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The circle of influence of testosterone

The mechanism of the connection between depression and anxiety and the male sex hormone, testosterone, was discovered

The mechanism of the connection between depression and anxiety and the male sex hormone, testosterone, was discovered. Courtesy of Prof. Shira Knafo
The mechanism of the connection between depression and anxiety and the male sex hormone, testosterone, was discovered. Courtesy of Prof. Shira Knafo

Anxiety is a typical stress response, which greatly affects the lifestyle of those who suffer from it. The road to finding an effective treatment for this phenomenon is still long, but a recent study carried out in the laboratory of Prof. Shira Knafo at Ben-Gurion University of the Negev, in which the biological mechanism that activates the process that leads to anxiety was discovered, may mark an important step in progress in this field.

What is the question? What is the biological process that activates the feelings of anxiety?

Clinical evidence suggests the potential of testosterone (the male sex hormone) in relieving anxiety and depression, especially in men with low testosterone due to hypogonadism (a syndrome describing an increased decrease in the function of the gonads). This is a natural process that occurs in men over the age of 40, and which manifests itself in a decrease of approximately one percent in the testosterone levels in the body, every year. However, a more significant and faster decline in testosterone levels is accompanied by various symptoms such as fatigue, obesity, reduction in muscle mass, as well as depression and anxiety. But what is the connection between testosterone levels and anxiety? This is the latest research topic of Prof. Kanafo, who won a research grant from the National Science Foundation.

The study began with an observation: rats that showed a very high level of anxiety exhibited very low levels of a specific receptor called tachykinin receptor 3 (TACR3) in the brain region that is also closely related to learning and memory processes. This receptor is part of a group known as tachykinin receptors, and it responds to a substance called neurokinin. The relationship between TACR3 deficiency, sex hormones, anxiety and flexibility of the nervous system, aroused the researchers' curiosity.

The rats were classified based on their behavior in a common test for measuring anxiety levels in rodents Elevated plus maze. The researchers then isolated the area of ​​the brain associated with learning and anxiety (hippocampus) of the rats, and used gene expression analysis to identify the genes that were expressed differently in rats with very low anxiety compared to the genes that were expressed in rats with severe anxiety. One gene that stood out in this test was the gene for the TACR3 receptor. When appropriate proteins bind to this receptor, it encourages a process that leads to testosterone production. A mutation in the gene that codes for the receptor may damage its function - resulting in a significant reduction in testosterone production in the body (a phenomenon called "congenital hypogonadism").

"Young men with low testosterone," says Prof. Kanafo, "show a marked lack of sexual development that is often accompanied by depression and anxiety, which prompted us to test the role of TACR3 during anxiety." During the research, the scientists discovered, among other things, that the effect in this case is mutual. That is, that testosterone itself may, in certain situations, affect the expression of TACR3 in the hippocampus, in what can be described as a kind of circular process. This dynamic interplay between TACR3 and sex hormones has profound implications for anxiety-like behaviors in living organisms.

The study was able to characterize for the first time where TACR3 is located in the rat brain, how its expression changes during sexual development, and how sex hormones affect its presence in the hippocampus. The study also tested the effects of drugs that regulate TACR3 on the plasticity processes of the nervous system.

The study was able to characterize for the first time where TACR3 is located in the rat brain, how its expression changes during sexual development, and how sex hormones affect its presence in the hippocampus.

Later, the scientists cloned the TACR3 gene, to express or block its activity in nerve cells. This time the researchers encountered another fascinating phenomenon: rats with increased levels of anxiety (which lack TACR3), lacked a crucial component in the long-term strengthening of the connections of the brain stem gland cells. The researchers also discovered that changes in TACR3 function through drugs or molecular tools had a profound effect on the flexibility of the nervous system. This discovery adds a new layer of understanding to the complex relationship between TACR3, anxiety and neural connectivity.

At this stage, the researchers harnessed the power of two innovative tools created in the molecular cognition laboratory at Ben-Gurion University of the Negev, with the support of the National Science Foundation. The first tool, known as FORTIS has a high-level detection capability of changes in surface AMPA receptors within living neurons. Using this tool, the researchers were able to prove that a substance that inhibits the expression of the TACR3 receptor produces a sharp increase in AMPA receptors on the surface. This phenomenon explains the corresponding disruption of the long-term synaptic strengthening process (a phenomenon called LTP). The second pioneering tool included an innovative application called cross-correlation as a measure to assess connectivity between neurons in a multi-electrode array. This tool played a central role in revealing the significant impact of TACR3 manipulations on neuronal connectivity.

"Using the innovative tools created in the laboratory, we were able to discover that defects resulting from an inactive TACR3 can be effectively corrected through the administration of testosterone," says Prof. Kanafo. "What makes this discovery even more exciting is the potential for testosterone therapy to counteract these changes. The discovery also offers future hope for innovative approaches to dealing with anxiety-related challenges associated with testosterone deficiency."

This research offers solutions beyond just anxiety disorder. His findings hold promise for people dealing with disorders in sexual development or sexual function, who also suffer from depression and anxiety increased, emphasizing the potential of testosterone treatments to improve their quality of life. The findings that emerged provide important insights into the complexity of anxiety disorder and offer hope for future therapeutic approaches.

Prof. Kanafo adds that this study, which focused on the male sex hormone, and included mainly male rats and men, may pave the way for further studies that will focus on the possible connections between anxiety and depression and the female sex hormones, such as progesterone and estrogen, and will also consider the effects of the menstrual cycle.

Life itself:

Prof. Shira Knafo, 52 years old, married and mother of two, lives in Be'er Sheva. Studied medicine, combined with scientific research, at Ben Gurion University, and specialized in psychobiology, and learning and memory processes. After a long deliberation between practicing medicine or scientific research - she chose research. "Today this circle is closed," she says, "when I guide physician-researchers." In her few free hours she likes to travel, and is interested in history. "I consume historical knowledge in various formats: movies, series, books - and conversations with researchers at the university."

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