Stories about: Joseph Majzoub

Could targeting specific neurons in the hypothalamus relieve anxiety?

anxiety hypothalamus
(Ichiban Yada/Sketchport.com)

Anxiety disorders are the most common mental illness in the U.S., but lack an ideal treatment. The current drugs, SSRIs and benzodiazepines, have many side effects. More recently developed treatments seek to block corticotropin-releasing hormone (CRH), the classic stress hormone that activates our “fight or flight” response; in people with anxiety, CRH gets activated at the wrong time or too intensely.

But in clinical trials, results have been disappointing: of the eight completed phase II and III trials of CRH antagonists for depression or anxiety, six have been published, with largely negative findings, says Joseph Majzoub, MD, of the Division of Endocrinology at Boston Children’s Hospital.

Rong Zhang, PhD, who works in Majzoub’s research lab, had a hunch that blocking CRH throughout the brain, as was done in these trials, isn’t the best approach. “Blocking CRH receptors all over the brain doesn’t work,” she says. “We think the effects work against each other somehow. It may be that CRH has different effects depending on where in the brain it is produced.”

Today in Molecular Psychiatry, Zhang, Majzoub and colleagues demonstrate that certain neurons in the hypothalamus play a central, previously unknown role in triggering anxiety. When they used genetic tricks to selectively remove the CRH gene from about 1,000 of these neurons in mice, the effect was startling — they erased the animals’ natural fears.

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A mutation and a mystery: Weight gain without a change in energy use

Why did the mouse at left gain so much weight?

Two mice scurry around in an enclosure crossed through with light beams. The beams track their movement to measure their energy expenditure, along with the amount of oxygen they breathe in and carbon dioxide they exhale. The mice, who are siblings, are equally active and are held to the same diet, but there’s one critical difference: One mouse is noticeably heavier than the other.

“These [heavier] mice aren’t burning the fat,” says Joseph Majzoub, MD, chief of endocrinology at Boston Children’s Hospital. “They’re somehow holding onto it.”

In fact, the mice have to be underfed by 10 to 15 percent just to stay as slim as their siblings. Their experiences seem to parallel those of people who complain of gaining weight even when they don’t eat more than others. When allowed to eat as much as they want, the mice quickly begin to eat three to four times as much as the others and balloon to more than twice their size.

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