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.
Blocking just certain neurons releasing CRH would be enough to alter behavior in a major way.”Mice with the targeted deletions readily walked elevated gangplanks, explored brightly lit areas and approached novel objects — things normal mice shun.
If a practical way could be found to block CRH this selectively in humans, it could be helpful for treating severe anxiety disorders or post-traumatic stress disorder (PTSD), Majzoub believes.
The targeted cells were in the paraventricular nucleus of the hypothalamus, an area known to control the release of stress hormones. But to Zhang’s surprise, the loss of CRH in the targeted cells affected not only hormone secretion, but also dramatically reduced anxiety behaviors in the mice (vigilance, suspicion, fear).
CRH, she found, “goes to many nuclei in the brain that control the behavioral stress response, and that was a total surprise to us.”
“Every parameter we looked at indicated that this animal was much less inhibited,” adds Majzoub. “The behavioral response was completely blunted.”
In the “gangplank” experiment, one of many assays available in Boston Children’s Neurobehavioral Developmental Core, the genetically altered mice were perfectly willing to venture onto an elevated maze, even the “open” section whose protective walls were removed:
Similarly, when presented with an open field, the modified mice explored much more of its center, rather than hang out at the periphery like the control mice:
“It was a total surprise to us that the locus of control is in a tiny part of the hypothalamus,” says Majzoub. “Blocking just certain neurons releasing CRH would be enough to alter behavior in a major way. We don’t know how to do that, but at least we have a starting point.”
This study was supported by the National Institutes of Health (5K01MH096148-03 and T32DK007699-30).