New Israeli study uncovers molecular connection between anxiety and testosterone

Ben-Gurion University researchers use cutting-edge genetic sequencing to connect the dots between a protein in the brain, low male hormone levels, and mental condition

Renee Ghert-Zand is the health reporter and a feature writer for The Times of Israel.

Illustrative image of man looking anxious and depressed. (OcusFocus/iStock)
Illustrative image of man looking anxious and depressed. (OcusFocus/iStock)

A recent peer-reviewed study by scientists at Ben-Gurion University of the Negev reveals the molecular mechanism linking anxiety and testosterone.

There has been clinical evidence for some time of a link between anxiety and depression and low levels of testosterone in males, especially those with hypogonadism, a medical condition characterized by the inability to reach puberty, or reduced sexual function. However, until this new research, the full nature of the connection was not clear. The missing piece of the puzzle appears to be a receptor in the brain.

Published in December in Molecular Psychiatry, the study, led by Prof. Shira Knafo, head of the university’s molecular cognitive lab, began with the observation of hundreds of laboratory rats.

“I was trying to understand why the rats, who were all from the same litter, behaved differently. Some showed a very high level of anxiety, some a very low level of anxiety, and the majority were in the middle with a normal amount of anxiety,” Knafo told The Times of Israel.

“About five to 10 percent of the rats behaved outside the norm and I wanted to know why,” she said.

Knafo and her team took male rats from both extremes and used a standard elevated plus maze test to classify them based on their behavior in measuring anxiety levels. Then the scientists isolated the ventral hippocampus of the rats’ brains and performed gene expression analysis to identify genes with variations between the rodents with extremely low anxiety and those with severe anxiety.

Illustrative: Prof. Shira Knafo, head of the Molecular Cognitive Lab at Ben-Gurion University, used rats to study the mechanism linking anxiety to testosterone. (Jason Snyder via Wikimedia Commons)

“We looked at the data, and we found several genes that are expressed differently in the anxious rats. One of them was TACR3 [which encodes for the TACR3 protein],” Knafo said.

Knafo said she wasn’t very familiar with the TACR3 gene and protein and that a search of the research literature revealed little. In the meantime, she did an additional test in the lab to confirm that TACR3 expression was indeed much lower in the anxious rats.

Fascinated by these findings, Knafo decided to dig deeper. She came across a paper showing that male children with a mutation in the TACR3 protein have congenital hypogonadism and don’t produce enough testosterone to go through puberty.

“So at that point, we had a link between this TACR3 and puberty. But what was the connection to anxiety? Then I found that people with hypogonadism have problems with anxiety and depression,” Knafo said.

“Okay, so now I could start to do a study and understand what’s going on, what the connection is between TACR3, anxiety, and testosterone. It was a triangle [of possibly related factors] and a nice way of entering into a subject that is not well understood,” she said.

Illustrative image of students in the campus at of Ben-Gurion University of the Negev, on May 8 2013. (Dudu Greenspan/ Flash90)

At this point, the team took a pharmacological approach. The first thing they did was investigate the link between testosterone and anxiety, knowing that rats (and human males) have lower testosterone the younger they are.

They put rats aged 44 days and 90 days into the same sort of maze as before. The younger rats exhibited more anxious behavior by choosing to go more often into the closed arms of the maze, as opposed to the open arms.

Blood tests on the rats showed a correlation between the amount of testosterone in the blood and the amount of time they spent in the open arms of the maze.

“The more testosterone they have, the less anxiety they have.  It was a direct linear correlation,” Knafo said.

Prof. Shira Knafo, head of the Molecular Cognitive Lab at Ben-Gurion University. (Dani Machlis/BGU)

The researchers then injected testosterone into some of the rats and discovered that this raised the level of the hormone in the blood leading to boosted levels of TACR3 in their brains. The subsequent injection of a drug that blocks TACR3 reduced the level of testosterone in the rats’ blood.

“So it’s like a mutual regulation. The TACR3 affects the amount of testosterone and the testosterone affects the amount of TACR3,” Knafo said.

Having established this connection between anxiety and depression, TACR3, and low testosterone on the molecular level, Knafo said she would be excited to see clinical trials take the research forward to see if giving testosterone to people with anxiety could help.

“But I want to stress that this is not something for someone with anxiety or depression to just do on their own,” Knafo said.

“Certainly males with hypogonadism should seek guidance from physicians about genetic screening for TACR3 mutations and treatment with testosterone. But this all has to be done with medical supervision and with careful consideration because there are side effects to taking testosterone, including risk for cancer,” she said.

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