Scientists have been studying for decades the activity patterns in human and animal brains by observing when different groups of brain cells turn on. However, knowing how long  neurons stay active and when they turn off again have remained a mystery. Now, scientists at Scripps Research have developed a new technology that lets them track when, after a burst of activity, brain cells shut off—a process known as inhibition. Their technique, provides a new way to study not only the normal functioning of the brain, but how the brain’s “off switches” may go awry in normal behaviors as well as in diseases and disorders.

The findings are published in Neuron in an article titled, “Phosphorylation of pyruvate dehydrogenase inversely associates with neuronal activity.”

“It’s generally agreed that the inhibition of neurons is really the major way the brain is regulating activity,” said senior author Li Ye, PhD, professor and Abide-Vividion chair at Scripps Research. “Scientists have been looking for a way to look at inhibition on a more trackable way, and until now, few had found it.”

Ye teamed up with John Yates, a professor of molecular medicine at Scripps Research. They wanted to study how brain cells changed when they were actively firing—emitting an electrical charge to pass messages to their neighbors—compared to when they were done firing. The scientists used optogenetics and measured levels and characteristics of different proteins and their modifications. They identified that one protein, pyruvate dehydrogenase (PDH), was very rapidly changed immediately after brain cells were inhibited.

“When neurons are firing, you need a lot of energy, and this PDH protein is involved in producing that energy,” explained Ye. “But the brain really wants to conserve energy, so when a cell is done firing, we found that the brain rapidly shuts off the PDH protein. This happened much faster than anything else we saw in gene expression.”

To shut off PDH, the researchers found, cells add molecular tags called phosphates to the protein. Ye and his colleagues found antibodies that only recognized this inactive, phosphorylated form of PDH (pPDH). To test whether levels of pPDH could be used as a proxy for brain cell inhibition, Ye’s team used these antibodies to measure pPDH in mice that had been given anesthesia. Nearly the entire brain lit up with high levels of pPDH, correctly showing how most of the brain is inactive during anesthesia.

“There are a lot of questions that this technology can help us answer,” explained Ye. “If the brain can’t turn cells off, or if they’re turned off faster or slower than usual, what happens? How does the inhibition of neurons play a role in different diseases?”

Ye and his colleagues are continuing to fine-tune the use of pPDH, but they say that other researchers are already using the technology—the antibodies used to measure pPDH are commercially available. Their new method could help identify what goes awry in numerous brain conditions such as depression, post-traumatic stress disorder, and Alzheimer’s disease.

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