Clinical anxiety affects up to 30 percent of Americans who are in
great need of better treatments with fewer side effects. A study from
Boston Children's Hospital, published September 6 by the journal Molecular Psychiatry,
finds that certain neurons in the hypothalamus play a central,
previously unknown role in triggering anxiety. Targeting them, rather
than the whole brain, could potentially provide a more effective
treatment for anxiety and perhaps other psychiatric disorders, say
researchers Joseph Majzoub, MD, and Rong Zhang, PhD, in the Division of
Endocrinology.
Experiments in mice showed that blocking the stress hormone
corticotropin-releasing hormone (CRH) selectively in this group of
neurons erased the animals' natural fears. Mice with the deletion
readily walked elevated gangplanks, explored brightly lit areas and
approached novel objects -- things normal mice avoid.
CRH, discovered nearly 40 years ago, coordinates our physical and
behavioral stress response, often termed the "fight-or-flight" response.
This response helps us survive in the face of threats, but when it is
activated at the wrong time or too intensely, it can lead to anxiety
and/or depression.
For this reason, several drug companies have developed CRH-blocking
drugs as possible alternatives to SSRIs and benzodiazepines, which have
side effects, for treating anxiety disorders. However, the 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 Majzoub.
Zhang had a hunch that blocking CRH throughout the brain, as was done
in the above drug 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."
Using genetic engineering, Zhang and her colleagues selectively
removed the CRH gene from about 1,000 nerve cells in the hypothalamus of
mice. (To do this, they used a genetic trick, knocking out the gene
only in cells expressing another gene called SIM1.)
The
targeted cells were in the paraventricular nucleus, an area of the
hypothalamus known to control the release of stress hormones (such as
cortisol). But to Zhang's surprise, the loss of CRH in those cells
affected not only hormone secretion, but also dramatically reduced
anxiety behaviors (vigilance, suspicion, fear) in the mice.
"We already knew that CRH controlled the hormonal response, but the
big surprise was that the behavioral response was completely blunted,"
says Majzoub. "It was a very robust finding: Every parameter we looked
at indicated that this animal was much less inhibited."
In the "gangplank" experiment, for example, the genetically altered
mice were perfectly willing to venture onto an elevated maze, even the
"open" section whose protective walls were removed.
Similarly, when the mice were 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.
Another surprise was that CRH secreted in the paraventricular nucleus
goes to more places in the brain than originally thought -- including
areas that control the behavioral stress response. "It was a total
surprise to us that the locus of control is in a tiny part of the
hypothalamus," says Majzoub.
Majzoub acknowledges that blocking CRH production in just a subset of
neurons would be technically challenging in humans. But if this could
be done, it could be helpful for treating severe anxiety disorders or
post-traumatic stress disorder (PTSD).
"Blocking just certain neurons releasing CRH would be enough to alter
behavior in a major way," he says. "We don't know how to do that, but
at least we have a starting point."
Source: http://www.news-medical.net/news/20160907/Targeting-specific-neurons-in-the-brain-may-provide-effective-treatment-for-anxiety.aspx
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