived at the Allen Institute where the tissue processing researchers had prepared and sliced it. Just a couple hours before that, it had been part of a patient’s brain. The patient underwent surgery for a brain tumor that morning and agreed to donate to research the small healthy bit of their brain the surgeon removed to access their tumor.
The slices, still alive and about the size of a toddler’s fingernail, are ready for study. Lee, a neuroscientist at the Allen Institute, oversees much of the day-to-day work in this lab, the electrophysiology lab, casually known as e-phys. He peers into the dish to see what his team will be working with that day. E-phys researchers probe living neurons to record their electrical activity.
“You can see all the layers, so that’s good,” he said. The pieces come from the layered, outer layer of the brain known as the cortex. The scientists look for landmarks above and below the layers to orient themselves. The landmarks are there, as are all the layers.
But the upper layers are ripped in each slice, little jagged edges on the tiny floating pieces. It must have happened during surgery. Today, Lee and his colleagues are looking for a kind of neuron known as a deep-layer excitatory neuron — he’s hoping that the lower layers are intact enough, but he’s worried.
One of the experimentalists on the e-phys team, Ramkumar Rajanbabu, prepares a piece and slips it under the microscope. A craggy sea of gray appears on the monitor screen. It looks like the surface of the moon, but Rajanbabu points out several neurons and even a blood vessel as he dials controls back and forth to find what he’s looking for.
“This is the true test — we’ll be able to tell if there are healthy cells there or not,” Lee said. “We always try because these samples are so precious. But sometimes we just can’t get any to record from.”
Rajanbabu and the other research associates in the lab spend much of their days recording neurons’ electrical communiques. Some of the process is automated, but much of the work relies on their specialized expertise. It takes him about 30 minutes to get the information he needs from a single neuron, Rajanbabu said. But if there’s a dearth of healthy neurons to choose from, as can happen with tissue from older patients, the process can take longer.
He scrolls through several screens of gray, pointing out circular blobs that he tells us are dead cells. He’s looking for a particular kind of neuron, a pyramidal neuron, that has a telltale triangular shaped body. Pyramidal neurons are a broad class of neurons that include several different types; their functions also vary based on their location in the cortex.
Rajanbabu isn’t happy with the first two neurons he tries. The process includes gently piercing the outer layer of the neuron’s central body with a delicately thin glass pipette, maintaining the right amount of pressure on the glass so the cell doesn’t collapse or explode, and then inserting an even thinner electrode into the cell to jolt it with electricity and record its electrical responses.
On the third try, Rajanbabu gets a hit. Now the automation takes over — his computer runs a series of pre-programmed electrical currents into the neuron, checking for the quality of the cell’s response at each step. Any failures in this series means they need to move onto another neuron.
These cells are part of the Institute’s “Patch-seq pipeline,” a bucket-brigade style of data collection in which different expert teams handle different types of experiments, all on the same cells. After the e-phys researchers gather data about the neurons’ electrical characteristics, other teams take over to analyze their 3D shapes and their gene expression, measuring which genes are switched on or off in different kinds of neurons.
All this work is part of a larger effort to understand the different kinds of neurons and other cells that make up the brain, a lengthy “parts list” that is still being written.
Photos by Erik Dinnel, Senior Producer at the Allen Institute, and text by Rachel Tompa, Senior Editor at the Allen Institute. Get in touch at [email protected].