Finding Brain Circuits Tied to Alertness

Everybody knows that it’s important to stay alert behind the wheel or while out walking on the bike path. But our ability to react appropriately to sudden dangers is influenced by whether we feel momentarily tired, distracted, or anxious. How is it that the brain can transition through such different states of consciousness while performing the same routine task, even as its basic structure and internal wiring remain unchanged?

A team of NIH-funded researchers may have found an important clue in zebrafish, a popular organism for studying how the brain works. Using a powerful new method that allowed them to find and track brain circuits tied to alertness, the researchers discovered that this mental state doesn’t work like an on/off switch. Rather, alertness involves several distinct brain circuits working together to bring the brain to attention. As shown in the video above that was taken at cellular resolution, different types of neurons (green) secrete different kinds of chemical messengers across the zebrafish brain to affect the transition to alertness. The messengers shown are: serotonin (red), acetylcholine (blue-green), and dopamine and norepinephrine (yellow).

What’s also fascinating is the researchers found that many of the same neuronal cell types and brain circuits are essential to alertness in zebrafish and mice, despite the two organisms being only distantly related. That suggests these circuits are conserved through evolution as an early fight-or-flight survival behavior essential to life, and they are therefore likely to be important for controlling alertness in people too. If correct, it would tell us where to look in the brain to learn about alertness not only while doing routine stuff but possibly for understanding dysfunctional brain states, ranging from depression to post-traumatic stress disorder (PTSD).

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Cool Videos: Reconstructing the Cerebral Cortex

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This colorful cylinder could pass for some sort of modern art sculpture, but it actually represents a sneak peak at some of the remarkable science that we can look forward to seeing from the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. In a recent study in the journal Cell [1], NIH grantee Jeff Lichtman of Harvard University, Cambridge, MA and his colleagues unveiled the first digitized reconstruction of tissue from the mammalian cerebral cortex—the outermost part of the brain, responsible for complex behaviors.

Specifically, Lichtman’s group mapped in exquisite detail a very small cube of a mouse’s cerebral cortex. In fact, the cube is so tiny (smaller than a grain of sand!) that it contained no whole cells, just a profoundly complex tangle of finger-like nerve cell extensions called axons and dendrites. And what you see in this video is just one cylindrical portion of that tissue sample, in which Licthtman and colleagues went full force to identify and label every single cellular and intracellular element. The message-sending axons are delineated in an array of pastel colors, while more vivid hues of red, green, and purple mark the message-receiving dendrites and bright yellow indicates the nerve-insulating glia. In total, the cylinder contains parts of about 600 axons, 40 different dendrites, and 500 synapses, where nerve impulses are transmitted between cells.

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Who Knew? A Neural Circuit Just for Itching

Itch line (red) with touch, pain, and temperature lines (white) going through DRG before going to the spinal cord.

Itch-inducing agents activate a discrete population of peripheral sensory neurons that produce a signaling molecule called natriuretic polypeptide b (Nppb). The release of Nppb from these primary pruriceptive neurons triggers a dedicated itch biocircuit to generate the sensation of itch. [Images courtesy of Mark Hoon, National Institute of Dental and Craniofacial Research, NIH]

The occasional itch—be it a bug bite or rash—is annoying. But there are millions of people with chronic itching conditions, like eczema and psoriasis, who are constantly scratching their skin. This is more than a little irritation—it drastically reduces their quality of life and is a perpetual distraction. Current anti-itch treatments include topical corticosteroid creams, oral antihistamines, and various lotions. But researchers at NIH have gone beyond the skin’s surface and discovered a critical molecule at the root of that itchy feeling [1].

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The Brain: Now You See It, Soon You Won’t

A post mortem brain is a white, fatty, opaque, three-pound mass. Traditionally scientists have looked inside it by cutting the brain into thin slices, but the relationships and connections of the tens of billions of neurons are then almost impossible to reconstruct.   What if we could strip away the fat and study the details of the wiring and the location of specific proteins, in three dimensions? An NIH funded team at Stanford University has done just that, developing a breakthrough method for unmasking the brain.

Using a chemical cocktail, they infuse the brain with a hydrogel that locks in the brain’s form and structure in a type of matrix. Then the fatty layer that coats each nerve cell is stripped away, leaving a transparent brain (check out the transparent mouse brain below). The hydrogel prevents the brain from disintegrating into a puddle once the fat is gone.

Photo on the left shows an opaque mouse brain. Photo on the right (after CLARITY) shows a nearly transparent mouse brain.

Caption: CLARITY transforms a mouse brain at left into a transparent but still intact brain at right. Shown superimposed over a quote from the great Spanish neuroanatomist Ramon y Cajal.
Credit: Kwanghun Chung and Karl Deisseroth, Howard Hughes Medical Institute/Stanford University

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