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The mechanism that dramatically links anxiety and testosterone has been discovered

Surveys indicate a strong link between low levels of testosterone and anxiety disorder, although the exact nature of this relationship remains unclear. Clinical evidence suggests the potential of testosterone in alleviating anxiety and depression, especially in men with low testosterone.

Illustration: Prof. Shira Knafo using artificial intelligence
Illustration: Prof. Shira Knafo using artificial intelligence

The Laboratory for Molecular Cognition led by Prof. Shira Kanafo at Ben-Gurion University of the Negev, revealed a dramatic connection between anxiety disorder, a receptor in the brain (TACR3) and testosterone. Innovative tools developed in the laboratory made it possible to discover that defects in neural connections can be corrected by administering testosterone. This discovery offers hope for innovative approaches to tackling anxiety-related challenges. The research findings were published in the prestigious journal Molecular Psychiatry .

Anxiety is a typical stress response, but for those dealing with anxiety disorders it can significantly affect daily life. Research suggests a strong link between low levels of testosterone and anxiety disorder, although the exact nature of this relationship remains unclear. Clinical evidence suggests the potential of testosterone in alleviating anxiety and depression, especially in men with low testosterone due to hypogonadism (a syndrome describing decreased gonadal function). However, this relationship has lacked a comprehensive explanation until now.

The basis for the research began as part of 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 reacts 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 to measure anxiety levels in rodents (elevated plus (maze). They then isolated the area of ​​the brain associated with learning and anxiety (hippocampus) of the rats and used gene expression analysis to identify those that were expressed differently in rats with very low anxiety compared to for those with severe anxiety. One gene that stood out was a gene called TACR3. Previous research has revealed that mutations in genes associated with this gene lead to a condition known as "congenital hypogonadism" that causes a lack of sex hormones, including testosterone. "Young men with low testosterone show a marked lack of sexual development that is sometimes accompanied by are closely associated with depression and anxiety, which prompted us to test the role of TACR3 during anxiety," explained Prof. Kanafo.

Among the findings of this study, one discovery stood out in particular: sex hormones, especially testosterone, have an extraordinary ability to influence the expression of TACR3 in the brainstem glands. 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 examined the effects of drugs that regulate TACR3 on the plasticity processes of the nervous system. In addition, they cloned the tacr3 gene to express or block its activity in neurons.

This time the researchers encountered another fascinating phenomenon - rats with increased levels of anxiety lacked a crucial component in the long-term strengthening of the connections of the brain stem gland cells. A phenomenon called LTP is a phenomenon that symbolizes the strengthening of neural connections, which is essential for learning and memory. However, in anxious rats that lack TACR3, something unusual happened - the neural connectivity was stronger, preventing the strengthening of the LTP phenomenon. 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.

Now the researchers have harnessed the power of two innovative tools created in the molecular cognition laboratory at Ben-Gurion University of the Negev. 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 demonstrate that a TACR3 inhibitor produces a sharp increase in surface AMPA receptors. This phenomenon explains the parallel disruption of the long-term synaptic strengthening process - 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 by administering testosterone," said Prof. Kanafo. "What makes this discovery even more exciting is the potential for testosterone therapy to counteract these changes, and that it offers hope for novel approaches to addressing the 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 increased anxiety, emphasizing the potential of testosterone treatments to improve their quality of life. The researchers were able to crack the complex mechanisms behind anxiety and opened a window to new treatments that include testosterone. The findings that emerged provide important insights into the complexity of anxiety disorder and offer hope for future therapeutic approaches.

The research group included:

Wojtas, MN, Diaz-González, M., Stavtseva, N., Shoam, Y., Verma, P., Buberman, A., Izhak, I., Geva, A., Basch, R., Ouro, A. , Perez-Benitez, L., Levy, U., Borcel, E., Nuñez, Á., Venero, C., Rotem-Dai, N., Veksler-Lublinsky, I. & Knafo, S. Interplay between hippocampal TACR3 and systemic testosterone in regulating anxiety-associated synaptic plasticity. Molecular Psychiatry (2023).

This study (No. 536/19) was funded by the National Science Foundation.

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One response

  1. The problem with taking testosterone is damage to fertility. Therefore, anyone who has a fertility problem or does not want to harm their fertility is advised not to take testosterone.

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