Health & Medicine

UC Davis researchers seek autism treatment in monkey’s brains

Three rhesus macaques hang out in their enclosure at the primate research center at UC Davis on Tuesday in Davis, Calif. A team of UC Davis researchers published a study in July that could lead to breakthroughs in treatments for human behavioral health conditions, which is based on a study using the brains of rhesus monkeys.
Three rhesus macaques hang out in their enclosure at the primate research center at UC Davis on Tuesday in Davis, Calif. A team of UC Davis researchers published a study in July that could lead to breakthroughs in treatments for human behavioral health conditions, which is based on a study using the brains of rhesus monkeys. rpench@sacbee.com

Medicine isn’t an option for the kids UC Davis psychiatry professor David Amaral sees in his decadelong study tracking the brain development of autistic children.

That likely won’t change in the near future, he said, because “we’re still trying to figure out what brain systems are impacted by autism.”

He and his partners are working to change that. A gene therapy they used for a recent breakthrough study may one day point the way to just such a medicinal treatment for autism and other behavioral health conditions, such as schizophrenia.

It involves re-engineering specific cells so they respond to medicine instead of a body’s normal signals, opening the door to treatments that would alter the way malfunctioning brain cells interact.

For epilepsy, that could mean inhibiting the cells that contribute to seizures when they become overstimulated.

For certain kinds of autism, it could lead to treatments that regulate how parts of the brain communicate with each other.

“This is a technique that when I was a student would have been considered science fiction,” said Amaral, director of research at UC Davis’ MIND Institute.

Also, similar to science fiction, the method his team used comes with a comically ominous acronym – DREADD. It stands for Designer Receptor Exclusively Activated by Designer Drugs.

This is a technique that when I was a student would have been considered science fiction.

David Amaral, director of research at UC Davis’ MIND Institute

Amaral and his team were the first to demonstrate the procedure could be used to “turn off” a part of a primate’s brain so scientists could study how closing one function would affect other parts of the brain.

That would help them understand how the brain works as a whole, and possibly learn to target malfunctioning cells in a person experiencing a behavioral health condition. The team published its findings last week in the journal Neuron.

Previously, scientists had used the technique only on smaller mammals. Making the jump to a rhesus macaque monkey suggested it may work in the future on a person.

The team’s work took place at the California National Primate Research Center at UC Davis, where several colonies of rhesus macaque monkeys are available for medical research.

The primate center is a well-guarded compound west of the UC Davis main campus laid out in a series of office buildings and laboratories.

Behind the labs are large, outdoor enclosures holding thousands of rhesus macaques. They’re cared for by veterinarians, given regular medical checkups and fed local produce at least once a week. Some of the monkeys live into their teens and past 20 years of age.

The research there unfolded over months, beginning with an operation in which Amaral inserted a manufactured gene into the neurons – brain cells – of four rhesus macaques. He targeted the amygdala, a portion of the brain that’s associated with fear, pleasure, depression and anxiety.

The new gene caused neurons in the amygdala to produce receptors that would ignore normal chemical signals in the body. Instead, the receptors became responsive only to a kind of drug that temporarily floods and “turns off” the entire brain cell.

Those were the “designer receptors” and the “designer drug” in the DREADD acronym.

You want to do it in monkeys because you want to show it’s safe. And then, at a certain point along the way, you want to to show it’s safe for humans.

David Amaral, director of research at UC Davis’ MIND Institute

Researchers used MRI scans to evaluate the monkeys’ brains just after the surgery and again several months later when they injected the drug.

They found that the drug succeeded in shutting down the amygdala, which in turn triggered different kinds of activity in other parts of the brain.

“Similar techniques in the future may control abnormal activity in disorders such as epilepsy and Parkinson’s disease,” said John Morrison, the primate center’s director. “Understanding how brain areas form networks is critical for determining the origin of pathology and eventually developing effective interventions.”

The team benefited from work by Bryan Roth, of the University of North Carolina School of Medicine, who created the designer receptor and the vector Amaral used to connect the gene with monkey brain cells.

David Grayson, one of Amaral’s graduate students, also designed a computer model based on previous amygdala research that supported the team’s findings.

All four of the monkeys selected for the study were euthanized so the team could conduct an autopsy that determined the genes continued to produce receptors for the drug a year after the surgery.

UC Davis and Amaral consider the work to be a more humane method of primate brain research than previous techniques allowed.

“It’s a necessary evil to do animal studies. I don’t see any other way to do it,” Amaral said.

For instance, attempting to shut down a portion of a brain in the past often meant permanently damaging through surgery the region that scientists wanted to study. In that scenario, researchers also would have to maintain a control group of healthy monkeys.

The method his research supported, by contrast, allows the monkeys selected for the study to be their own control group because they’d return to normal behavior once the medicine passed through their bodies.

That means the study required half as many subjects as past models, and it did not involve destroying portions of an animal’s brain.

“You want to do it in monkeys because you want to show it’s safe,” he said. “And then, at a certain point along the way, you want to to show it’s safe for humans.

“We’re a ways away from that. Things are really moving rapidly, and gene therapy, I think, will be used in humans and it will be based in part on proof of safety that we’re demonstrating here.”

Adam Ashton: 916-321-1063, @Adam_Ashton

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