Under the Hood

Anxiety Treatment Update: Targeting Hypothalamus Brain Cells Reduces Fear, Suspicion

Many of us experience bouts of fear and uncertainty when confronted by the unfamiliar. Once we're able to process everything within our surroundings, we begin to feel more at ease, but for the thirty percent of Americans with anxiety, even familiar, day-to-day situations can result in debilitating fear. A recent study published in molecular Psychiatry found targeting specific brain cells, rather than the whole brain, could potentially provide a more effective treatment for anxiety.

"Blocking just certain neurons releasing CRH (corticotrophin-releasing hormone) would be enough to alter behavior in a major way," said Dr. Joseph Majzoub working in Boston Children’s Hospital Division of Endocrinology, in a statement.

CRH is the main element that drives the body’s response to stress. It promotes anxiety in part by reducing cannabinoids in our amygdala. This happens when CRH  increases FAAH in the amygdala, which causes a reduction in the endocannabinoid anandamide. Endocannabinoids balance our stress and anxiety responses.

Several drug companies have developed CRH-blocking drugs as alternatives to SSRIs (Selective Serotonin Reuptake Inhibitors) and benzodiazepines, which have side effects, for treating anxiety disorders. However, out of the eight completed phase II and III trials of CRH antagonists for depression or anxiety, six have been published, with largely negative findings, according to Majzoub and his colleagues.

However, Majzoub and his colleague Rong Zhang, also part of the Division of Endocrinology, found targeting brain cells in the paraventricular nucleus — an area of the hypothalamus known to control the release of stress hormones (such as cortisol) — could significantly affect anxious behaviors in mice.

Anxious woman Scientists find targeting specific brain cells rather than the whole brain could significantly reduce anxiety behaviors. Photo courtesy of Pixabay, Public Domain

Using genetic engineering, the researchers selectively removed the CRH gene from about 1,000 nerve cells in the hypothalamus of mice. They used a genetic trick, knocking out the gene only in cells expressing another gene called SIM1. Majzoub and Zhang found this influenced hormone secretion, and dramatically reduce anxiety behaviors, like vigilance, suspicion, and fear in an animal model featuring mice. When the mice were presented with an open field, the modified mice explored much more of its center, instead of hanging out at the periphery like the control mice in a previous experiment.

The mice readily walked elevated gangplanks, explored brightly lit areas and approached novel objects, which are things they would normally avoid.

"We already knew that CRH controlled the hormonal response, but the big surprise was that the behavioral response was completely blunted," said Majzoub. "It was a very robust finding: Every parameter we looked at indicated that this animal was much less inhibited."

In addition, the researchers were surprised to find CRH that is secreted in the paraventricular nucleus goes to more places in the brain than originally thought, such as areas that control the behavioral stress response.

However, Majzoub believes blocking CRH production in just a subset of neurons would be technically challenging in humans. If this could be done, it could help treat severe anxiety disorders or post-traumatic stress disorder (PTSD).

Although the scientists don’t know how to do this in humans, the research is a starting point they hope to build on. 

Source: Zhang R, Asai M, Mahoney CE et al. Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice. Molecular Psychiatry. 2016.

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